CVS

Cardiovascular curriculum, 2012

Cardiovascular system: Heart

Introduction, Physiologic anatomy, Heart valves, Heart sounds.

Properties of cardiac muscle (Syncytium, electrical activity (Rhythmicity, Excitability and conductivity ).
Con. on Properties (Contractility).
Cardiac cycle.
Electrical potential of the heart (ECG Characteristics).
ECG: Cardiac axis and vector.
ECG: Cardiac arrythmias
Cardiovascular Center.
Heart rate.
Stroke volume.
Cardiac output & Venous return.

Cardiovascular system: Circulation

Arterial Blood pressure.
Regulation (control) of Blood pressure.
Microcirculation, lymphatics and edema.
Blood flow.
Shock.
Syncope (Fainting).
Coronary circulation & ischemic heart disease.
Cerebral circulation.


Lect. 1
Cardiovascular system

Introduction to the CVS (Physiologic anatomy, Heart valves and sounds).

Objectives:
Explain the functions of the heart.
Describe the flow of blood through the heart.
Explain the functions of the heart valves.
Explain the mechanism of the heart sounds.
The heart
The heart is a muscular organ enclosed in a fibrous sac (the pericardium).The pericardial sac contains watery fluid that acts as a lubricant as the heart moves within the sac. The wall of the heart is composed of cardiac muscle cells, termed the myocardium. The inner surface of the wall is lined by a thin layer of endothelial cell; the endothelium. The heart is actually two separate pumps; a right heart which pumps blood through the pulmonary artery into the lung, and a left heart which pumps blood through the aorta into the peripheral organ. Each of these two pumps is consists of two chambers, an atrium and a ventricle, separated by atrioventricular valve (left; mitral valve and right; tricuspid valve). Blood exists from the right ventricle through the pulmonary valve to the pulmonary trunk, and from the left ventricle through the aortic valve into the aorta.
Pulmonary and Systemic Circulations
Blood whose oxygen content has become partially depleted and carbon dioxide content has increased as a result of tissue metabolism returns to the right atrium. This blood then enters the ventricle, which pumps it into the pulmonary trunk and pulmonary arteries. The pulmonary arteries branch to transport blood to the lungs, where gas exchange occurs between the lung capillaries and the alveoli of the lungs. Oxygen diffuses from the air to the capillary blood; while carbon dioxide diffuses in the opposite direction. The blood that returns to the left atrium by way of the pulmonary veins is therefore enriched in oxygen and partially depleted of carbon dioxide. The blood that is ejected from the right ventricle to the lungs and back to the left atrium completes one circuit: called the pulmonary circulation.
Oxygen-rich blood in the left atrium enters the left ventricle and is pumped into a very large, elastic artery; the aorta. The aorta ascends for a short distance, makes a U-turn, and then descends through the thoracic and abdominal cavities. Arterial branches from the aorta supply oxygen-rich blood to all of the organ systems and are thus part of the systemic circulation. As a result of cellular respiration, the oxygen concentration is lower and the carbon dioxide concentration is higher in the tissues than in the capillary blood. Blood that drains into the systemic veins is thus partially depleted of oxygen and increased in carbon dioxide content. These veins empty into two large veins; the superior and inferior venae cavae that return the oxygen-poor blood to the right atrium. This completes the systemic circulation; from the heart (left ventricle), through the organ systems, and back to the heart (right atrium).

Physiology of cardiac muscle

The heart is composed of three major types of cardiac muscle.
1- The atrial muscle.
2- The ventricular muscle.
3- Specialized excitatory and conductive muscle fibers; an excitatory system of the heart that helps spread of the impulse (action potential) rapidly throughout the heart.


Physiologic anatomy of cardiac muscle
Cardiac muscle cells (myocytes) are striated as they have typical myofibrils containing thin actin and thick myosin filaments, similar to those found in skeletal muscle, which slide along each other during the process of contraction.
Unlike skeletal muscle (no gap junction), adjacent myocardial cells are joined end to end at structures called intercalated discs, which are cell membranes that have very low electrical resistance. Within the intercalated discs, there are electrical synapses or gap junctions, these gap junctions are protein channels that allow ions to flow from the cytoplasm of one cell directly into the next cell and, therefore action potentials to move with ease from one cardiac myocyte to another. That is, when one of these cells becomes excited, the action potential spreads rapidly throughout the intercalated discs and gap junctions to stimulate the neighbor cell, so the myocardium act almost as if it is a single cell; a syncytium, i.e., the cardiac muscle contracts or behaves as a single functional unit (syncytium property).

Innervations of the heart

The heart receives a rich supply of sympathetic and parasympathetic nerve fibers. The parasympathetic contained in the vagus nerves release acetylcholine which acts on the muscarinic receptors. The sympathetic postganglionic fibers release norepinephrine (noradrenaline) which acts on beta one (β1) adrenergic receptors distributed on cardiac muscle. The circulating epinephrine hormone from adrenal medulla also combines with the same receptors (β1 receptors).

Blood supply of the heart

The myocardial cells receive their blood supply through arteries that branch from the aorta, named coronary arteries.
Coronary veins drain into a single large vein, the coronary sinus, which drain into the right atrium.

The function of the heart valves

The atrioventricular valves (AV valves) are composed of thin membranous cusps (fibrous flaps of tissue covered with endothelium), which hangdown in the ventricular cavities during diastole. After atrial contraction and just before ventricular contraction, the AV valves begin to close and the leaflets (cusps) come together by mean of backflow of the blood in the ventricles towards the atria.
The AV valves include:
The mitral valve; the left AV valve; bicuspid valve, which consists of two cusps (anterior and posterior), located between left atrium and left ventricle.
The tricuspid valve; the right AV valve, which consists of three cusps, located between right atrium and right ventricle.
The function of AV valves is to prevent backflow (prevent regurgitation; leakage) of blood into the atria during ventricular contraction. Normally they allow blood to flow from the atrium to the ventricle but prevent backward flow from the ventricle to the atria. The atrioventricular valves contain and supported by papillary muscles.

The aortic and pulmonary valves each consist of three semilunar cusps that resemble pockets projecting into the lumen of aorta and pulmonary trunk. They contain no papillary muscle. During diastole the cusps of these valves become closely approximated to prevent regurgitation of blood from aorta and pulmonary arteries into the ventricles. During systole the cusps are open towards arterial wall, leaving a wide opening for ejection of blood from the ventricles. In other words, the pulmonary and aortic valves allow blood to flow into the arteries during ventricular contraction (systole) but prevent blood from moving in the opposite direction during ventricular relaxation (diastole).

*All valves close and open passively. That is, they close when a backward pressure gradient pushes blood backward, and they open when a forward pressure gradient forces blood in the forward direction.
*There are no valves at entrance of superior, inferior vena cava and pulmonary veins into the atria. What prevents the backflow of blood from the atria toward the veins is the compression of these veins by the atrial contraction. However little blood is ejected back into veins, this represents the venous pulse seen in the neck veins (jugular veins) when the atria contracting.




Function of papillary muscles
The AV valves (mitral and tricuspid) are supported by papillary muscles that attach to the flaps of these valves by the chordae tendineae.The papillary muscles originated from the ventricular walls and contract at the same time when the ventricular walls contract, but these muscles do not help the valves to close or open. Instead, they pull the flaps of the valves inward, toward the ventricles to prevent too much further bulging of the flaps (cusps) backward toward the atria during ventricular contraction, to prevent leakage of blood into the atria (keep the valve flaps tightly closed). In other words, contractions of papillary muscles prevent evertion of the flaps of the AV valves into the atria which could be induced by high pressure produced by contraction of the ventricles.

Figure: Mitral (two cusps) and Aortic (three cusps) valves.

Heart Sounds
When the stethoscope is placed on the chest wall over the heart, two sounds are normally heard during each cardiac cycle (1st & 2nd heart sounds). Heart sounds are associated with closure of the valves with their associated vibration of the flaps of the valves and the surrounding blood under the influence of the sudden pressure changes that develop across the valve. That is, heart sound does not produced by the opening of the valve because this opening is a slow developing process that makes no noise.
1-The first heart sound (S1): is caused by closure of the AV valves when ventricles contract at systole. The vibration is soft, low-pitched lub.
2-The second heart sound (S2): is caused by closure of the aortic and pulmonary valves when the ventricles relax at the beginning of diastole. The vibration is loud, high-pitched dup. It is rapid sound because these valves close rapidly and continue for only a short period i.e., rapid, short and of higher pitch dup.
3-The third heart sound (S3): is caused by rapid filling of the ventricles, by blood that flow with a rumbling motion into the almost filled ventricles; at the middle one third (1/3) of diastole i.e., it is caused by the vibrations of the ventricular walls during the period of rapid ventricular filling that follows the opening of AV valves. It is a low-pitched sound and can be heard after the S2. It is heard in normal heart; in children and in adult during exercise. It is also heard in anemia, and AV valve regurgitation.
4-The fourth heart sound (S4): it is an atrial sound when the atria contract (at late diastole). It is a vibration sound (similar to that of S3) associated with the flow of blood into the ventricle. It is not heard in normal hearts but occurs during ventricular overload as in severe anemia, Thyroitoxicosis (hyperthyroidism) or in reduced ventricular compliance and in hypertension. If present, it is heard before S1. (S4, S1, S2, S3).

Heart murmurs

They are abnormal sounds, can be produced by blood flowing rapidly in the usual direction but through an abnormally narrowed valve (stenosis), by blood flowing backward through a damaged, leaky valve (incompetent, regurgitant valve) or by blood flowing between the two atria or two ventricles through a small hole: ASD (atrial septal defect), VSD (ventricular septal defect).

*Pitch = the audible range of frequencies (cycles/sec).

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Lect.2
Properties of the cardiac muscle
In addition, to the syncytium property, the cardiac muscle has the property of:
Automaticity and rhythmicity (Autorhythmicity).
Excitability and conductivity.
Contractility
Autorhythmicity, Excitability and conductivity:

Electrical activity of the heart (action potential):

Objectives:
Describe action potentials in cardiac muscle cells.
Explain how the SA node functions as the pacemaker.
Explain the ionic basis of the action potential of the SA node and ventricular muscle cells.
Specialized excitatory and conductive system of the heart: consists of:
1. Sinus node "SA" node: also called sinoatrial node, located in the right atrium. It is concerned with the generation of rhythmical impulse; it is the pacemaker of the heart that initiates each heart beat. This automatic nature of the heart beat is referred to as automaticity.
2. Internodal pathways conduct the impulse generated in SA node to the AV node.
3. The AV node (atrioventricular node), located near the right AV valve at the lower end of the interatrial septum, in the posterior septal wall of the right atrium. At which impulse from the atria is delayed before passing into the ventricles.
4. The AV bundle (bundle of His) conducts the impulse from the atria into ventricles.
5. The left and right bundles of purkinje fibers, which conduct the cardiac impulse to all parts of the ventricles. The purkinje fibers distribute the electrical excitation to the myocytes of the ventricles.



Figure: organization of the AV node.


Figure: The cardiac conduction system.


The SA node as the pacemaker of the heart: (Automaticity & rhythmicity)
Automaticity is the property of self-excitation (i.e. the ability of spontaneously generating action potentials independent of any extrinsic stimuli) while rhythmicity is the regular generation of these action potentials. In other words, the cardiac impulse normally arises in the SA node, which has the capability of originating action potentials and functioning as pacemaker. This action potential then spreads from the SA node throughout the atria and then into and throughout the ventricles.
The contractile cardiac muscle cells don't normally generate action potentials but they can do in certain pathological conditions. This mean that all parts of the conduction system are able to generate a cardiac impulse; (autorhythmicity), but the normal primary pacemaker is the SA node, while the AV node is a secondary pacemaker and the Purkinje system is a tertiary (or latent) pacemaker. The AV node acts only if the SA node is damaged or blocked, while the tertiary pacemaker takes over only if impulse conduction via the AV node is completely blocked.
The SA node discharges at an intrinsic rhythmical rate of 100-110 times per minute (sinus rhythm). Under abnormal condition; the AV nodal fibers can exhibit rhythmical discharge and contraction at a rate of 40 to 60 times/minute. While those of purkinje fibers discharge at a rate between 15 and 40 times/minute.
Autorhythmicity is a myogenic property independent of cardiac innervation. This is evidenced by the following:
Completely denervated heart continues beating rhythmically.
Hearts removed from the body and placed in suitable solutions continuebeating for relatively long periods.
The transplanted heart (denervated heart) has no nerve supply but they beat regularly.
Self-excitation of SA node:
What causes the SA node to fire spontaneously?
Although the SA node discharges at an intrinsic rhythmical rate of 100-110 times per minute but the pulse rate averages 70 or 80 times per minute, this is because of the effect of vagal tone. SA node does not have a stable resting membrane potential which starts at about 60 mV. This is due to the inherent leakiness of the SA nodal fibers to Na+ ions that causes this self-excitation (Na+ influx). in other words, because of the high Na+ ions concentration in the ECF as well as the negative electrical charge inside the resting sinus nodal fibers, the positive Na+ ions outside the fibers tend to leak to the inside, rising the membrane potential up to a threshed to fire an action potential.
Atrioventricular node (AV node):
The conductive system is organized, so that cardiac impulse will not travel from the atria into ventricles too rapidly. There is a delay of transmission of the cardiac impulse in the AV node to allow time for the atria to empty their blood into the ventricles before ventricular contraction begins.
Cardiac action potentials:
Action potential of SA node
The resting membrane potential of SA node is of -55 to -60 mV (millivolts). The cause of this reduced negativity "less negative" is that the cell membrane of the sinus fibers are naturally leaky to sodium ions "Na+ influx". Therefore; Na+ influx causes a rising membrane potential "gradual depolarization" which when reaches a threshold voltage at about - 40 mV, the fast calcium and sodium channels opened, leading to a rapid entry of both Ca+2 and Na+ ions causing the action potential to about 0 mV (zero), to be followed by repolarization which is induced by K+ efflux out of the fiber because of the opening of K+ channels. This repolarization carries the resting membrane potential down to about -55 to -60 mV at the termination of action potential.

Figure: Action potentials of the SA node.

Action potential of ventricular cardiac muscle fiber
The membrane potential of cardiac ventricular muscle fiber cells is about -90 mV; the interior of the cell is electrically negative with respect to the exterior due to disposition; distribution of ions mainly Na+, K+ and Ca+2 ions across its membrane.
The action potential (AP) is an electrical signal or impulse produced by ionic redistribution that the potential changes into positive inside the cell (depolarization), to be followed by restoration of the ions; returning back to the resting potential (repolarization). Stimulation of cardiac muscle cells by SA produces a propagated action potential, that is responsible for muscle contraction i.e., excitation-contraction coupling. In other words, stimulation of cardiac muscle cells specifically those of the ventricles is performed by the propagated AP of the SA node from which the electrical impulses originating and propagated over the heart. According to the figure (a), the propagated AP of the SA node depolarized the ventricular muscle fiber cells rapidly with an overshoot (phase 0), followed by a plateau at around zero potential level (phase 2). This plateau is unique for the heart muscle; and is followed by phase 3 and 4; as final repolarization i.e., for the potential to return to baseline.

Ionic basis of the action potential of the cardiac ventricular muscle fiber cell:

The action potential of cardiac ventricular muscle fiber cell includes the following phases (a):

Phase 0 (upstroke): initial rapid depolarization with an overshoot to about +20 mV are due to opening of the voltage-gated Na+ channels with rapid Na+ influx.
Phase 1 (partial repolarization): initial rapid repolarization is due to K+ efflux (K+ outflow) followed the closure of Na+ channels when the voltage reaches at nearly +20 mV.
Phase 2 (plateau): subsequent prolonged plateau is due to slower and prolonged opening of the voltage-gated Ca+2 channels with Ca+2 influx, Ca+2 enter through these channels prolong depolarization of the membrane.
Phase 3 (rapid repolarization): final repolarization is due to opening of the voltage-gated K+ channels at zero voltage with rapid K+ outflow (K+ efflux) followed the closure of Ca+2 channels and, this restores the membrane to its resting potential.
Phase 4 (complete repolarization): The membrane potential goes back to the resting level (-90 mV) i.e., restoration of the resting potential. This is achieved by the Na+-K+ pump that works to move the excess K+ in and the excess Na+ out.


Figure (a): The action potential of the ventricular muscle fiber.



Figure: Rhythmical action potentials from a purkinje and ventricular muscle fibers.



Figure: Rhythmical discharge of SA nodal fiber, compared with action potential of ventricular muscle fiber.


Refractory period:
Absolute refractory period (ARP), it is the interval during which no action potential can be produced, regardless of the stimulus intensity i.e., no stimulus however strong, can produce a propagated action potential. It lasts the upstroke plus plateau and initial repolarization till mid-repolarization at about -50 to -60 mV. It means that the cardiac muscle can not be exited during the whole period of systole and early part of diastole. This period prevents waves summation and tetanus.
Relative refractory period (RRP), it is the interval during which a second action potential can be produced but at higher stimulus intensity i.e., the heart responds only to stronger stimuli. It lasts from the end of ARP (midrepolarization) and ends shortly before complete repolarization i.e., it lasts for a short period during diastole.



Figure: Relationship between membrane potential changes and contraction in a ventricular muscle cell. The refractory period lasts almost as long as the contraction.


Lect. 3

Con. on Properties of the cardiac muscle:

Contractility

Objectives:
Describe the major properties of cardiac muscle.
Discuss Frank-Starling law.
Describe how an action potential causes contraction (cardiac excitation-contraction coupling).

Contractility is the ability of the cardiac muscle to contract.

The effect of various factors on contractility is called inotropism; a positive (+ve) inotropic effect means an increase in myocardial contractility, whereas a negative (-ve) inotropic effect means a decrease in myocardial contractility.

Excitation-Contraction coupling in the heart muscle:

As in skeletal muscles, the depolarization wave reaching via the T tubules causes the opening of Ca+2 channels in the sarcoplasmic reticulum adjacent to the T-tubules. The released Ca+2 from the cisternae of the sarcoplasmic reticulum (activator Ca+2; aCa+2) binds to troponin C, leading to cross bridge formation between actin and myosin, which results in contraction.
In cardiac muscle, the amount of this activator Ca+2 is often insufficient to initiate contraction, but it can be increased indirectly by the following mechanism:
The depolarization wave in the T-tubules opens the long-lasting Ca+2 channels in the T-tubule membrane, and sarcolemma, Ca+2 diffuses from the ECF through these channels into the cardiac muscle fibre cell causing a small increase in the cytosolic (fluid of the cytoplasm) calcium concentration in the region of the T-tubules and adjacent sarcoplasmic reticulum. This Ca+2 is called depolarizing Ca+2, and although its amount is normally very small, yet it is important because it acts as a signal for the release of large amount of activator Ca+2 from the cisternae of sarcoplasmic reticulum, it is mainly this cytosolic Ca+2 that causes the contraction, i.e. once Ca+2 is in the cytoplasm, it binds to troponin and stimulates contraction. As a result, myocardial cells contract when they are depolarized. The force of contraction is directly proportional to the amount of cytosolic Ca+2.
Contraction ends when the cytosolic Ca+2 concentration restored to its original level. In other words, relaxation of the cardiac muscle occurs as a result of release of the actin-myosin combination, this is achieved by decreasing the intracellular Ca+2 to its pre- contraction level, which occurs by:
1- Active re uptake of Ca+2 into the sarcoplasmic reticulum by Ca+2 pump (primary active transport of Ca+2).
2- Active pumping of excess Ca+2 outside the fibres by Na+- Ca+2 exchanger carrier protein (secondary active transport ; counter transport).


The heart normally cannot be stimulated again until after it has relaxed from its previous contraction because myocardial cells have long refractory periods that correspond the long duration of their action potentials. Summation of contractions and tetanus are thus prevented, and the myocardium must relax at each contraction to ensure the rhythmic pumping action of the heart.



Figure: (2) = slow calcium channel, dCa+2 = depolarizing calcium, (3) = Ca+2-pump (active transport), (4) = Na+-Ca+2 Exchanger, aCa+2 = activator calcium.

Factors that affect cardiac contractility:

Mechanical
Cardiac
Extra cardiac

Mechanical factors:
Preload (venous return)
Afterload

The preload:

The preload is the load that determines the initial length of the resting muscle before contraction. The level of the preload is represented by the end-diastolic volume (EDV) i.e., by the venous return (VR). It affects the tension developed in the muscle. When the venous return (EDV), increases, the strength of ventricular contraction increases too, leading to an increase in the stroke volume (Frank-Starling law).

Frank-Starling's law of the heart

This law describes the length-tension relationship in muscles; it states that the force of contraction of the ventricles depends on the initial length of ventricular muscle fibers. In such a way, that the force of myocardial contraction is directly proportional to the initial length of the cardiac muscle fibres (i.e. to the preload (VR) or EDV). This means that the greater the degree of stretching of the myocardium before contraction, the greater the force of contraction. In other words, Frank-Starling law reflects the relationship between ventricular end-diastolic volume (EDV) and stroke volume; when the blood returns to the heart during the filling phase, this blood will distend the ventricles so the ventricles will produce more powerful contraction to pump the increased volume of the blood.
The Significance of Frank-Starling's law
The Starling's law allows autoregulation of myocardial contractility (regulation of the contractility by changing the length of the muscle fibers), in the following conditions:
(1) In normal hearts. Starling's law allows changes in the right ventricularoutput to match changes in the venous return (VR), and maintains equaloutputs from both ventricles. For example, if the systemic VR increases, the EDV of the right ventricle increases, leading to a forceful contractionthat increases its output to match the increased VR. At the same time, theincreased right ventricular output increases the pulmonary VR to the leftventricle, which also increases its EDV, resulting in an increase of its output, which balances the increased right ventricular output.
(2) In denervated hearts (e.g. transplanted hearts); autoregulation of myocardial contractility becomes the main mechanism.
(3) In cases of rise of the arterial blood pressure: the stroke volume of the left ventricle would decrease. However, the retained blood in the left ventricle plus blood returning to it from the left atrium during the next diastole increase the EDV. This leads to a forceful contraction, thus the accumulated blood in the left ventricle will be ejected in spite of the increased arterial blood pressure.


The Afterload:
The afterload is the load that the muscle faces when it begins to contract. In the intact heart, the afterload is produced by the aortic impedance which is determined by:
The aortic pressure (arterial systolic blood pressure).
The arterial wall rigidity (arteriosclerosis).
Blood viscosity (polycythemia).
Cardiac factors:
The myocardial mass.
The heart rate.
The myocardial mass:
A significant injury or loss of the functioning ventricular muscle (e.g. due to ischemia or necrosis) decreases the force of myocardial contractility. This also occurs in cases of heart failure.
The heart rate:
The force of cardiac contractility is affected by the frequency of stimulation. An increase in the frequency of stimulation (i.e. shortening the intervals between the stimuli) causes a proportional increase in the force of contraction.
Accordingly, tachycardia causes a +ve inotropic effect while bradycardia exerts a -ve inotropic action. The +ve inotropic effect in tachycardia is due to the increase in the number of depolarization (which increases the intracellular Ca+2 content and its availability to the contractile proteins (troponin C)).

Extra cardiac factors:

These factors affect the cardiac inotropic state and they include the following:
Neural
Physical
Chemical

Neural factors:

Sympathetic stimulation and noradrenaline exert a +ve inotropic effect by increasing;
Cyclic-AMP in the cardiac muscle fibres (which leads to activation of the Ca+2 channels and more Ca+2 influx from the ECF).
The heart rate.
Conversely, parasympathetic stimulation and acetylcholine exert a -ve inotropic effect (by opposite mechanism) but on the atrial muscle only (since the vagi nerves don't supply the ventricles).
Physical factors:
A moderate rise of the body temperature strengthens cardiac contractility (by increasing the Ca+2 influx and ATP formation in the muscle) while an excessive rise of the body temperature (e.g. in fever) exhausts the metabolic substrates in the cardiac muscle and decreases its contractility. Hypothermia also decreases cardiac contractility.
Chemical factors:
(A) Hormones:
Catecholamines (epinephrine, norepinephrine and dopamine), glucagon and the thyroid hormones; all exert a +ve inotropic effect.
(B) Blood gases:
Moderate hypoxia (O2 lack) and hypercapnia (CO2 excess) increase the cardiac contractility, whereas severe hypoxia and hypercapnia directly depress the cardiac muscle and decrease its contractility.
(C) H + ion concentration (pH):
An increase of the blood [H+] i.e. drop of the blood pH (acidosis) produces a -ve inotropic effect, whereas a decrease of the blood [H+] i.e. rise of the blood pH (alkalosis) produces a + ve inotropic effect.


(D) Inorganic ions:
Sodium: Hypernatraemia favors Na+ influx and Ca+2 efflux by the Na+-Ca+2 exchanger carrier, thus it has a -ve inotropic effect. On the otherhand, hyponatraemia exerts a +ve inotropic effect by an opposite mechanism.
Potassium: Hyperkalaemia has a -ve inotropic effect (weakens the myocardial contractility; flaccidity) and may stop the heart in diastole. This is because the excess K+ in the ECF decreases the resting membrane potential (more positive resting membrane potential; closer to the threshold)) in the cardiac muscle fibers, so the amplitude of the action potential is reduced leading to less influx of the depolarizing Ca+2 and in turn less release of activator Ca+2 from the sarcoplasmic reticulum. In addition, Hyperkalaemia increases excitation and decreases conduction leading to ectopics and dilated, flaccid heart. On the other hand, hypokalaemia produces a +ve inotropic effect by an opposite mechanism.
Calcium: Hypercalcaemia exerts a +ve inotropic effect as a result of more cytosolic Ca+2. Whereas hypocalcaemia has a little (or no) -ve inotropic effect, since lowering of the serum Ca+2 level causes fatal tetany before affecting the heart. However, hypocalcaemia causes cardiac flaccidity like Hyperkalaemia.

(E) Toxins:

Several toxins (e.g. certain snake venoms and the toxin released by the diphtheria microorganisms) produce a-ve inotropic effect (mostly by a direct action on the contractile mechanism of the cardiac muscle).
(F) Drugs:
Cardiac glycosides (e.g. digitalis; Digoxin): These drugs inhibit the Na+-K+ ATPase in the sarcolemma of the cardiac muscle fibres, so the intracellular Na+ concentration increases. This decrease the Na+ influx, thus Ca+2 efflux through the Na+-Ca+2 exchanger is also decreased. Accordingly, the intracellular Ca+2 concentration increases, producing a +ve inotropic effect. Digitalis also increases the slow Ca+2 influx during the action potential.
Xanthines (e.g., caffeine and theophylline; bronchodilator): They exert a +ve inotropic effect.
Ouinidine, barbiturates, procainamide (and other anesthetic drugs) as well as Ca+2 blocker drugs all have a -ve inotropic effect by decreasing Ca+2 influx into the cardiac muscle fibres.

Lect. 4

The Cardiac cycle
Objectives:
Describe the pressure profiles in the left atrium, left ventricle and the aorta for a single cardiac cycle.
Explain the origin and indicate the positions of the 1st and 2nd heart sounds.
Draw the profile of pressure changes in the external jugular vein, labeling the three component waves.
Draw a classical ECG waveform on the time-base schedule.

The cardiac events that occur from the beginning of one heartbeat to the beginning of the next are called the cardiac cycle. Each cycle is initiated by spontaneous generation of an action potential in the sinus node which travels rapidly through both atria and then through the A-V bundle into the ventricles.
Because of this special arrangement of the conducting system from the atria into the ventricles, there is a delay of more than 0.1 second during passage of the cardiac impulse from the atria into the ventricles. This allows the atria to contract, pumping blood into the ventricles before the strong ventricular contraction begins. Thus, the atria act as primer pumps for the ventricles, and the ventricles in turn provide the major source of power for moving blood through the bodys vascular system.
In a normal heart, cardiac activity is repeated in a regular cycle. At a normal heart rate of about 72 beats/minute; for the atria, the cycle lasts for about 0.15 second in systole and 0.65 second in diastole. For the ventricles, the duration of each cardiac cycle lasts about 0.8 second. If the heart rate increases, the diastole decreases, which means that the heart beating very fast may not remain relaxed long enough to allow complete filling of the ventricles before the next contraction.
For the ventricles, the two major phases of the cardiac cycle are:
The diastole; a period of ventricular relaxation in which the ventricles fill with blood and it last for about 0.5 second.
The systole; a period of ventricular contraction and blood ejection, lasting about 0.3 second.
Phases of the cardiac cycle:
The cardiac cycle starts by atrial systole followed by ventricular systole then by diastole of the whole heart.
Atrial systole (atria as a pump):
It is the first phase of cardiac cycle. Blood normally flows continually (passively) from the veins into the atria and about 75% of the blood in the atria flow directly into the ventricles even before the atrial contraction. Then, atrial contraction usually causes an additional 25% filling of the ventricles. So the heart can continue to operate satisfactorily under most condition without this extra 25%, yet this 25% is needed in case of exercise.


Pressure changes in the atria during cardiac cycle
During atrial contraction; right atrial pressure raises 4 to 6 mmHg, while the left atrial pressure raises 7 to 8 mmHg. In the atrial pressure curve, there are 3 major pressure elevations called the a, c and v atrial pressure waves:
a wave is caused by atrial contraction.
c wave is caused by bulging of the tricuspid valve into the right atrium during ventricular contraction because of increasing pressure in the ventricles.
v wave result from slow flow of blood into the right atrium from the veins while the AV valve are closed during ventricular contraction. So the v wave is due to atrial filling.



Figure: Atrial pressure curve.

Clinical importance of atrial waves

Venous pulsations occur only in large veins near the heart like the jugular veins in the neck (the jugular venous pulsations). The jugular venous pulse reflects changes in right atrial pressure (the central venous pressure), i.e. the pressure changes within the right atrium are communicated to the neck jugular veins. To make the jugular venous pulsations visible in the neck, the person has to be supine with his back at a slight angle to the horizontal (45 degree). In this position, the a and v waves can be seen in the jugular veins when the neck is carefully examined. When the venous pressure is raised as in heart failure disease, the jugular veins become more prominent and the pulsation can be observed in the neck.
x-descent is caused by pulling the AV ring down during ventricular systole; drop in right atrial pressure.
y-descent is caused by the opening of the AV valve and the escape of the blood from the atrium into the ventricle; drop in right atrial pressure.



Figure: Normal jugular venous sphygmogram.



Figure: The position to examine normal jugular venous pulsation. JL = upper level where jugular pulsations appear (jugular level). SA = sternal angle level.

Ventricular cardiac cycle

The ventricular cardiac cycle consists of three phases:
Phase one: Ventricular filling.
Phase two: Ventricular systole.
Phase three: Isovolumic, isometric relaxation.


Ventricular filling
During ventricular systole, the accumulated large amounts of blood in the atria because of the closed AV valves push the AV valves open and allow blood to flow rapidly into the ventricles. During atrial contraction, an additional amount of blood flows into the ventricles represent 25% of the filling of the ventricles.



Figure: Ventricular pressure curve.

Ventricular systole:

Subdivided into two phases:
Isovolumic, isometric contraction (isovolumetric contraction).
Ventricular ejection.

Isovolumetric contraction

It is ventricular contraction but without blood ejection (no emptying) just to close the AV valves and to open semilunar valves by the rise in intraventricular pressure (from 0 to 80 mmHg in the left ventricle). It is the isovolumetric contraction, which means only the tension is increasing in the ventricular muscle without shortening of the muscle and with no change in blood volume.

Ventricular ejection

The blood ejected from the ventricles into pulmonary trunk and aorta when the ventricular pressure rises and forces the semilunar valves open.
Left ventricular pressure rises above 80 mmHg.
Right ventricular pressure rises above 8 mmHg.


Figure: Ventricular volume curve.


Isovolumetric relaxation:
Isovolumic, isometric relaxation; following ventricular systole, ventricular relaxation begins suddenly and ventricular pressure falls. The blood in the aorta and pulmonary trunk backflows toward the heart closing the semilunar valves. For another 0.03 to 0.06 second, the ventricular muscle continues to relax, even though the ventricular volume does not change giving rise to the period of isovolumic relaxation in which the intraventricular pressure falls rapidly back to their low diastolic levels. Meanwhile, the atria have been filling with blood. When the pressure exerted by the blood on the atrial side of AV valves exceeds that in the ventricles, AV valves forced open and the ventricular filling phase begins again for a new cycle of ventricular pumping.

Aortic pressure curve:

When the left ventricle contracts, the intraventricular pressure rises rapidly until the aortic valve opens. So blood immediately flows out of the ventricle into the aorta, causes the wall of this artery to stretch and the pressure rise. Then, at the end of the systole, after the left ventricle stops ejecting blood and the aortic valve closes, the elastic recoil of the arteries maintains a high pressure even during diastole (diastolic pressure = 80 mmHg).The systolic pressure inside the aorta is equal to 120 mmHg. Incisura: is caused by a short period of backward flow of blood from the ventricle immediately before closure of the valve followed then by sudden cessation of the backflow.



Figure: Aortic pressure curve.

Relationship of the ECG to the cardiac cycle (Timing):

The ECG (electrocardiogram) shows the P, QRS and T waves. They are electrical voltages generated by the heart and recorded by the ECG:
P-wave is caused by atrial depolarization; this is followed by atrial contraction, which causes a slight rise in the atrial pressure curve after the P wave.
About 0.16 second after the onset of the P wave, the QRS waves appear as a result of electrical depolarization of the ventricles, which initiates contraction of the ventricles and causes the ventricular pressure to begin rising, as shown in the figure. Therefore, the QRS complex begins slightly before the onset of ventricular systole.
T-wave represents ventricular repolarization at which the ventricles begin to relax. Therefore, the T wave occurs slightly before the end of ventricular contraction.
Relationship of the Heart Sounds to Heart Pumping
When listening to the heart with a stethoscope, one does not hear the opening of the valves because this is a relatively slow process that normally makes no noise. However, when the valves close, the cusps of the valves and the surrounding blood vibrate under the influence of sudden pressure changes, giving off sound that travels in all directions through the chest. When the ventricles contract, one first hears a sound caused by closure of the A-V valves. The vibration is low in pitch and relatively long-lasting and is known as the first heart sound. When the aortic and pulmonary valves close at the end of systole, one hears a rapid snap because these valves close rapidly, and the surroundings vibrate for a short period. This sound is called the second heart sound.

Lect. 5

Electrical potential of the heart


The electrocardiogram (ECG):
Objectives:
Draw an ECG classical waveform and label each component (P, QRS, T).
Draw diagrams indicating the 6 standarad limb leads (I,II,III,aVR,aVL,aVF).

The ECG is the recording of the electrical potential of the heart that extend to the body surface. By placing the electrodes of an ECG instrument on the skin surface, you can record the waves of depolarization and repolarization that are generated by the cardiac muscle. The apparatus used is called the electrocardiograph; it is formed basically of a sensitive galvanometer and an amplifier.
A standard ECG consists of 12 leads:
3 Bipolar standard limb leads (I, II, III).
3 unipolar limb leads (aVR, aVL, aVF).
6 unipolar chest leads.
Bipolar standard limb leads (I, II, III):
These leads record the differences between the potentials in 2 limbs, by applying electrodes usually at the wrist and ankle. The 3 standard bipolar limb leads include:
Lead I: This records the difference between the potential in the left arm (LA) and that in the right arm (RA).
Lead 11: This records the difference between the potential in the right arm (RA) and that in the left leg (LL).
Lead III: This records the difference between the potential in the leftleg (LL) and that in the left arm (LA).
Einthoven's triangle: This is an equilateral triangle, the sides of which represent the 3 bipolar standard limb leads while the heart lies at its centre.

Unipolar limb leads (aVR, aVL, aVF):

These measure the absolute (actual) potential at a certain point. This is carried out by applying one electrode from the electrocardiograph to the desired point (it is active, +ve or exploring electrode) while the other electrode represents a common reference point inside the instrument; it is the -ve electrode (0 potential) i.e. the unipolar leads measure the potential differences between active electrodes and zero potential.
They are augmented unipolar limb leads that have magnified amplitudes by about 50 % without any change in their configuration, so they are called aVR, aVL and aVF (a = augmented).

Unipolar chest leads:

Unipolar leads (precordial or chest leads) record the absolute potential at 6 standard points on the anterior chest wall designated as V1 to V6, the locations of which are as follows:
V1: At the right margin of the sternum in the 4th right intercostal space.
V2: At the left margin of the sternum in the 4th left intercostal space.
V3: Midway between V2 and V4.
V4: At the left midclavicular line in the 5th intercostal space.
V5: At the left anterior axillary line in the 5th intercostal space.
V6: At the left midaxillary line in the 5th intercostal space.

The precordial leads look at the heart in a horizontal plane from the front & left sides. Leads V1 & V2 look at the right ventricle and reflect its activity, V3 & V4 look at the interventricular septum and reflect its activity, while leads V5 & V6 look at the left ventricle and reflect its activity.

Connections of the electrocardiograph:

By specific electrodes, the electrocardiograph is connected to the 4 limbs and the chest at the same time. The right leg connection is used to "earth" the subject (to minimize interference currents). It is arranged so that an upward (+ ve) deflection is produced when a depolarization wave is moving toward the exploring electrode or a repolarization wave is moving away from it, and vice versa.

Calibration of the electrocardiograph:

The electrocardiograph is calibrated so that a change of 1 mV upward or downward produces a deflection of 10 mm amplitude (10 small squares; 2 large squares), thus each mm between the horizontal lines (voltage calibration lines) equals 0.1 mV. In other words, the thin horizontal lines calibrated at 1 mm interval and the thick horizontal lines at 5 mm intervals. The vertical lines are time calibration lines in which duration of each mm (small square) equals 0.04 second, each inch (2.5cm) is 1 second, divided into 5 large squares, each large square (5 small squares) represents 0.20 second.

Calculation of heart rate from ECG paper:

If the heart rhythm is regular, the heart rate (HR) ran be counted by dividing the number of large squares between two consecutive R waves into 300 or small squares into 1500. If the rhythm is irregular, one can multiply the number of complexes in 6 seconds by 10.


Speed:
It is the speed at which the chart paper moves. The standard speed is 25 mm/sec. The importance of another speed (50 mm/sec) is in case of tachycardia (e.g. HR of 180 beat/min), to obtain a proper ECG.

Sensitivity:

It means mm deflection for 1 mV (range; 5-10-20). The higher the sensitivity of the instrument, the more the deflection and vise versa. The standard sensitivity is 10 mm/mV (2 large squares), in cardiomegally you must reduce the sensitivity.

ECG waves:

ECG (Electrocardiograph) is an indirect recording of electrical potential of the heart. Normal ECG consists of the following waves:
P wave caused by the depolarization process of the atria; i.e., correspond to atrial depolarization just before contraction (i.e., not atrial contraction).
QRS complex of waves caused by the depolarization process of the ventricles; again before ventricular contraction (i.e., not ventricular contraction).
T wave caused by the repolarization of the ventricles; the ventricles recover from the state of depolarization.



Duration and intervals:
P wave, duration; 0.07-0.14 seconds and not higher than 3 mm.
PR interval, This is measured from the beginning of the P wave to the beginning of the QRS complex; to the onset of the Q wave if there is one and to the onset of the R wave if there is no Q wave. This interval corresponds to the time taken for the impulse to travel from the sinus node to the ventricular muscle. It ranges normally between 0.12- 0.21 seconds. Abnormal PR interval is either long as in first degree heart block or short as in WPW syndrome.
QRS complex, duration; 0.06 0.10 seconds. Abnormal wide QRS indicate bundle branch block.
T wave, duration; 0.25 -0.35 seconds and not taller than 10 mm in chest leads.
QT interval, it represents the total time from the onset of ventricular depolarization to the completion of repolarization. It indicates the duration of ventricular systole i.e. contraction of the ventricle lasts from the beginning of the Q wave to the end of the T wave. Normally it is about 0.35 seconds; range 0.28 0.44 seconds.








Lect.6

Electrical axis and cardiac vector
Objectives:
State the relationship between the direction of cardiac vector with the direction (-ve, +ve) and amplitude of an ECG waves.
Draw diagram indicting the axes of limb leads.

Cardiac vector:

The cardiac vector is the net result of the directions of the spread of depolarization waves from the SA node through the atria, AV node, interventricular septum, ventricles, and to the apex of the heart, the last part of the heart to be depolarized is the base of the heart.
Vector that occurs during depolarization of the ventricles
When the cardiac impulse enters the ventricles through the AV bundle, the first part of the ventricles to become depolarized is the left endocardial surface of the septum, then this depolarization spreads rapidly to involve both endocardial surfaces of the septum, the endocardial surface of the two ventricles and finally it spreads through the ventricular muscle to the outside of the heart and thereafter, the heart vector points toward the base of the left ventricle.

Figure: Vectors that occur during depolarization of the ventricles.

Figure: Gensis of the QRS complex. The first phase, directed from left to right across the septum, produce Q wave in V6 and an R wave in V1. The second phase, due to depolarization of the left ventricle from endocardium to epicardium, results in a tall R wave in V6 and a deep S wave in V1. Phase 3, depolarization of the basal parts of ventricles producing a terminal S wave in V6 and a terminal R wave in V1.


Electrical axis of the ventricular QRS:
In relation to the bipolar limb leads (I, II, III), the cardiac vector or axis can be calculated. The relationship among the six limbs leads, i.e., the axis of each standard bipolar and unipolar limb leads can be presented in the following diagram:

The mean electrical axis of the ventricular QRS

The average direction of the depolarization waves in all ventricular muscle fibres is called the mean electric axis of the ventricles or mean ORS axis or vector.
Depolarization in cardiac muscle fibres can be represented by an arrow pointing to the + ve direction. This arrow is called a vector.
In normal heart, the direction of the cardiac vectors of the ventricles is normally toward the apex of the heart. In other words, the direction of the electrical potential is from the base of the ventricles toward the apex..
The mean ORS axis has a magnitude & direction, and is related to the anatomical axis of the heart. The normal electric axis is directed downwards and to the left between - 30 and +110 (average + 60). Clinically, the electrical axis of the heart is determined from the standard bipolar limb leads; lead I and lead III as follows:
First, record the maximum potential (that of QRS wave; R wave) and polarity (+ve or ve), to determine the maximum potential, you might need to subtract the area of the negative wave from the area of the positive wave. This means that the net QRS deflection in each lead is calculated by subtracting the amplitude of the largest -ve wave in the QRS from that of the R wave.
Second, a distance equal to the net deflection in each lead is drawn as anarrow on the corresponding axis of the bipolar limb lead (clock), starting from its zero potential point and pointing to the resulting polarities (+ve or -ve).
Third, draws perpendicular lines form both ends of the arrows; th apices of the two net potentials of lead I and III, the point of intersection of these two lines represents the mean electrical axis or the mean QRS vector of the ventricles.
In a normal heart, the average direction of the vector of the heart during spread of the depolarization waves through the ventricles; the mean QRS vector, is about +59 degrees, as shown in the following figures:




Figure: Determination of projected vectors in leads I, II, and III where vector A represent the instantaneous potential in the ventricles.



Figure: The mean electrical axis of the heart (59 degree) plotted
From lead I and lead III.


The cardiac vector affects the configuration of the ECG waves in the various leads. The normal direction of the mean QRS vector is downwards and to the left and is generally between 30 and +110 degrees.

Axis deviation:

Axis deviation occurs if the electric axis of the heart is beyond the normal range and it may be to the right or to the left. QRS axis further right that of +110 constitutes Right axis deviation (RAD), QRS axis left that of 30 constitutes Left axis deviation (LAD).

Right axis deviation

This normally occurs in vertical hearts (e.g. in tall slender subjects), but pathologically, it is common in right ventricular hypertrophy and right bundle branch block. In this case, the projection of the mean QRS axis is toward the -ve pole in lead I and toward the +ve pole in lead III, so in ECG, there are deep -ve waves (S waves) in lead I and high +ve waves (R waves) in lead III, as shown in the following figure.



Figure: Right axis deviation and a slightly prolonged QRS complex.

Left axis deviation

This normally occurs in horizontal hearts (e.g. in short obese subjects and pregnant women) but pathologically, it is common in left ventricular hypertrophy and left bundle branch block. In this case, the projection of the mean QRS axis is toward the +ve pole in lead I and toward the -ve pole in lead III, so in ECG there are high +ve waves (R waves) in lead I and deep -ve waves (S waves) in lead III.




Figure: Example of left axis deviation. Figure: left axis deviation caused by left bundle branch block. Note also the greatly prolonged QRS complex.


Lect. 7

Cardiac arrhythmia

Objectives:
List the types of arrhythmias.
Identify on ECG: ectopic beats, atrial & ventricular fibrillation, heart block.

The causes of the cardiac arrhythmias are usually one or a combination of the following abnormalities in the rhythmicity-conduction system of the heart:
1- Abnormal rhythmicity of the pacemaker.
2- Shift of the pacemaker from the sinus node to other parts of the heart.
3- Blocks at different points in the transmission of the impulse through the heart.
4- Abnormal pathways of impulse transmission through the heart.
5- Spontaneous generation of abnormal impulses in almost any part of the heart.

Types of arrhythmias

1- Abnormal sinus rhythms.
2- Conduction block.
3- Premature Contractions.
4- Paroxysmal tachycardia.

1-Abnormal sinus rhythms:

Sinus Tachycardia.
Sinus Bradycardia.
Sinus Arrhythmia.


Tachycardia
The term "tachycardia" means fast heart rate, usually defined as faster than 100 beats per minute. The electrocardiogram is normal except that the rate of heartbeat is increased. The general causes of tachycardia are:
increased body temperature,
Stimulation of the heart by the sympathetic nerves.



Sinus tachycardia, HR = 150 (300/2)

Bradycardia

The term "bradycardia" means a slow heart rate, usually defined as less than 60 beats per minute. Examples:
Bradycardia in Athletes.
Vagal Stimulation. In patients with carotid sinus syndrome; arteriosclerosis of the carotid sinus causes excessive sensitivity of the baroreceptors located in the arterial wall; as a result, mild pressure on the neck elicits a strong baroreceptor reflex, causing intense vagal stimulation of the heart and extreme bradycardia. Sometimes this reflex is so powerful that it stops the heart.



Sinus bradycardia of 40 beats per minute.
(300/7.5 = 40)

Sinus Arrhythmia

The heart rate is increased during inspiration and decreased during expiration. The ECG is normal except that the number of the cycles varies with the two phases of respiration. It is a common normal finding in young adults and children.



Sinus arrhythmia, acceleration of sinus rate during inspiration
and slowing during expiration.


2-Conduction block:
Sinoatrial Block.
Atrioventricular Block (Heart Block).
First Degree Heart Block.
Second Degree Heart Block.
Third Degree Heart Block.

Sinoatrial Block

The impulse from the sinus node is blocked before it enters the atrial muscle. There is sudden cessation of P- wave with standstill of the atrium (missed beat).



Sinoatrial nodal block (missed beat).

Atrioventricular Block (Heart Block)

Impulses pass from the atria into the ventricles is through the A-V bundle (the bundle of His). Conditions that can either decrease or block the impulse through this bundle are:
Ischemia of the A-V node or A-V bundle fibers by coronary insufficiency.
Compression of the A-V bundle by scar tissue or by calcification.
Inflammation of the A-V node or A-V bundle, which can results frequently from different types of myocarditis, such as occur in diphtheria and rheumatic fever.
Extreme stimulation of the heart by the vagus nerves blocks impulse conduction through the A-V node. Such vagal excitation occasionally results from strong stimulation of the baroreceptors in people with the carotid sinus syndrome.

First Degree Heart Block (Prolonged P-R interval)

The normal time between the beginning of the P wave and the beginning of the QRS complex is 0.12 0.21 second, when the heart is beating at a normal rate. This P-R interval usually decreases in length with faster heartbeat and increases with slower heartbeat. When the P-R interval increases above a value of about 0.21 second in a heart beating at normal rate, the P-R interval is said to be prolonged and the patient is said to have first degree incomplete heart block (in acute rheumatic fever). The following Figure shows an electrocardiogram with a prolonged P-R interval. Thus, first degree heart block is defined as a delay of conduction from the atria to the ventricles but not actual blockage of conduction.




First-degree heart block, prolonged P-R interval.

Second Degree Heart Block

The atria beat at a faster rate than the ventricles, and there are dropped beats of the ventricles. This condition is called second degree incomplete heart block, as shown in the following figures; a progressive prolongation of the P-R intervals as well as one dropped beat as a result of failure of conduction from the atria to the ventricles.
At times, every other beat of the ventricles is dropped, so that a "2:1 rhythm" develops in the heart, with the atria beating twice for every single beat of the ventricles. Sometimes other rhythms such as 3:2 or 3:1 also develop.



Second-degree heart block, progressive PR prolongation failure of
P-wave conduction to the ventricle (missed ventricular beat).



Second-degree heart block, with missed ventricular beat.

Third Degree Heart Block (Complete heart block)

Complete block of the impulse from the atria into the ventricles. The P waves become dissociated from the QRS-T complexes. As shown, the rate of ventricular beat is less than 40 per minute. Furthermore, there is no relation between the rhythm of the P waves and that of the QRS-T complexes because the ventricles have escaped from control by the atria, and they are beating at their own natural rate.



Complete heart block. P-waves are dissociated
from the QRS complexes.
3-Premature Contractions:
A premature contraction is a contraction of the heart before the time that normal contraction would have been expected. This condition is also called extrasystole, premature beat, or ectopic beat. Most premature contractions result from ectopic foci in the heart, which emit abnormal impulses at odd times. The possible causes:
Local areas of ischemia.
Small calcified plaques at different points in the heart, which press against the adjacent cardiac muscle so that some of the fibers are irritated.
Toxic irritation of the A-V node, Purkinje system, or myocardium caused by drugs, nicotine, or caffeine. Mechanical initiation of premature contractions is also frequent during cardiac catheterization.


Premature Atrial Contractions
The following figure shows a single premature atrial contraction, The P-wave of this beat occurs too soon in the heart cycle, and the P-R interval is shortened, indicating that the ectopic origin of the beat is near the A-V node. Also, the interval between the premature contraction and the next succeeding contraction is slightly prolonged, which is called a compensatory pause. One of the reasons for this is that the premature contraction originated in the atrium some distance from the sinus node, and the impulse had to travel through a considerable amount of atrial muscle before it discharged the sinus node. Consequently, the sinus node discharged late in the premature cycle, and this made the succeeding sinus node to be discharged late. Premature atrial contractions occur:
In healthy people.
In athletes.
Mild toxic conditions resulting from; excess smoking, lack of sleep, ingestion of too much coffee, alcoholism, and the use of various drugs.



Atrial premature beat.

Premature Ventricular Contractions

The electrocardiogram of the following figure shows a series of premature ventricular contractions (PVCs) alternating with normal contractions. PVCs cause specific effects in the electrocardiogram, as follows:
The QRS complex is usually prolonged.
The QRS complex has a high voltage.
The T wave has a potential polarity opposite to that of the QRS complex.
Some PVCs result from factors such as cigarettes, coffee, lack of sleep, and emotional irritability. Other PVCs originate from infracted or ischemic areas of the heart.



Ventricular ectopic beats, broad QRS complex.

4-Paroxysmal tachycardia:

Abnormalities in any portion of the heart, including the atria, the Purkinje system, or the ventricles, can cause rapid rhythmical discharge of impulses that spread in all directions throughout the heart. The term "paroxysmal" means that the heart rate usually becomes rapid in paroxysms, with the paroxysms beginning suddenly and lasting for a few seconds, a few minutes, a few hours, or much longer. Then the paroxysms usually end suddenly as they begun, with the pacemaker of the heart shifting back to the sinus node.
Paroxysmal tachycardia:
Supraventricular arrhythmias:
Atrial tachycardia;
a- Supraventricular tachycardia (SVT).
b- Atrial fibrillation (AF).
c- Atrial flutter.
Junctional tachycardias (AV nodal paroxysmal tachycardia).
Ventricular paroxysmal tachycardia.
Ventricular tachycardia (VT).
Ventricular fibrillation (VF).


Supraventricular arrhythmias:
Atrial tachycardias (arising from atrial myocardium) or junctional tachycardias (AV node tachycardia), both of which are called Supraventricular tachycardias, usually occurs in young, otherwise healthy people.
They are originated above the bifurcation of bundle of His. The unique characteristics of these arrhythmias are:
1- Narrow QRS.
2- P-wave either visible, irregular in shape and with shorter duration or invisible.
3- Variable PR interval due to variable rate of conduction at AV node.
Atrial tachycardias:
a- paroxysmal Supraventricular tachycardia (SVT)
As shown in the following record, there is a sudden increase in the rate of heartbeat from about 95 to about 150 beats per minute. It can be seen that an inverted P-wave occurs before each of the QRS-T complexes during the paroxysm of rapid heartbeat, and this P-wave is partially superimposed on the normal T wave of the preceding beat. This indicates that the origin of this paroxysmal tachycardia is in the atrium, but because the P-wave is abnormal, the origin is not near the sinus node.






Supraventricular tachycardia, no P wave (missed) or obscured.

b- Atrial fibrillation

A frequent cause of atrial fibrillation is atrial enlargement resulting from heart valve lesions, or from ventricular failure with excess damming of blood in the atria. The dilated atrial walls predispose to atrial fibrillation, which is irregular irregularity of the rhythm with no or obscured P-wave.



Atrial fibrillation, no P wave or obscurred.




Atrial fibrillation; irregular rhythm (irregular irregularity).



Atrial fibrillation; Fine, high frequency, and very low voltage P- wave.

c- Atrial Flutter

In Atrial flutter, the electrical signal travels as a single large wave front always in one direction around and around the atrial muscle mass. As shown in the following Figure, this wave travels from top to bottom to top around the openings of the superior and inferior venae cavae. Atrial Flutter causes a rapid rate of contraction of the atria, usually between 200 and 350 beats per minute. But not all can stimulate the ventricles, therefore, there are usually two to three beats of the atria for every single beat of the ventricles.
In the Atrial flutter ECG trace, the P waves are strong (saw-teeth appearance), the QRS-T complex follows an atrial P wave only once for every two to three beats of the atria, giving a 2:1 and a 3: 1 rhythm.



Pathways of impulses in atrial flutter and atrial fibrillation.



Atrial flutter; saw-teeth appearance of the P-wave.

Junctional tachycardias (AV nodal paroxysmal tachycardia)

Paroxysmal tachycardia often results from an aberrant rhythm that involves the AV node. This usually causes normal QRST complexes but missing or obscured P-waves.





Ventricular Paroxysmal Tachycardia (VT):
The electrocardiogram of ventricular paroxysmal tachycardia has the appearance of a series of ventricular premature beats occurring one after another without any normal beats inbetween. Ventricular tachycardia frequently initiates the lethal condition of ventricular fibrillation because of rapid stimulation of the ventricular muscle.



Ventricular paroxysmal tachycardia.

a- Ventricular tachycardia (VT)

VT refers to a rhythm originating from a ventricular ectopic focus at a rate greater than 100 beats per minute. The ECG shows a wide-complex tachycardia with no associated P-wave.



Ventricular tachycardia, regular wide QRS tachycardia
at a rate of 170 / min.

b- Ventricular fibrillation (VF)

Ventricular fibrillation results from cardiac impulses that have gone here and there within the ventricular muscle mass. Stimulating first, one portion of the ventricular muscle, then another portion, then another, and eventually feeding back onto itself to re-excite the same ventricular muscle over and over. Multiple factors can spark the beginning of ventricular fibrillation:
(1) Sudden electrical shock of the heart.
(2) Ischemia of the heart muscle, of its specialized conducting system, or both.



Ventricular fibrillation.


Lect. 8

Ccardiovascular innervations:

Cardiovascular centers
Objectives;
Identify morphologically differences between types of cardiovascular centers.

There are 2 main centers:

Vasomotor center (VMC).
Cardioinhibitory centre (CIC).
Vasomotor center:
This center located bilaterally in the reticular substance of the medulla and lower pons. The center transmits parasympathetic impulses through the vagus nerves to the heart and sympathetic impulses through the spinal cord and peripheral sympathetic nerves to the heart and to the blood vessels of the body. It includes the following areas or centers:
1-Vasoconstrictor center (VCC):
Its neurons secrete norepinephrine to excite the vasoconstrictor neurons of the sympathetic system throughout the spinal cord. Stimulation of the VCC increases the sympathetic discharge to:
The blood vessels (leading to generalized vasoconstriction (VC)).
The adrenal medullae (leading to secretion of Catecholamines).
The heart (increasing heart rate).
2-Vasodilator center (VDC):
Its fibers ascend upward to the vasoconstrictor center, inhibiting the activity of this area (VCC), thus causing vasodilation. Stimulation of this center leads to generalized vasodilatation (VD) by inhibiting the activity of the VCC.
3-Sensory area:
Its neurons receive sensory nerve signals from the vagus and glossopharyngeal nerves. This area controls the activities of the vasoconstrictor and vasodilator centers, an example are the baroreceptor reflex that controls the blood pressure.


At the same time, the vasomotor center controls the heart activity:
The lateral portion of the vasomotor center transmits excitatory impulses through the sympathetic nerve fibers to the heart to increase heart rate and contractility.
The medial portion of this center transmits impulses through the vagus nerves to the heart to decrease the heart rate.
Therefore, the vasomotor center can either increase or decrease heart activity.
Cardioinhibitory center:
This includes mainly the dorsal motor nucleus of the vagus (plus parts of the nucleus ambiguus and nucleus of tractus solitarius). It sends inhibitory signals to the heart via the vagus nerve.





Innervation of the heart:

The heart receives sympathetic and parasympathetic nerve supply. The sympathetic nerve supply to the heart is connected to, and controlled by, the vasoconstrictor center. The parasympathetic vagal supply to the heart is connected to, and controlled by, the cardioinhibitory center. There are also afferent nerve fibers from the heart join the sympathetic and parasympathetic nerves to the CNS.
The sympathetic cardiac nerves
The preganglionic fibers arise from the lateral horn cells of the upper five thoracic spinal segments. They relay in the three cervical and upper five thoracic sympathetic ganglia. Postganglionic fibers arise from the cervical and thoracic ganglia and proceed to supply the atria, ventricles, and the conducting system of the heart.
The parasympathetic cardiac nerves
The preganglionic fibers arise from the cardioinhibitory center in the medulla. The fibers proceed as vagal fibers to relay in terminal ganglia in the wall of the atria. Short postganglionic fibers arise from terminal ganglia & proceed to supply the atria, SA node, & AV node, but the ventricles are not supplied by vagus nerve.

Innervation of the blood vessels:

The vessels which are most affected by the vasoconstrictor nerve fibers are:
The high resistance vessels (the arterioles).
The capacitance vessels (mainly the big veins).
The vessels constrict when the sympathetic discharge to them increases and dilate when the sympathetic discharge decreases.
The vasoconstrictor nerves
All the blood vessels of the body except the capillaries are supplied with sympathetic vasoconstrictor fibers. These fibers are connected with, and under control of, the medullary vasoconstrictor center. The chemical transmitter of all the sympathetic vasoconstrictor fibers is noradrenaline. It acts on the (alpha); α-adrenergic receptors on the smooth muscles of the blood vessels leading to their constriction.
The vasodilator nerves
The vasodilator nerves include sympathetic, parasympathetic, and somatic nerves. None of them is under the control of the vasomotor center.
A- The sympathetic vasodilator system
These are sympathetic vasodilator cholinergic nerves which supply the blood vessels of skeletal muscle. The activity of this system is centrally controlled by the motor cerebral cortex in the frontal lobe of the brain. Descending fibers from the motor cortex proceed downwards, relay in the anterior hypothalamus and midbrain. Fibers from the hypothalamus and midbrain descend through the brainstem without relay, to end on specific lateral horn cells in the spinal cord. These lateral horn cells send preganglionic fibers which activate the postganglionic sympathetic vasodilator fibers. Thus, this sympathetic vasodilator system is not under the control of the vasomotor center. It helps to increase the blood flow through skeletal muscles during exercise.


In addition, this system is activated by sudden strong emotions which may lead to widespread vasodilation → severe hypotension → brain ischemia → syncope (transient loss of consciousness).
Other sympathetic cholinergic vasodilator fibers are those which supply sweat glands. Their activity is controlled by the heat loss center in the anterior hypothalamus. Another example of sympathetic cholinergic fibers is those which supply piloerector muscles of the hairs.
B- The parasympathetic vasodilator system
All parasympathetic nerves contain vasodilator fibers except the oculomotor nerve. The vasodilator fibers in the vagus are generally weak, but parasympathetic stimulation has almost no effects on most blood vessels.
C- The somatic vasodilator fibers
These are fibers of the cutaneous pain-conducting nerves. They are short branches which emerge from the main-stem nerve fibers near their termination in the skin. They supply the cutaneous blood vessels. Their chemical transmitter is substance P which is a strong vasodilator.

The resting tones to the heart:

The VCC and CIC are normally continuously active during rest leading to tonic discharge to the heart known as the sympathetic and vagal tones respectively.
* The resting sympathetic tone to the heart
This is positively inotropic (increasing the ventricular pumping power 20-25 %) and positively chronotropic (tending to increase the heart rate to about 120 beats /minute). However, the chronotropic effect is antagonized by the stronger vagal tone. So blocking the sympathetic activity reduces the ventricular pumping power only but doesn't decrease the normal heart rate.
* The resting parasympathetic tone to the heart (vagal tone)
The inhibitory vagal tone is the continuous discharge of impulses in the vagus nerves at the SA node during rest, reducing its rhythmicity; decreasing the heart rate to about 72 beats/min. which is well below the inherent rate of SA node rate that is of 100 beats/minute. It doesn't affect the ventricular pumping power (because the vagi don't supply the ventricles). Thus, vagotomy increases the heart rate to about 120 beats per minute (because of the dominance of sympathetic tone). In other words, in resting state, there is more parasympathetic activity (vagal tone) to the heart than sympathetic, so the normal resting heart rate is of 72 beats/minute.

Vasomotor tone: (the resting tone to the blood vessel)

Under normal conditions, the vasoconstrictor area of the vasomotor center transmits a continuous discharge of impulses to the vasoconstrictor neurons in the lateral horn of the spinal cord and in turn to the sympathetic vasoconstrictor nerve fibers, maintaining a partial state of contraction in the blood vessels, keeping the normal level of arterial pressure.

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Lect. 9


The heart rate
Objectives:
Define heart rate.
Summarize the factors that regulate heart rate.
The heart rate refers to the ventricular rate of beating per min. It can be determined by counting the arterial radial pulse, the heart sounds (using the stethoscope) or the number of cycles in an ECG record /minute. Normally, it averages 72 beats/minute (range 60-100 beats/minute) in young adult males during rest. Heart rate higher than 100 beats/minute is called tachycardia and a rate lower than 60 beats/minute is called bradycardia. Mechanisms that affect the cardiac rate are said to have a chronotropic effect (chrono = time). Those that increase cardiac rate have a positive (+ve) chronotropic effect (B2 agonists (Salbutamol;Ventolin)); those that decrease the rate have a negative (-ve) chronotropic effect (B blockers (Propranolol; Inderal).
The heart rate is basically determined by the strength of the vagal tone, and is normally subjected to many physiological variations such as:
It is about 120 beats/minute in newly born infants (due to absence of the vagaltone) then it decreases to about 72 beats/minute at the age of 20 years.
It is more in females than in males (due to less vagal tone in females).
It is slowest in athletes (due to a stronger vagal tone than in sedentary persons).
It sometimes shows diurnal variations (being lowest in the early morning).
Regulation of the heart rate:
The heart rate is regulated (SA node discharge) by the following factors:
SA node activity.
Chemical.
Neural.



Figure: Factors that influence the heart rate.
Nervous regulation of the heart rate:
The heart receives both sympathetic and parasympathetic (vagal) nerves. Activity in the sympathetic nerves increases the heart rate, while activity in the parasympathetic nerves decreases the heart rate.
Functions of the cardiac sympathetic nerves
The sympathetic nerves supply all parts of the heart (atria, ventricles, conduction system and the coronary vessels). When activated, they lead to the following:
A- An increase in:
Heart rate (+ve chronotropic effect).
Contractility (+ve inotropic effect).
Excitability (causing extrasystole or paroxysmal tachycardia)
Conductivity (thus decreasing the AV nodal delay).
B- An increase of the cardiac output.
C- Vasodilation of the coronary vessels (by the effect of the metabolites formed asa result of the increased myocardial activity).
Functions of the cardiac parasympathetic nerves
They supply atria, SA & AV nodes and coronary vessels but not the ventricles. When activated, they lead to depression of all cardiac properties, resulting in a decrease of:
- Rhythmicity i.e. the heart rate (-ve chronotropic effect).
- Atrial contractility (-ve inotropic effect).
- Atrial excitability (terminate an attacks of atrial tachycardia or extrasystole).
- Conductivity (prolongs AV nodal delay).
2- A decrease of the cardiac output.
3- Vasoconstriction of the coronary vessels (secondary to decreased metabolite formation due to the decreased cardiac activity).
The heart rate is nervously regulated through the cardiovascular centers which control the sympathetic and parasympathetic discharge to the heart. The activity of these centers is affected by:
A- Higher centers.
B- Reflexes.
Higher centers:
(1) The cerebral cortex. Cortical influence on heart rate is evident in emotions (the heart rate is altered on seeing, hearing or thinking of a certain event).
(2) The hypothalamus and limbic system. These structures (with the cortex) are concerned with emotional reactions. Most emotions are associated with tachycardia and vasoconstriction which increases the arterial blood pressure (ABP), (e.g. before starting a race, or examination) but some are associated with bradycardia and vasodilation which decreases the ABP (e.g. when hearing shocking news).
(3) The respiratory center. Respiratory sinus arrhythmia; this term refers to the increase of the heart rate during inspiration and to the decrease of heart rate during expiration that occurs normally in young subjects and children. The tachycardia that occurs during inspiration is due to; excitation of the vasoconstrictor center (VCC) by the inspiratory center, and Bainbridge reflex which is initiated during inspiration by rise of the right atrial pressure as a result of increase of the venous return.
Reflexes:
Bainbridge reflex (atrial stretch reflex)
An increase in the right atrial pressure or increased distention of the right atrium leads to heart acceleration. Impulses are discharged mostly from atrial receptors via afferent nerve fibers to the medullary VCC leading to reflex increase in sympathetic tone to the heart, increasing the heart rate.
Baroreceptor reflex
This reflex is initiated by stretch receptors, which are located in the carotid sinus and aortic arch. They are stimulated when stretched; signals from the carotid arteries are transmitted through the glossopharyngeal nerves while signals from the arch of aorta are transmitted through the vagus nerves into; the cardiovascular centers.
The baroreceptor signals inhibit the vasoconstrictor center and excite the vagal center (CIC) resulting in vasodilation, decreased heart rate. In other words, a rise in arterial blood pressure produces reflex decrease in heart rate whereas a fall in arterial blood pressure produces reflex increase in heart rate.
The carotid sinus reflex
An external pressure on the carotid sinus area (behind the angle of the mandible) produces reflex slowing of the heart rate and peripheral vasodilation. The applied external pressure stimulate the baroreceptors in the carotid sinus which leads to reflex increase in the vagal tone to the heart (bradycardia) and decrease in the sympathetic vasoconstrictor tone (vasodilation). On the same basis, an attack of paroxysmal atrial (but not ventricular) tachycardia can be terminated by initiating a carotid sinus reflex, through external massaging of the carotid sinus. A strong blow on the carotid sinus area could lead to complete cardiac arrest. Some individuals pathologically have an abnormal hypersensitivity of the carotid sinus. Thus, mild pressure on the carotid sinus area e.g. during shaving or by a tight collar, produces bradycardia and generalized vasodilation, which may markedly decrease the cardiac output and arterial blood pressure resulting in brain ischemia and fainting. Such cases can be treated by anticholinergic drugs (Atropine) to block the vagal discharge to the heart.


Chemical regulation of the heart rate:
Effect of changes in blood gases.
Hypoxia.
Hypercapnia and acidosis.
Hypoxia:
Moderate hypoxia (O2 lack) increases the heart rate by 3 mechanisms:
Direct mechanism (by stimulating the SA node pacemaker cells).
Central mechanism (by inhibiting the CIC).
Reflex mechanism (by stimulating the VCC through exciting the peripheral chemoreceptors in the carotid and aortic bodies.
On the other hand, severe hypoxia causes reduction of the heart rate due to inhibition of the SA node activity and paralysis of the medullary cardiovascular centers.

Hypercapnia and acidosis:

A moderate hypercapnia (CO2 excess) and acidosis (increased H+ ion concentration) increase the heart rate by the following mechanisms:
Inhibition of the CIC.
Stimulation of the VCC through exciting the peripheral chemoreceptors.
Stimulation of the VCC through exciting the central chemoreceptors.
On the other hand, severe hypercapnia or acidosis decreases the heart rate due to inhibition of SA node activity and paralysis of medullary cardiovascular centers.

B- Effects of hormones, drugs and chemicals:

Adrenaline; Small doses increase the heart rate by a direct action on the beta one (B1) receptors in the SA node.
Thyroxine: This increases the heart rate by direct stimulation of the SA node and increasing its sensitivity to catecholamines.
Atropine: This accelerates the heart by blocking parasympathetic activity.
Histamine: This is a potent vasodilator (VD) substance which leads to marked drop of the ABP, resulting in heart acceleration.
Bile salts: inhibit SA node activity & stimulate the CIC leading to bradycardia.
Autonomic drugs: Sympathomimetic drugs (amphetamine) cause tachycardia while parasympathomimetic drugs (acetylcholine) cause bradycardia.


SA node activity:
Factors that directly affect the SA node activity:
Body temperature; (physical factors) An increase of the body temperature by 1 C increases the heart rate by 10-20 beats/minute and vice versa.
Mechanical factors; Right atrial distension may directly excite the SA node leading to tachycardia.
Chemical factors; The SA node is directly excited by mild hypoxia, Catecholamines, thyroxine, while it is directly inhibited by severe hypoxia and hypercapnia, bile salts, and cholinergic drugs.
Thyroid hormones (T3, T4) again have direct action on SA node. Increases in the level of circulating thyroid hormones increases the rate at which SA node beats e.g., in case of Thyroitoxicosis disease, there is an increase in heart rate, (resting tachycardia; HR > 100 beats/minute).

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Lect. 10

Stroke Volume

Objectives:
Describe how a change in preload, afterload, and myocardial contractility will affect cardiac performance.
Stroke volume (SV) is defined as the amount of blood pumped out by each ventricle per beat. It is about 70 ml/beat at rest but may increase to 150 ml/beat with exercise.
The stroke volume equals to the amount of blood present in the ventricle when systole starts just before the initiation of ventricular contraction. However, the ventricles dont completely empty themselves of blood during contraction (2/3 of blood is ejected, 1/3 is left there) therefore, a more forceful contraction can produce an increase in stroke volume.
Substruction of end-systolic volume (ESV) from end-diastolic volume (EDV) produce stroke volume (SV).
SV = EDV - ESV.
EDV: the ventricular blood volume at the end of the diastole; normally EDV = 110 to 120 ml.
ESV: the ventricular blood volume at the end of the systole; normaly ESV = 40 ml.
* Strok volume = 70 to 80 ml.
Regulation of Stroke Volume
The stroke volume is regulated by three variables:
The end-diastolic volume (EDV).
Sympathetic nervous system input to the ventricles (myocardial contractility; strength of ventricular contraction).
The total peripheral resistance.


The end-diastolic volume is the amount of blood in the ventricles immediately before they begin to contract (preload). The stroke volume is directly proportional to the preload; an increase in EDV results in an increase in stroke volume. This relationship is known as the Frank-Starling law. In other words, the ventricle contracts more forcefully during systole when it has been filled to a grater degree during distole.

The stroke volume is also directly proportional to the myocardial contractility which is influenced by cardiac sympathetic nerves (norepinephrine) and circulating epinephrine secreted from adrenal medulla. Thus, when the ventricles contract more forcefully as a result of sympathetic nerve stimulation or epinephrine which is independend of a change in end-diastolic ventricular volume, they pump more blood (increased stroke volume).

The total peripheral resistance which is the impedance to blood flow in the arteries (aortic impedance). The pressure in the arterial system before the ventricle contracts is, in turn, a function of the total peripheral resistance. The higher the peripheral resistance, the higher the pressure. Thus, an increased arterial pressure tends to reduce stroke volume. The total peripheral resistance thus presents an impedance to the ejection of blood from the ventricle, or an afterload imposed on the ventricle after contraction. This means that the stroke volume is inversely proportional to the total peripheral resistance; the greater the peripheral resistance, the lower the SV.

Ejection Fraction (EF%):

The proportion of the end-diastolic volume that is ejected against a given afterload depends on the strength of ventricular contraction. Normally, contraction strength is sufficient to eject 70 to 80 ml of blood out of a total end-diastolic volume of 110 to 120 ml (2/3 of blood is ejected). The ejection fraction is thus about 65%.
In other words, the ejection fraction is the ratio of stroke volume to end-diastolic volume (EDV) and it reflects the ventricular contractility, expressed as percentage, normally it averages at rest 65% (again, about 2/3 of the EDV is ejected).
Increased ventricular contractility causes an increase in ejection fraction.
EF% = SV / EDV X 100.
EF% = 80/120 X 100 = 2/3 %. (more than 55% considered as normal).
In heart failure, the EF is reduced; < 50%.
EF can be measured by Echocardiogram (Echo) that can measure the EDV, ESV and so the SV.

Myocardial contractility:

It is defined as the strength of contraction at any given EDV.
Myocardial contractility exerts a major influence on stroke volume and in turn on the cardiac output. It is reduced in heart failure.
It is measured by Ejection Fraction.
Myocardial contractility is affected by the following factors :
The preload (i.e., EDV): controls the power of cardiac contractility by Frank-Starling's law.
Sympathetic nerve supply: The resting cardiac sympathetic tone increases thecardiac pumping power to 13-15 litres/minute, and maximal sympathetic stimulation (e.g. in severe muscular exercise) increases it to about 25 litres/ minute.
The afterload (i.e., aortic impedance): An increase in the afterload(e.g. due to rise of the arterial blood pressure, aortic stenosis or polycythaemia) reduces the cardiac pumping power, and vice versa.
Ventricular hypertrophy; This may normally occur in some athletes as a result of prolonged strenuous exercises, and it can increase the cardiac pumping power up to about 35 litres minute.


Cardiac compliance:
It is the stretchability, elasticity, it is the change in volume per unit change in pressure = ∆V/∆P, decreased compliance in which there is a myocardial stiffness, this is in disease condition which will affect cardiac output as in cases of cadiomyopathies, and pericardial effusion.

Afterload:

It is the resistance that oppose cardiac output, e.g., increased arterial systolic pressure (systolic hypertension), valve disease that obstruct the outflow of blood as in case of aortic stenosis disease. So increased afterload will reduce cardiac output.
On the other hand, reduced total peripheral resistance (reduced afterload) causes high cardiac output. Conditions that can decrease the total peripheral resistance and at the same time increase the cardiac output to above normal include:

1. Beriberi. This disease is caused by insufficient quantity of the vitamin thiamine (vitamin B1) in the diet. Lack of this vitamin causes diminished ability of the tissues to use some cellular nutrients, and the local tissue blood flow mechanisms in turn cause marked compensatory peripheral vasodilation. Sometimes the total peripheral resistance decreases to as little as one-half normal. Consequently, the long-term levels of venous return and cardiac output also often increase to twice normal.

2. Arteriovenous fistula (shunt, also called an AV shunt): occurs between a major artery and a major vein, in which blood flow directly from the artery into the vein. This greatly decreases the total peripheral resistance and, likewise, increases the venous return and cardiac output.

3. Hyperthyroidism. In hyperthyroidism, the metabolism of most tissues of the body becomes greatly increased. Oxygen usage increases, and vasodilator products are released from the tissues. Therefore, the total peripheral resistance decreases markedly because of the local tissue blood flow control reactions throughout the body; consequently, the venous return and cardiac output often increase to 40 to 80 percent above normal.

4. Anemia. In anemia, two peripheral effects greatly decrease the total peripheral resistance, as a consequence, the cardiac output increases greatly. One of these is reduced viscosity of the blood, resulting from the decreased concentration of red blood cells. The other is diminished delivery of oxygen to the tissues, which causes local vasodilation.

Low cardiac output: (Abnormalities)

Fainting: low cardiac output leads to ischemia of the brain; causing fall down (fainting). It is a protective mechanism to correct the brain ischemia through increasing blood supply to the brain.
Shock: also low cardiac output that may cause hypotension, again leading to ischaemia to the brain.

Methods for measuring cardiac output:

In animal experiments, cardiac output can be measured using any type of flowmeter (electromagnetic, or ultrasonic flowmeter) which can be placed on the aorta or pulmonary arteries i.e., blood flow in the root of aorta can be recorded by an electromagnetic flowmeter.
In the human, CO is measured by indirect methods that do not require surgery.
Two methods commonly used are:
The oxygen fick method.
The indicator dilution method.
Another method is by Echocardiography; it consists of emitting Ultrasonic waves to the heart. Such echoes record the ventricular movements, from which both the EDV and ESV and so the SV can be calculated. The CO then can be measured by multipling the SV X HR.
..
ESV ( contractility and afterload.
EDV ( cardiac compliance and preload (venous return).


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Lect. 11

Cardiac output
Objectives:
Define cardiac output, heart rate, and stroke volume.
Describe how heart rate and stroke volume interact to control cardiac output.
state the influence of venous return on cardiac output.
Define the terms preload, and afterload.
Cardiac output is the amount of blood pumped by each ventricle per minute, expressed in liters/minute. Normally, it is about 5 liters per minute.
The cardiac output (CO) is determined through multiplying the heart rate (HR) by the stroke volume (SV).
CO = HR X SV
Heart rate = the number of heart beats/minute (aveage; 72 beat/minute).
Stroke volume = the volume of blood ejected by each ventricle with each beat.
If the HR = 72 beats/min., and the SV is of 70 ml;
Cardiac output = 72 X 70 = 5.04 Liters.
As the cardiovascular system is a closed system, cardiac output of the left ventricle equals to the cardiac output of the right ventricle i.e., the two sides of the heart have the same output per minute. It is also the volume of blood flowing through either the systemic or pulmonary circulation per minute. In other words, cardiac output is the quantity of blood pumped into the aorta each minute by the heart. This is also the quantity of blood that flows through the circulation.
cardiac output= arterial blood flow = pulmonary blood flow.
Cardiac output varies widely with the level of activity of the body. Therefore, the level of body metabolism, exercise, age and size of the body influence the cardiac output. For young, healthy men, the resting cardiac output averages about 5.6 liter/min., for young women, this value is 10-20% less, but it is not constant. It might be increased even up to 30 liters/min., depending on the activity of the body. Therefore, cardiac output is a variable parameter usually it is not less than 5 liter/min., at rest to supply the body with oxygen and to maintain normal BMR (basal metabolic rate). The highest cardiac output recorded is 48 liters/min., in the Roadrunners (Hyperdynamic circulation which mean the same blood volume; 5 liters circulating at a higher speed). Blood volume is about 5 - 6 liters. So the heart pumps the whole blood in one minute.


Control of cardiac output:
The cardiac output is controlled (either increased or decreased or maintained) by the following factors.
Venous return (preload).
Heart rate (HR)
Myocardial contractility.
Cardiac compliance.
Afterload.

Venous return:

The venous return (VR) is the amount of the blood flowing from the tissues into the veins and then into the right or left atrium each minute. So in steady state, they are equal (CO = VR) because what is pumped out from the left ventricle equals to what returned to the right side of the heart. In other words, It is the quantity of blood flowing from the veins into the right atrium each minute. It represents the preload. The venous return and CO must be equal to each other.

The CO is controlled by venous return through the following mechanisms:

Frank-Starling law; the heart pumps automatically whatever amount of blood flows into the right atrium from the veins. This law states that when increased quantities of blood flow into the heart, this stretches the walls of the heart chambers. As a result of the stretch, the cardiac muscle contracts with increased force to empty the expanded chambers i.e. the extra blood that flows into the heart (VR) is automatically pumped without delay into the aorta and flows again through the circulation.

The effect of the venous return on the heart rate by mean of stretching the heart. Stretch of the SA node in the wall of the right atrium has a direct effect on the rhythmicity of the SA node itself to increase heart rate 10 15% .

Another factor, the stretched right atrim initiates a nervous reflex called the Bainbridge reflex, passing first to the medullary vasomotor center and then back to the heart by sympathetic nerves, to increase the heart rate. The increase in the heart rate then helps to pump the extra blood.

Decrease in Cardiac Output Caused by Decreased Venous Return.

Anything that interferes with venous return also can lead to decreased cardiac output. Some of these factors are the following:
1. Decreased blood volume.
Resulting most often from hemorrhage. Loss of blood decreases the filling of the vascular system to such a low level that there is not enough blood in the peripheral vessels to create peripheral vascular pressures high enough to push the blood back to the heart.

2. Acute venous dilation.

In case of sudden and acute vasodilatation especially the peripheral veins involved. This results most often when the sympathetic nervous system suddenly becomes inactive. For instance, fainting often results from sudden loss of sympathetic nervous system activity, which causes the peripheral vessels, (veins), to dilate markedly. This decreases the filling pressure of the vascular system because the blood volume can no longer create adequate pressure in the flaccid peripheral blood vessels. As a result, the blood pools in the vessels and does not return to the heart.

3. Obstruction of the large veins.

When the large veins leading into the heart become obstructed, so that the blood in the peripheral vessels cannot flow back into the heart. Consequently, the cardiac output falls markedly.

4. Decreased tissue mass, especially decreased skeletal muscle mass.

With normal aging or with prolonged periods of physical inactivity, there is usually a reduction in the size of the skeletal muscles. This, in turn, decreases the total oxygen consumption and blood flow needs of the muscles, resulting in decreases in skeletal muscle blood flow and cardiac output.

* Regardless of the cause of low cardiac output, if the cardiac output falls below that level required for adequate nutrition of the tissues, the person is said to suffer circulatory shock. This condition can be lethal within a few minutes to a few hours.

Heart rate and cardiac output:

In resting state, (the venous return is constant), changes in heart rate between 100-200 beats/min., not affect CO markedly. However, high heart rate (more than 200 beats/minute) in patient with ventricular tachycardia (VT) or supraventricular tachycardia (SVT) may affect CO to be insufficient to maintain the nutritional needs of the body because such increase in heart rate will reduces the duration of ventricular diastole and so reduce the time available for ventricular filling that will reduce the stroke volume. On the other hand, slow heart rate may also reduce CO, as in complete heart block disease (HR < 40 beats/minute).

In exercise, (the venous return is increased), cardiac output is increased to meet the body need by increasing in both heart rate and stroke volume, the increase in heart rate is through sympathetic stimulation as the exercise is a stressful situation, while the increase in stroke volume is through the increase in venous return by the action of skeletal muscles that squeezed and pumped the blood toward the heart, and through the increased myocardial contractility.
So, the heart rate is effective in increasing the CO if the venous return is increased, otherwise the stroke volume will be decreased and so the decreased CO.


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Lect. 12

Arterial blood pressure
Objectives:
Define the terms systemic arterial pressure, systolic pressure, diastolic pressure, pulse pressure, and mean arterial pressure.
Describe the principles and application of sphygmomanometry for the measurement of systemic arterial pressure.
State the influence of decreased aortic distensibility, increase in heart rate, and increase or decrease in peripheral resistance on systolic and diastolic systemic arterial pressures.

Arterial blood pressure is the pressure exerted by the blood on the arterial walls (BP). It normally fluctuates during the cardiac cycle between a maximum called the systolic blood pressure (SBP) and a minimum called the diastolic blood pressure (DBP).
The systolic BP normally averages 120 mmHg in young adult males (range 90 -140 mmHg), and is produced by ejection of blood into the aorta during left ventricular systole (>140 represents systolic hypertension). The diastolic BP normally averages 80 mmHg (range 60 - 90 mmHg), and is produced as a result of the elastic recoil of the aorta during ventricular diastole (> 90 mmHg represents diastolic hypertension).
The arterial blood pressure (ABP) is often reported as the systolic over the diastolic pressure (e.g. 120/80). BP value less than normal lower limit called hypotension (e.g. SBP < 90 mmHg).
Pulse pressure: The difference between both the systolic and diastolic BP and it normally averages 40 mmHg.
Pulse pressure = systolic BP diastolic BP =120 80 = 40 mmHg.

The mean arterial blood pressure:

Mean BP = Diastolic BP + 1/3 pulse pressure = 80 + 13 = 93 mmHg.

Importance (function) of the arterial blood pressure:

It maintains tissue perfusion (i.e. blood flow) throughout various tissues, including those lying above the heart level (in spite of the force of gravity).
It produces the capillary hydrostatic pressure, which is the main force concerned with tissue fluid formation (interstitial fluid).
The diastolic blood pressure performs the following functions:
It maintains blood flow to the tissues during ventricular diastole (thus the blood flow to the tissues becomes continuous, not intermittent).
It is essential for the normal coronary blood flow.
It prevents blood stasis in the arteries during ventricular diastole.


JJJIMeasurement of the arterial blood pressure:
This is performed by the sphygmomanometer apparatus, which consists of an inflatable rubber cuff connected to a mercury manometer. The cuff can be air inflated by a small hand pump (bulb), and deflated by opening the attached air-control valve. This apparatus can measure the arterial BP by 2 methods:
1-Palpatory method
This is an inaccurate method that measures the systolic pressure only. The cuff is wrapped around the arm so that it surrounds the brachial artery. The radial pulse is then palpated by the middle 3 fingers of one hand, and then the cuff is inflated by the other hand till the pulse disappears (indicating complete obstruction of the brachial artery). The cuff is then slowly deflated by opening the air-control valve while the radial pulse is still palpated, till it first becomes palpable. At this moment, the level of the column of mercury represents the systolic blood pressure which is equal to the cuff pressure. Diastolic BP can not measured by this method.
2-Auscultatory method
This is an accurate method that measures both the systolic and diastolic blood pressures. The cuff is wrapped around the arm and the stethoscope is placed just below it on the brachial artery at the medial side of the biceps tendon in the anticubital fossa. The cuff is inflated; elevating the column of mercury to a level higher (20-30 mmHg), till the radial pulse become impalpable indicating obstruction of the brachial artery, and then it is slowly deflated. As the cuff pressure falls, certain sounds called korotkow's (Korotkoff's) sounds are heard along with the heart beats. These sounds are produced as a result of turbulent blood flow in the brachial artery and their quality changes in 5 steps:
1- When the cuff pressure becomes just below the systolic pressure, a spurt of blood passes through the narrowed brachial artery producing intermittent turbulence; heard as tapping sounds (1st korotkow's sound). The height of mercury column when the first sound is heard represents the arterial systolic blood pressure.
2- As the cuff pressure is lowered, the sounds become murmur-like.
3- With further lowering of the cuff pressure, the sounds become louder.
4- When the cuff pressure approaches the diastolic pressure, the turbulent flow becomes continuous (because the vessel is still constricted), and the sounds become dull and muffled (4th korotkow's sound). The height of mercury column when the muffled sound is heard represents the arterial diastolic blood pressure.
5- When the cuff pressure becomes lower than the diastolic pressure, the sounds disappear because the blood flow becomes continuous but not turbulent (silent, laminar flow; 5th korotkow's sound).

The systolic pressures obtained by the palpatory method are usually 2-5 mmHg lower than those measured by the auscultatory method because:
The finger's sensitivity cannot determine exactly when the first beat is felt.
As the blood travels the distance from the cuff to the wrist, the cuff pressure is further decreased, thus recording a lower systolic pressure.

The silent gap:

During measuring the arterial BP by the auscultatory method, sometimes (especially in hypertension) the korotkow's sounds disappear (after 2nd korotkow's sound) for a variable gap at pressures well above the diastolic pressure then reappear again (3rd korotkow's sound). This occurs due to unknown causes and may lead to recording of false low systolic pressure values (3rd korotkow's sound) if the sounds above the gap are missed and only those below the gap are heard. However, this is avoided by:
(a) Palpating the radial pulse while inflating the cuff till it disappears (in this case, the cuff pressure is certainly above the systolic pressure)
(b) Determining the systolic pressure first by the palpatory method, then raising the cuff pressure above the recorded value.




Figure: Silent interval in severe hypertension, it is not normally present.

Physiological factors that affect the arterial blood pressure:

Age: The arterial BP is very low at birth (about 70-80/40-50 mmHg) then it rises progressively till about 120/80 mmHg at the age of 20 years. Its rise continues gradually after that age, but its rate increases markedly after the age of 40 years due to the normal gradual loss of arterial elasticity, so that it becomes normally about I50/90 mmHg after the age of 60years.
Sex: The arterial BP is generally slightly higher in adult males than in females. However, it becomes slightly higher in females after the menopause.
Body region: The arterial BP is normally higher in the lower limbs than in the upper limbs.
Body built: The arterial BP is usually high in obese persons.
Race: The arterial BP is often high in western countries (probably due to genetic factors, but stress, environmental or dietary factors may contribute).
Diurnal variation: The arterial BP is normally lowest in the early morning and highest in the afternoon.

Meals: The arterial BP increases slightly after meals (especially the systolic) due to vasodilatation (VD) in the splanchnic area, which increases both the venous return (VR) and cardiac output (CO).
Exercise: The arterial BP markedly increases during exercise, especially the systolic (the diastolic pressure is often not changed or even decreases).
Emotions: The arterial BP increases considerably in most emotions especially the systolic (due to increased sympathetic stimulation).
Intercourse: The systolic BP often increases during intercourse.
Sleep: The arterial BP is often slightly decreased during quiet sleep (due to decrease of the sympathetic activity) but it may increase during nightmares.
Environmental temperature: In hot environments, the systolic pressure may increase slightly due to tachycardia, but the diastolic pressure often fells due to cutaneous VD. On the other hand, exposure to cold increases both the systolic and diastolic pressures due to cutaneous vasoconstriction (VC).
Gravity: On standing, the force of gravity increases the mean arterial pressure and the venous pressure below a reference point in the heart (in the right atriurn) and decreases them above that point by about 0.77 mmHg.
Respiration: The arterial BP shows rhythmic fluctuations during the respiratory cycle. It is decreased during inspiration (although the systemic VR and right ventricular CO are increased) because the lung vascular capacity is increased and accommodates most of the right ventricular CO, so the pulmonary VR is decreased resulting in reduction of both the left ventricular CO and the arterial BP. It is then increased during expiration due to squeeze of the pulmonary vascular bed (which increases the pulmonary VR and left ventricular CO).


Factors that determine and maintain the blood pressure:  1- Cardiac output (CO).
2- Total peripheral resistance (PR).
3- Elasticity of the aorta and large arteries.
4- Blood volume and circulatory capacity.

The cardiac output and the total peripheral resistance are the most important factors affecting blood pressure. In other words, the blood pressure is determined by the cardiac output multiplied by the peripheral resistance.

BP = CO X PR

1-Cardiac output:
The arterial BP is directly proportionate to the CO, which equals the product of the stroke volume (SV) multiplied by the heart rate (HR).
CO = SV X HR
Effect of changes in the stroke volume on the blood pressure:
With a constant HR, an increase in the SV raises systolic pressure with no significant change in diastolic pressure. The opposite occurs when the SV is decreased.
Effect of changes in the heart rate on the blood pressure:
With a constant venous return, an increase in the HR raises mainly the diastolic pressure with no significant change in the systolic pressure. The rise of the diastolic pressure is due to shortening of the diastolic periods (which leads to blood accumulation in the arteries, thus preventing fall of the diastolic pressure to the normal level). On the other hand, the constant systolic pressure is due to the decreased ventricular filling which decreases the SV. The opposite occurs when the HR is decreased.

2- Total peripheral resistance:

It is the sum of all the vascular resistances within the systemic circulation.
The PR is essential for maintenance of the arterial B.P. particularly the diastolic pressure. It is produced mainly in the arterioles and is determined by 3 factors:
(a) The radius (or diameter) of the vessel.
(b) Blood viscosity.
(c) The length of the vessel.
Normally the total peripheral resistance can only be determined by the arteriolar diameter, because the other 2 factors are normally kept constant.


3- Elasticity of the aorta and large arteries:
Part of the pumping energy of the heart is expended in distension of the aorta & large arteries. This energy is released during cardiac diastole causing elastic recoil of the walls of these vessels. Such effect is essential for production and maintenance of a relatively high diastolic BP. In addition to maintenance of a high diastolic pressure, the elasticity of the aorta and large arteries also prevent excessive rise of the systolic BP. This is clear when there is rise in the systolic pressure in severe arteriosclerosis in which the elasticity of the aorta and large arteries is lost and the blood flow to the tissues becomes rather intermittent i.e. mainly during systole.
4- Blood volume and circulatory capacity:
These parameters are major factors in maintenance of the arterial BP especially the systolic BP as follows: When the blood volume increases (e.g. in diseases associated with excessive salt and water retention), the venous return is also increased leading to an increase of both the EDV and SV, thus the systolic pressure rises. Conversely, when the blood volume decreases (e.g. after a severe haemorrhage), the venous return, EDV and SV are also decreased, thus the systolic BP falls.

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Lect. 13

Regulation (control) of the arterial blood pressure:

Objectives:
Draw a "box and arrow" diagram illustrating the arterial baroreceptor reflex.
Describe the changes in blood pressure while going from lying to standing position.
Draw a diagram illustrating the mechanism that control the arterial BP by adjusting the body fluids and blood volume through modifying the excretion of water and salt by the kidneys.

Whenever the arterial BP is altered, the following 3 mechanisms respectively restore it to the normal level.
Short-term mechanisms.
Intermediate-term mechanisms.
Long-term mechanisms.




Short-term mechanisms
These are potent mechanisms, they act within a few seconds after alteration of the BP and their action lasts for several hours. They are mostly nervous reflexes that adjust the vascular capacity and resistance as well as the cardiac pump.
(1) Arterial baroreceptor reflex:
It is a neural reflex that maintains normal arterial pressure. This reflex is initiated by stretch receptors, which are located in the carotid sinus and aortic arch.
Signals from the carotid arteries are transmitted through the glossopharyngeal nerves while signals from the aortic arch are transmitted through the vagus nerves into; the medullary cardiovascular centers. They are stretch receptors that discharge when the arterial BP increases, in which case they discharge signals leading to stimulation of the CIC (resulting in reflex bradycardia) and VDC (resulting in generalized vasodilation) and inhibition of the VCC. Therefore, an increase in the arterial pressure increased the discharge rate of the baroreceptors, which reflexly decreases the arterial pressure because of both a decrease in peripheral resistance (vasodilation) and a decrease in cardiac output (CO).
In other word, when the arterial pressure decreases e.g. on sudden standing after prolonged recumbency or in case of hemorrhage, the discharge rate of the barorecrptors to the medullary cardiovascular center is decreased. This induces:
Increased heart rate because of increased sympathetic and decreased parasympathetic activities to the heart.
Increased ventricular contractility because of increased sympathetic activity to the ventricular myocardium.
Vasoconstriction (arteriolar and venous) because of increased sympathetic activity to the arterioles and veins.
The net result is an increased cardiac output (increased heart rate and stroke volume), increased total peripheral resistance (arteriolar constriction), and a return of blood pressure toward normal.






Figure: Baroreceptor reflex that help to maintain an adequate blood pressure upon standing (- ve feedback control of BP).

(2) Arterial chemoreflexes:

The receptors of these reflexes are located in the carotid and aortic bodies, and they are stimulated when the arterial BP is reduced below 60 mmHg (mainly as a result of local ischemia and hypoxia), in which case they discharge signals leading to stimulation of the VCC and inhibition of the CIC and VDC. This causes elevation of the arterial BP by increasing:
The cardiac pumping power and CO (by the resulting tachycardia).
The peripheral resistance (by the generalized Vasoconstriction (VC)).
Catecholamine secretion from the adrenal medullae.
(3) Release of adrenal medullary catecholamines:
Hypotension stimulates the release of adrenaline and noradrenaline from the adrenal medulla. Adrenaline improves the cardiac pumping by stimulating the myocardial contractility and rhythmicity. In high doses, adrenaline produces general vasoconstriction and increase the peripheral resistance. Noradrenaline is a strong vasoconstrictor. The two catecholamines act to raise a low blood pressure back toward normal.
(4) The CNS ischemic response:
In cases of reduction of the arterial BP below 60 mmHg, brain ischemia occurs. The resulting local hypoxia (and to a little extent also hypercapnia and acidosis) stimulate the VCC, resulting in generalized VC which elevates the arterial BP and maintains the cerebral blood flow.
(5) The abdominal compression reflex:
Whenever the VCC is stimulated the medullary reticular formation is simultaneously excited and sends signals in the somatic nerves to skeletal muscles, specially the abdominal muscles, leading to an increase of their tone. This is an important mechanism to raise the arterial BP since it increases the intraabdominal pressure, which compresses the abdominal veins resulting in an increase of the venous return and consequently, the CO (which helps elevation of the arterial BP).
Intermediate-term mechanisms
These mechanisms control the arterial BP by adjusting the vascular capacity and resistance as well as the blood volume. They act within a few minutes after alteration of the BP and their action lasts for several days. During this time, the nervous, rapid short-term mechanisms usually fatigue and become less effective. They include the following:
(1) Capillary fluid shift mechanism:
This mechanism occurs especially when the arterial BP is altered as a result of changes in the blood volume. An increase in the blood volume increases the capillary hydrostatic pressure, and this helps fluid filtration into the tissue spaces, thus the blood volume is decreased leading to reduction of the arterial BP toward the normal level.
(2) Stress relaxation mechanism:
A rise of the arterial BP stretches the arteries and increases the tension in their walls. However, after sometime (varying from a few minutes to a few hours) the arteries relax and the tension in their walls decreases. This is called stress relaxation of the arteries, and it helps lowering of the arterial BP.
(3) Renin-angiotensin vasoconstriction mechanism:
A fall of the arterial BP leads to renal ischemia. This stimulates secretion of a hormone called renin from the juxtaglomerular cells of the kidney, which acts on a plasma ά2 globulin called angiotensinogen (a polypeptide synthesized by the liver) forming angiotensin I. An enzyme called ACE (angiotensin-converting enzyme) converts angiotensin 1 into angiotensin II (especially in the lungs), which has a potent vasoconstrictor effect that helps elevation of the arterial BP
(4) Right atrial mechanism:
This occurs especially when the arterial BP is altered as a result of changes in the blood volume. An increase in the blood volume stimulates the volume receptors in the right atrium resulting in the following effects:
Generalized VD (which decreases the peripheral resistance and increasesthe venous capacity) including VD of the afferent renal arterioles (whichincreases the glomerular filtration, leading to more water and salt excretion).
Reflex inhibition of secretion of the antidiuretic hormone (ADH). This helpswater excretion by the kidney.
The secretion of ANP (atrial natriuretic peptide), this also helps salt and water excretion by the kidney. All these effects help lowering of the arterial BP, and opposite effects (elevation of BP) occur when the blood volume is decreased.
Long-term mechanisms
These mechanisms control the arterial BP by adjusting the body fluids and blood volume through modifying the excretion of water and salt by the kidneys. This occurs by variations in: (a) Glomerular filtration. (b) Secretion of the aldosterone hormone.
A fall of the arterial BP reduces glomerular filtration, so the renal excretion of water and salt is decreased. At the same time, renin is secreted and angiotensin II is formed, which in addition to producing VC, it also stimulates aldosterone secretion from the adrenal cortex, which increases Na+ reabsorption in the renal tubules. These effects increase the body fluids and blood volume, which elevates the arterial BP to the normal level. On the other hand, a rise of the arterial BP increases glomerular filtration, producing pressure diuresis which leads to excessive loss of water and salt in the urine. At the same time, renin secretion is inhibited and angiotensin II is not formed, thus aldosterone secretion is inhibited, leading to loss of Na+ and water in the urine. These effects reduce the arterial BP to the normal level.


Figure: The renin-angiotensin-aldosterone system.
Importance of Salt (NaCl) in the Arterial blood Pressure Regulation:
An increase in salt intake is more likely to elevate the arterial pressure than is an increase in water intake. The reason for this is that pure water is normally excreted by the kidneys almost as rapidly as it is ingested, but salt is not excreted so easily. When the salt accumulates in the body, it increases the extracellular fluid volume for two basic reasons:
1. When there is excess salt in the extracellular fluid, the osmolality of the fluid increases, and this in turn stimulates the thirst center in the brain, making the person drink extra amounts of water to return the extracellular salt concentration to normal. This increases the extracellular fluid volume.
2. The increase in osmolality caused by the excess salt in the extracellular fluid also stimulates the hypothalamic-posterior pituitary gland secretory mechanism to secrete increased quantities of antidiuretic hormone (ADH). ADH then causes the kidneys to reabsorb greatly increased quantities of water from the renal tubular fluid, thereby diminishing the excreted volume of urine but increasing the extracellular fluid volume. Thus, for these important reasons, the amount of salt that accumulates in the body is the main determinant of the extracellular fluid volume. Because only small increases in extracellular fluid and blood volume can often increase the arterial pressure greatly, accumulation of even a small amount of extra salt in the body can lead to considerable elevation of arterial pressure.


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Lect. 14

The microcirculation and the lymphatic system
Objectives:
State (with the aid of diagram) the basic structure of a precapillary sphincter and a capillary.
Define the term oncotic (colloid osmotic) pressure and state how it is conferred to plasma.
State and explain briefly the effects on tissue fluid formation in a vascular bed of: altered capillary hydrostatic pressure, decreased plasma protein concentration, elevated central venous pressure, increased capillary permeability, and obstruction of lymph drainage.
Define the term edema.

Structure of the microcirculation:

The arterioles divide into smaller vessels called metarterioles and true capillaries arise from both the arterioles and metarterioles. The openings of the true capillaries are surrounded by minute smooth muscles called precapillary sphincters which respond well to various stimuli.
Capillaries are generally made up of a single layer of endothelial cells surrounded by a basement membrane and special cells called pericytes, which are contractile cells and also release many vasoactive agents. Capillaries are divided into 3 main types:
1-Continuous capillaries (in all muscles and the brain):
In this type, the edges of the endothelial cells interdigitate forming intercellularclefts (slit pores) between the cells. These pores generally permit passage of molecules. However, their size varies widely in different regions e.g. they are much smaller in the brain than in skeletal muscles; helps the development of a blood brain barrier.
2-Fenestrated capillaries (in the kidneys, intestinal villi and most endocrine glands):
In this type, the cytoplasm of the endothelial cells itself is interrupted, forming gaps called fenestrations that are closed by thin membranes (except in the renal glomeruli) and permit passage of relatively large molecules.
3-Sinusoidal capillaries (in the liver, spleen and bone marrow): In this type, the capillaries (which are called sinusoids) have very wide lumens and are extremely porous because;
Their endothelium is discontinuous.
There are large gaps between the endothelial cells that are not closed by membranes.


.

Trans-capillary exchange mechanisms:

The transport of fluids across the capillary walls occurs by the following mechanisms
Diffusion:
This is the process by which a substance in solution expands to fill all of the available volume. It occurs down a concentration gradient i.e. substances diffuse from areas of high to areas of low concentration. Water and water-soluble substances (e.g. glucose, urea, Na+, Cl- & K+) diffuse only through the slit pores and fenestrae and their rates of diffusion are inversely proportionate to their molecular sizes. On the other hand, fat-soluble substances diffuse across the whole capillary wall i.e. through the pores as well as the cytoplasm of the capillary endothelial cells (since they dissolve in the phospholipid bilayer of the endothelial cell membranes), thus the diffusion of fat-soluble substances and gases (e.g. O2 and CO2) is normally greater and faster than water-soluble substances.
Filtration:
This is the process by which fluid and dissolved solutes are forced through the pores in the capillary membrane due to a difference in hydrostatic pressure on the two sides, and the amount of fluid filtered per unit time is proportionate to:
(a) The difference in pressure.
(b) The capillary surface area and permeability.
The force of filtration is opposed by the force of osmosis, and both forces are concerned with the bulk flow of fluids and solutes across the capillary walls through formation and drainage of the interstitial fluid.
Transcytosis:
This is the mechanism of transport of large molecules across the capillary membrane. These molecules are transported through the capillaries by endocytosis into their lining endothelial cells followed by exocytosis at the interstitial side of these cells. Small amounts of protein leave blood stream to interstitial fluid by this mechanism.
Diapedesis:
This is the mechanism of transport of a whole cell across the capillary membrane e.g. leukocytes leave the bloodstream toward areas of inflammation by this mechanism.

Formation and drainage of the interstitial fluid:

The spaces between the tissue cells are called the interstitium It consists of thick bundles of collagen fibres and thin filaments formed of hyaluronic acid and protein, as well as a fluid known as the tissue or interstitial fluid (IF). The IF is continuously formed and drained by the capillaries, and it contains almost the same constituents of the plasma except the plasma proteins.
Factors that affect tissue fluid formation and drainage:
The Starling's forces (the hydrostatic and osmotic forces that act across the capillary walls)
The capillary permeability.


The Starling's forces:
1-The hydrostatic capillary pressure (hcp):
This forces fluid outwards through the capillary membranes into the interstitial spaces, and it normally averages 35 mmHg at the arteriolar ends of capillaries and 12 mmHg at their venular ends.
2-The interstitial fluid pressure (ifp):
This forces fluid inwards through the capillary membranes, and it normally averages 1 mmHg.
3-The plasma colloid osmotic pressure or oncotic pressure (pop):
This is produced mainly by plasma albumin. It averages 25 mmHg and itcauses osmosis of fluid inwards through the capillary membranes.
4-The interstitial fluid colloid osmotic pressure (ifop):
This causes osmosis of fluid outwards through the capillary membranes into the interstitial spaces, and it normally averages 3 mmHg.

The (hcp) and (ifop) favour fluid filtration from the capillaries while the (pop) and (ifp) favour fluid reabsorption into the capillaries. Considering the balance of the Starling's forces at both ends of the capillaries, it is clear that at their arteriolar ends, the filtering forces exceed the reabsorbing forces by about 12 mmHg [(35 + 3) - (25 + 1)] resulting in fluid filtration, while at their venular ends, the reabsorbing forces exceed the filtering forces by about 11 mmHg [(25 + 1) - (12 + 3)] resulting in fluid reabsorption.
It was proved that the interstitial fluid pressure (ifp) is negative in certain areas e.g. the subcutaneous tissues (-2 to -3 mmHg), and in this case, it favours fluid filtration rather than reabsorption.




Figure: Fluid pressure and colloid osmotic pressure forces operate at the capillary membrane, tending to move fluid either outward or inward through the membrane pores.

THE LYMPH CIRCULATION

This circulation is concerned with return of the excess tissue fluid that is not reabsorbed at the capillaries back to the bloodstream. This fluid is called lymph, and it is similar to the plasma (being an isotonic colourless transparent fluid having a pH of 7.4) but it contains less protein and Ca+2 and has a higher A/G ratio (Albumin/Globulin ratio) since albumin is more easily filtered. Its average protein content is 3 gm %, but it varies in different organs and it clots (as it contains fibrinogen and prothrombin) and is rich in lymphocytes.
Lymph circulates in non-innervated vessels that form a lymphatic system. This system originates as minute lymphatic capillaries in the tissues (which are highly-permeable blind vessels lined by a single layer of endothelial cells) that drain the excess tissue fluid. These capillaries unite forming larger lymphatic vessels, which drain in the thoracic and right lymph ducts that open in the subclavian veins at the base of the neck. The lymph nodes are located along the course of the lymphatic vessels, and such vessels have smooth muscle in their walls and contain valves that allow unidirectional flow toward their central end.


EDEMA
This is fluid accumulation in tissues, which is either intra or extra-cellular.
Intracellular edema:
This is a non-pitting edema that is produced as a result of either:
Depression of the cell membrane metabolic activity e.g. due to ischemia. In this case, the lack of O2 and nutrients depress the Na+ pump mechanismand the excess Na+ inside the cells causes osmosis of water into the cells.
Inflammation: This increases the cell membrane permeability, allowing Na+ and other ions to diffuse into the cells with subsequent water osmosis.
Extracellular edema:
This is a pitting edema (i.e. pressing the skin by the finger produces a pit) except in cases of chronic lymphedema. It is due to accumulation of excessive amounts of interstitial fluid (mostly in the dependent parts of the body by the effect of gravity), and this has 2 main causes:
1- Excessive leakage of fluid from the capillaries.
This is produced by an increase of fluid filtration or a decrease of fluid reabsorption at the capillaries or both, which often occur due to either:
An increase of the capillary hydrostatic pressure: This occurs due to either elevation of the venous pressure (e.g. due to heart failure, venous obstruction) or arteriolar V.D. (e.g. by vasodilator drugs).
Hypoproteinaemia: This decreases the plasma colloid osmotic pressurewhich reduces tissue fluid reabsorption. It occurs due to either a decrease ofsynthesis of plasma proteins (e.g. in severe liver disease and undernutrition)or excessive loss of plasma proteins (commonly in the urine in cases of thenephrotic syndrome, or from damaged skin areas in cases of severe burns).

An increase of capillary permeability: This increases filtration of both tissue fluid and proteins (the latter farther increases filtration by increasing the osmotic pressure of the interstitial fluid). It occurs due to either inflammation, bacterial infections, allergic reactions (due to release of histamine), prolonged ischemia and certain toxins, vitamin deficiency (especially vitamin C) and excessive heat or cold.
Excessive retention of salt in the body: This is an important factor in the production of renal and cardiac edema.
2- Inadequate lymph drainage.
This occurs due to blockage of the lymph vessels, which leads to accumulation of both fluid and protein in the tissue spaces (the latter also increases fluid filtration by increasing the osmotic pressure of the interstitial fluid). The condition is called lymphedema, and if it persists, it causes a chronic inflammatory condition that leads to fibrosis of the interstitial tissue, and the edema becomes non-pitting. It often occurs in cancer, after certain surgical operations (e.g. radical mastectomy) and by infection with filaria worms. The latter obstruct the lymphatics, causing massive swelling of the affected organ (commonly the legs or scrotum), a condition known as elephantiasis.

Safety factors against production of edema:

Normally, the following 3 factors prevent occurrence of edema:
(1) Low compliance of the subcutaneous interstitium.
The negative interstitial fluid hydrostatic pressure in subcutaneous tissues holds these tissues together and makes compliance (their distensibility) to be low. Accordingly, small increases in tissue fluid volume cause large increases in hydrostatic pressure of the interstitial fluid, which opposes further fluid filtration and also increases the lymph flow; both effects prevent development of edema.
(2) Increasing the lymph flow.
The lymph flow can increase 10 - 50 folds when fluid begins to accumulate in the tissue spaces. This removes large amounts of the interstitial fluid and maintains the low compliance state of the subcutaneous interstitium, and both effects prevent development of edema.
(3) Washdown of interstitial fluid protein.
The increased lymph flow often results in reduction of the protein concentration in the interstitial fluid because the amount removed is usually greater than that filtered by the blood capillaries. Accordingly, the osmotic pressure of the interstitial fluid is decreased, which lowers the net filtration force across the capillaries and tends to prevent further accumulation of fluid.


The efficiency of the 3 edema safety factors is estimated by finding how much can the average capillary hydrostatic pressure increase above normal before edema occurs. Normally, it is about 17 mmHg (i.e. the capillary hydrostatic pressure can raise by 17 mmHg before significant edema occurs).

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Lect. 15

Blood Flow

Objectives:
List the physiological mechanisms that maintain blood flow in different organs by adjusting the diameter of their arterioles.
List vasoactive hormones together with the organs or cells from which their release is initiated.
Define the term blood flow autoregulation; name two vascular beds that demonstrate autoregulatory control of blood flow.

A- Regulation of local blood flow to tissues:

Blood flow in different organs is physiologically maintained by adjusting the diameter of their arterioles. The mechanisms of regulation of regional; local blood flow can be classified into: Short-term and long term regulation mechanisms.
Short-term regulation mechanisms:
These mechanisms adjust the minute-to-minute flow to the organs according to their metabolic needs. Four mechanisms are involved:
Metabolic autoregulation.
Nervous regulation.
Humoral regulation.
Myogenic autoregulation.
Metabolic autoregulation:
Increased metabolic activity dilates the blood vessels. This effect is mediated by:
Hypoxia, The increased O2 utilization by the tissues produces local hypoxia. The degree of vascular dilation is directly proportionate to the degree of hypoxia in arteriolar blood. In contrast, an increase in O2 level (hyperoxia) produce local vasoconstriction and decrease in blood flow.
Vasodilator metabolites, high metabolism with hypoxia produces a number of vasodilator metabolites, which include:
Adenosine; which is the most important vasodilator substance released from active tissues. An ischemic or hypoxic heart releases adenosine which dilates the coronaries and corrects the ischemia or hypoxia. Adenosine is also released by skeletal muscles and other tissues.
ADP and AMP which are produced by hydrolysis of ATP.
CO2 and H+ ions which act directly on the vascular smooth muscles and relax them. CO2 is a very powerful dilator of the cerebral blood vessels.
Lactic acid which is produced by anaerobic glycolysis. It has no direct vasodilator effect, but acts through elevation of H+ ion concentration.
K+ released from active cells. It relaxes the vascular smooth muscles.

The endothelium produces several molecules that promote smooth muscle relaxation (vasodilators), including nitric oxide (NO), bradykinin, and prostacyclin.


The Endothelium-Derived Relaxing Factor (EDRF): This is a powerful vasodilator substance secreted by the vascular endothelium. This substance chemically was found to be nitric oxide. It is released from the arterial endothelium when stimulated by bradykinin, VIP or ACH (acetylcholine), i.e. these vasodilator substances act through releasing EDRF and it is the EDRF which mediates the vasodilator effect of these substances. In the absence of EDRF, bradykinins and VIP are ineffective and ACH produces vasoconstriction not dilation. EDRF is also produced when the blood flow to a tissue is increased as a result of arteriolar dilatation, thus further increasing the blood flow to that tissue.
Nervous regulation:
All blood vessels except the capillaries are innervated. Regional vasodilator fibers supply the vessels of some organs. Vasodilation in specific organs occurs by the following mechanisms:
Activation of the parasympathetic vasodilator nerves produces vasodilation in their specific organs, e.g. the salivary glands.
Stimulation of the sympathetic vasodilator system dilates the skeletal muscle vessels and increases the blood flow in the skeletal muscles.
Stimulation of sympathetic cholinergic nerve supply to sweat glands dilates the gland vessels and increases the local blood flow.
Inhibition of the basal sympathetic vasoconstrictor tone to the vessels. Some organs receive no vasodilator fibers (e.g. the skin). Constriction or dilation of their vessels occurs by changing the sympathetic vasomotor tone.

Humoral regulation:

This is regulation by vasoactive substances released from the tissues into the blood and tissue fluids, examples:
Serotonin: This is a vasoconstrictor substance released from platelets during the platelet release reaction. It helps to stop bleeding from wounds. Serotonin is also found in chromaffin cells in the intestine.
Histamine: This is a strong vasodilator substance which is released from mast cells and basophiles in damaged or inflamed tissues. It is also released during allergic reactions. In small doses, histamine dilates the arterioles, but in large doses, it dilates all the vessels.
Prostaglandins (PG): These are hormone-like substances, some of them (PG F) are constrictors, but most of them (PG A and PG E) are dilators.
Bradykinins: These are strong vasodilator substances formed in tissues during inflammations or increased activity. The tissues release an activator substance to activate prekallikrein in tissue fluids into active kallikrein. Kallikrein acts on α 2 -globulin in tissue fluids to produce kallidin. Kallidin is then converted by tissue enzymes into bradykinin. Bradykinin is now believed to be the mediator of vasodilation in sweat and digestive glands when they are activated. Prekallikrein, kallikrein and α2-globulin are also found in plasma.
Myogenic autoregulation:
This is done by constriction when pressure increases and dilation when pressure decreases. This phenomenon is found in the vascular beds of certain organs like the kidney, brain, skeletal muscles, mesentery and the liver.
The mechanism of myogenic autoregulation is that when the blood pressure increases → distention of the arteriole and stretch of its wall → intrinsic myogenic contraction response → vasoconstriction → decrease in blood flow back towards normal.
The opposite reaction occurs when the blood pressure falls. This enables an organ like the kidney to maintain an almost constant blood flow in arterial blood pressure range of 80-160 mmHg. In the brain, changes in systemic arterial pressure are compensated by the appropriate responses of vascular smooth muscle.
A decrease in arterial pressure causes cerebral vessels to dilate, so that adequate rates of blood low can be maintained despite the decreased pressure. While, high blood pressure causes cerebral vessels to constrict, so that finer vessels downstream are protected from the elevated pressure. These responses are myogenic; they are direct responses by the vascular smooth muscle to changes in pressure.
Long-term regulation mechanisms:
These mechanisms adjust the basal blood flow over long periods of time. They take few hours up to few weeks to be fully effective. They correct any change in basal flow at blood pressure range of 50-250 mmHg. Three mechanisms are involved:
a- Opening of closed collaterals.
b- Formation of new vessels.
c- Narrowing or closure of some vessels.
Opening of closed collaterals:
When an artery or a vein is blocked, new vascular channels, which bypass the blocked segment, opens within one to two minutes. Such alternative vascular channels are normally found, but they are closed, Hypoxia and the metabolic vasodilators of the ischemic segment lead to their opening.
Formation of new vessels (angiogenesis):
Hypoxic tissues (either due to lack of O2 supply or high metabolic rate) produce angiogenic substances called angiogenins. These substances stimulate the sprouting of new vessels from the wall of venules and capillaries. Some of these vessels may grow up to form arterioles or even small arteries. The ability of young tissues to form new blood vessels in response to hypoxia is very high.
Narrowing or closure of vessels:
Increased blood flow (e.g. by increase in arterial blood pressure) or breathing air with high O2 content or depression of tissue metabolism elevates the local O2 level (hyperoxia). Blood vessels constrict. If hyperoxia lasts for a long time, structural changes take place in the vascular wall leading to permanent narrowing of the vascular lumen (e.g. arteriosclerotic changes which occur with chronic hypertension) some vessels might even get completely closed and obliterated.


B-Regulation of Blood Flow:
This is the Regulation of Blood Flow either by the autonomic nervous system or by the endocrine system. Angiotensin II, for example, directly stimulates vascular smooth muscle to produce generalized vasoconstriction. Antidiuretic hormone (ADH) also has a vasoconstrictor effect at high concentrations; this is why it is also called vasopressin. This vasopressor effect of ADH is not believed to be significant under physiological conditions in humans.
Regulation of blood flow by Sympathetic Nerves
Stimulation of the sympathoadrenal system produces an increase in the cardiac output and an increase in total peripheral resistance through α-adrenergic stimulation of vascular smooth muscle by norepinephrine and to a lesser degree, by epinephrine. This produces vasoconstriction of the arterioles in the viscera and skin.
In resting condition, when a person is calm, the sympathoadrenal system is active to a certain degree and helps set the tone of vascular smooth muscles. In this case, adrenergic sympathetic fibers (those that release norepinephrine) activate α-adrenergic receptors to cause a basal level of vasoconstriction throughout the body. During the fight-or-flight reaction, an increase in the activity of adrenergic fibers produces vasoconstriction in the digestive tract, kidneys and skin, and vasodilation in the skeletal muscles which receive cholinergic sympathetic fibers, that release acetylcholine as a neurotransmitter. Vasodilation in skeletal muscles is also produced by epinephrine secreted by the adrenal medulla, which stimulates beta-adrenergic receptors. In other words, during the fight-or-flight reaction, blood flow is decreased to the viscera and skin because of the α-adrenergic effects of vasoconstriction in these organs, whereas blood flow to skeletal muscles is increased.
Regulation of blood flow by Parasympathetic Nerves
Parasympathetic endings in arterioles are always cholinergic and always promote vasodilatation. Parasympathetic innervation of blood vessels, however, is limited to the digestive tract, external genitalia, and salivary glands. Because of this limited distribution, the parasympathetic system is less important than the sympathetic system in the control of total peripheral resistance.

Types of blood flow:

Laminar flow: The flow of blood in almost all vessels in the body is a smooth, streamline, laminar flow, i.e. the blood flows in several layers or laminae around a central layer. The central lamina moves at maximum velocity, whereas the outer laminae move at lower velocities. The outermost lamina is practically static and adherent to the vascular endothelium. The mean velocity of blood flow is the average of the velocities of all layers in the vessel. The RBCs generally travel in the central laminae, while the plasma generally travels in the outer laminae. The laminar flow is silent (i.e. producing no sounds). So, normally no sound is heard if a stethoscope is applied over a blood vessel. The friction forces on the vascular endothelium are minimal.
Turbulent Flow: This is disturbed blood flow in the form of eddies in various directions, in which fluid particles move in forward as well as side-to-side directions. Turbulence produces sounds (bruits or murmurs) that can be heard by the stethoscope. The friction forces of the turbulent flow on vascular endothelium are high. It may lead to excessive shedding of the lining endothelium (thus predisposing to intravascular clotting and development atherosclerosis).

Methods for measuring the blood flow rate:

Measuring blood flow through an organ
1-Plethysmography: recording change in volume of an organ after occluding its venous drainage. Rate of increase in volume of the organ equals rate of blood flow.
2-Fick's principle.
3-Plasma clearance: e.g., determination of renal blood flow.

Measuring blood flow through a blood vessel

1-Electromagnetic flow meters.
2-The ultrasonic Doppler flow meters.


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Laminar flow explains why the measured circulation times are shorter than real times. This is because the timing is made on the arrival of the first amount of the indicator to the end point. This first amount travels at maximum speed in the central axial stream, not at an average speed.

Total peripheral resistance:

It is the sum of all the vascular resistances within the systemic circulation.
Vasodilation in a large organ might, however, significantly decrease the total peripheral resistance and. by this means, might decrease the mean arterial pressure. In the absence of compensatory mechanisms, the driving force for blood flow through all organs might be reduced. This situation is normally prevented by an increase in the cardiac output and by vasoconstriction in other areas. During exercise of the large muscles, for example, the arterioles in the exercising muscles are dilated. This would cause a great fall in mean arterial pressure if there were no compensations. The blood pressure actually rises during exercise, however, because the cardiac output is increased and because there is constriction of arterioles in the viscera and skin.
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Paracrine Regulation of Blood Flow

Paracrine regulators are molecules produced by one tissue that help to regulate another tissue of the same organ. Blood vessels are particularly subject to Paracrine regulation. Specifically, the endothelium of the tunica interna produces a number of Paracrine regulators that cause the smooth muscle of the tunica media to either relax or contract.
The endothelium produces several molecules that promote smooth muscle relaxation, including nitric oxide, bradykinin, and prostacyclin. The endothelium-derived relaxation factor that earlier research had shown to be required for the vasodilation response to nerve stimulation appears to be nitric oxide.
The endothelium of arterioles contains an enzyme, endothelial nitric oxide synthase, which produces nitric oxide (NO) from L-arginine. The NO diffuses into the smooth muscle cells of the tunica media of arterioles and activates the enzyme guanylate cyclase, which converts GTP into cyclic GMP (cGMP) and pyrophosphate (PP,). The cGMP serves as a second messenger that, through a variety of mechanisms, acts to lower the cytoplasmic Ca+2 concentrations. This leads to smooth muscle relaxation and thus vasodilation. In many arterioles, a baseline level of NO production helps regulate the resting "tone" (degree of vasoconstriction/vasodilation) of the arterioles.
In response to ACh released from autonomic axons, however, the production of NO may be increased. This occurs through the following sequence of events:
(1) ACh stimulates the opening of Ca2+ channels in the endothelial cell membrane.
(2) The Ca2+ then binds to and activates calmodulin:
(3) Activated calmodulin, in turn, activate nitric oxide synthase and thus increase the production of NO. It is interesting in this regard that vasodilator drugs often given to treat angina pectorisincluding nitroglycerinpromote vasodilation indirectly through their conversion into nitric oxide.
The endothelium also produces Paracrine regulators that promote vasoconstriction. Notable among these is the polypeptide endothelin-1. This Paracrine regulator stimulates vasoconstriction of arterioles, thus raising the total peripheral distance. In normal physiology, this action may work together /ith those regulators that promote vasodilation to help regulate blood pressure.

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Intrinsic Regulation of Blood Flow
Intrinsic, or "built-in," mechanisms within individual organs provide a localized regulation of vascular resistance and blood flow.
Intrinsic mechanisms are classified as myogenic or metabolic. Some organs, the brain and kidneys in particular, utilize lese intrinsic mechanisms to maintain relatively constant flow rates despite wide fluctuations in blood pressure. This ability is termed autoregulation.
Myogenic Control Mechanisms
If the arterial blood pressure and flow through an organ are inadequateif the organ is inadequately perfused with blood the metabolism of the organ cannot be maintained beyond a limited time period. Excessively high blood pressure can also be dangerous, particularly in the brain, because this may result in the rupture of fine blood vessels (causing cerebrovascular accidentCVA, or stroke).
Changes in systemic arterial pressure are compensated for in the brain and some other organs by the appropriate responses of vascular smooth muscle. A decrease in arterial pressure causes cerebral vessels to dilate, so that adequate rates of blood low can be maintained despite the decreased pressure. High blood pressure, by contrast, causes cerebral vessels to constrict, so that finer vessels downstream are protected from the elevated pressure. These responses are myogenic; they are direct responses by the vascular smooth muscle to changes in pressure.
Metabolic Control Mechanisms
Local vasodilation within an organ can occur as a result of the chemical environment created by the organ's metabolism. The localized chemical conditions that promote vasodilation include
1) Decreased oxygen concentrations that result from increased Metabolic rate;
(2) Increased carbon dioxide concentrations;
(3) Decreased tissue pH (due to CO2, lactic acid, and other metabolic products); and (4) the release of adenosine or K+ from the tissue cells.
Through these chemical changes, the organ signals its blood vessels of its need for increased oxygen delivery.
The vasodilation that occurs in response to tissue metabolism can be demonstrated by constricting the blood supply to an area for a short time and then removing the constriction. The constriction allows metabolic products to accumulate by preventing venous drainage of the area. When the constriction is removed and blood flow resumes, the metabolic products that have accumulated cause vasodilation. The tissue thus appears red. This response is called reactive hyperemia. A similar increase in blood flow occurs in skeletal muscles and other organs as a result of increased metabolism. This is called reactive hyperemia. The increased blood flow can wash out the vasodilator metabolites, so that blood flow can fall to pre-exercise levels a few minutes after exercise ends.


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(1) Laminar blood flow : This is the normal smooth (streamline) flow of blood in the blood vessels. It is silent (i.e. producing no sounds) and laminar i.e. the blood flows in several layers or laminae (figure 62 A). The outermost layer of blood in contact with the vessel wall is almost completely static (i.e. not moving) while the other layers move by velocities that increase gradually from out inwards till becoming maximal in the central layer of the stream. The mean velocity is the average of velocities in all blood layers, and beyond a certain critical velocity, turbulence occurs (see below).
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^ It should be noted that the circulation times measured above reflect the maximum blood velocity and not the mean velocity. This is because these times are determined by the first appearance of the indicator substances at the end points (which depends on the maximal velocity in the centra! blood layer)- Therefore, the measured circulation times are actually shorter than the true times between the corresponding points.
(2) Turbulent blood flow: This is disturbed blood flow in the form of eddies in various directions. It produces sounds (= bruits or murmurs^ which can be heard by the stethoscope. It may lead to excessive shedding of the lining endothelium (thus predisposing to atherosclerosis). It specially occurs when the critical velocity is exceeded, in addition to other factors (see next).

There are several methods for measuring the blood flow rate through organs or through individual blood vessels.
Several methods could be used. The following are two widely used methods:

This is done by regulating the diameter of arterioles by constriction or dilation.

1-Electromagnetic flow meters: This technique depends on the principle that the flow of blood between two poles of a magnet generates an electromotive force (EMF) in the blood, because the RBC's cut the power lines in the magnetic field. The magnitude of the EMF is proportionate to the flow of blood. This EMF magnitude can be measured from the surface of the blood vessel.
2-The ultrasonic Doppler flow meters: A piezoelectric piece of crystal emit a pulse of ultrasonic waves (several million Hz) downstream the flowing blood. The sound waves that hit the RBC's are reflected back but at different slower frequency, because RBCs are moving away from the crystal. The amount and the wave length of the reflected waves are picked up by the crystal and the data are computed. The amount of the reflected waves is indicative of the density of RBCs which is indicative of the diameter of the vessel. The difference in wave length between the emitted and the reflected waves is indicative of the velocity of blood flow.

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Lect. 16

Shock

Objectives:
Define the term hypotensive shock and give three possible causes.
Summarize the cardiovascular reflexes elicited following the sudden loss of 1 liter of blood.(appearance, cvexam (pulse, Bp ) PCV
Explain the mechanisms that help compensate for circulatory shock. ( inc.h.r., stroke v . vasoconstriction samky =digestive t., aldosterone, ADH


Shock is a clinical syndrome of circulatory failure characterized by:
Low cardiac output.
Hypotension.
Inadequate tissue perfusion.

Causes and types:

According to the underlying cause, four main types of shock can be identified.
1-Hypovolaemic shock
This occurs as a result of severe reduction of the blood volume. Its manifestations are those of severe hemorrhage. It is called cold shock because the skin of the patient is cold due to severe cutaneous vasoconstriction.
Causes and types:
Hemorrhagic shock: could occur in severe hemorrhage; bleeding.
Traumatic shock (severe trauma): This may be complicated by precipitation of myoglobin (from the crushed muscles) in the renal tubules resulting in renal shutdown; kidney damage and anuria (crush syndrome).
Burn shock (extensive burns): It is a hypovolemic shock which follow extensive burns. It is mainly due to loss of large amounts of plasma from the burned areas (in burn there is loss of fluid and protein).
Surgical shock (major surgery): It is a hypovolemic shock which follows surgical operation (it is due to external and or internal bleeding).
Dehydration (e.g. in severe diarrhea, and Addison's disease). It is due to loss of large amount of Na+ in the urine or feces with the loss of water leading again to hypovolemic shock.

2-Distributive shock

This type of shock is caused by widespread vasodilation (VD) leading to state of hypovolemia despite that the blood volume is normal. In other words, the cardiac output is maldistributed to different organs where more blood goes to the inactive abdominal viscera, skeletal muscles and skin and less blood goes to the active, vital organs especially the heart and brain which become under-perfused. Its manifestations are generally similar to those of hypovolemic shock, but the skin is warm due to VD (hence the name, warm shock). Examples:
a- Neurogenic shock
This is a distributive shock which occurs on receiving sudden, shocking news or with strong emotions as extreme fear, grief or severe pain. Shocking news may cause failure of the sympathetic tone, i.e., there is loss (sudden withdrawal) of the sympathetic vasoconstrictor tone which results in widespread arterial and venous vasodilation. Venous return is reduced as blood pools in the venous system, leading to a drop in cardiac output and hypotension with resultant reduced cerebral blood flow that leads to fainting (a prolonged syncope; loss of consciousness due to cerebral ischemia). Neurogenic shock also could occur in case of upper spinal cord damage or spinal anesthesia.


b- Anaphylactic shock
This is a distributive shock caused by a severe allergic reaction to an antigen to which the subject was previously exposed, and sensitized, e.g. reexposure to an injection of penicillin. The resulting antigen-antibody reaction causes the release of large amounts of histamine from mast and basophiles which produces massive vasodilation and increased vascular permeability with edema that lead to the development of shock in addition to bronchospsm and laryngeal edema.
c- Septic shock
This is a distributive shock produced by the invasion of the blood stream by bacteria or their toxins; especially the gram-negative bacteria which release an endotoxin that stimulates the polymorphonuclear leucocytes and tissue macrophages to secrete many vasodilator cytokines (especially interlukin-1, tumor necrosis factor (TNF)). These substances produce massive vasodilation that lead to shock.

3-Cardiogenic shock (Congested shock)

This occurs as a result of inadequate pumping action of the heart (severe depression of myocardial contractility) which leads to reduction of the cardiac output and arterial BP (systolic pressure fails below 80 mmHg, the central venous pressure (right atrial pressure) is elevated above 18 mmHg (congestion).
Its manifestations are similar to those of hypovolemic shock plus congestion of the lungs and viscera due to failure of the heart to pump all the venous blood returned to it (hence the name, congested shock).
Causes:
1- Extensive myocardial infarction involving the left ventricle.
2- Acute myocarditis.
3. Heart failure.
4. Severe ventricular arrhythmia.

4-Obstructive shock

It is caused by marked restriction of the diastolic filling of the ventricles, e.g. pericardial effusion (tamponade; compression of the heart by accumulation of excess fluid or blood in the pericardial sac) or massive pulmonary embolism. The cardiac output is markedly reduced leading to hypotension and shock.
Causes:
(a) Large pneumothorax.
(b) Massive pulmonary embolism.
(c) Cardiac tumor.
(d) Cardiac tamponade.


Danger of shock How does it cause death?

Severe shock may be fatal if not rapidly and properly treated, especially if becoming irreversible. Death occurs as a result of development of multiple positive feedback cycles for death), for example:
Hypotension→ cerebral ischemia→ depression of the VCC→ VD and bradycardia → more hypotension (and so on till death).
Hypotension→ myocardial ischemia→ low cardiac output→ more hypotension, and so on till death (cardiac damage may be so severe that the cardiac output is not restored to normal even if the blood volume is increased).
A late cause of death is pulmonary damage due to pulmonary microembolism by thrombi formed by coagulant agents released from the damaged cells (acute or adult respiratory distress syndrome, ARDS).

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Lect. 17

Fainting (syncope)

Objectives:
Define the term syncope.
List the types of syncope. measurement of systemic arterial pressure.
State the influence of decreased aortic distensibility, increase in heart rate, and increase or decrease in peripheral resistance on systolic and diastolic systemic arterial pressures.

syncope is a sudden transient loss of consciousness. It usually results from cerebral ischemia; it is often due to cardiovascular abnormalities including either venous pooling or reduced cardiac output. A person who has fainted typically exhibits shallow breathing, a weak pulse, and low blood pressure.

Etiology or Types:

1) Vasovagal syncope:
fainting is due to hypotension produced as a result of sudden vasodilation associated with bradycardia. This is commonly occurs in strong emotions (Psychophysiological syncope). Higher brain centers involved with emotion inhibit sympathetic activity to the cardiovascular centers and enhance parasympathetic activity to the heart resulting in markedly reduced blood pressure and brain blood flow. Anther common example of vasovagal syncope is in case of blood donation.


2) Syncope due to reduction in venous return; by the increased intrathoracic pressure, this reduces the cardiac output leading to hypotension. Types:
Micturition syncope: hypotension; in addition to reflex bradycardia induced by voiding urine.
Defecation syncope.
Cough syncope.
Valsalva maneuver.

3) Orthostatic syncope or hypotension:

It means a rapid hypotension that occurs on sudden standing. It is accompanied by dimness of vision, dizziness and even fainting. It results from failure of the baroreflex to compensate for the sudden downward gravitational pull on the blood. On standing from supine position, the effect of gravity leads to pooling of blood in the lower part of the body→ decrease in venous return→ decrease in cardiac output →fall in arterial blood pressure (Orthostatic hypotension) → decreased cerebral blood flow→ brain ischemia→ syncope (Orthostatic syncope or fainting).. It may occur in normal persons, in hypovolemia, idiopathic, and in patients with diseases that damage the sympathetic nervous system e.g., diabetes and syphilis, and in primary autonomic insufficiency (decreased production of catecholamines due to Dopamine B-hydroxylase enzyme defficiency.

4) Carotid sinus syncope; carotid sinus syndrome.

An external pressure on the carotid sinus area might produce syncope due to reflex slowing of the heart rate and peripheral vasodilation. The applied external pressure stimulate the baroreceptors in the carotid sinus which leads to reflex increase in the vagal tone to the heart (bradycardia) and decrease in the sympathetic vasoconstrictor tone (vasodilation). On the same basis, an attack of paroxysmal atrial tachycardia can be terminated by initiating a carotid sinus massage. A strong blow on the carotid sinus area could lead to complete cardiac arrest. Some individuals pathologically have an abnormal hypersensitivity of the carotid sinus. Thus, mild pressure on the carotid sinus area e.g. during shaving or by a tight collar, produces bradycardia and generalized vasodilation, which may markedly decrease the cardiac output and arterial blood pressure resulting in brain ischemia and fainting.

5) Neurocardiogenic syncope; reduced cardiac output:

Syncope due to heart block or sinus arrest.
syncope may also occur in severe arrhythmias (tachycardia more than 160 beat/minute or in bradycardia less than 40 beat/minute),
Myocardial infarction with pump failure.
Valve diseases (aortic stenosis, mitral stenosis).
Long QT syndrome.
Cardiomyopathy (HOCM).
Congestive heart failure.


5) Deglutition syncope: due to VD and bradycardia induced by swallowing.

6) Effort syncope: common in patients having aortic or pulmonary valve stenosis.

Lect. 18

The Coronary Circulation

Objectives:
Describe the intrinsic mechanisms involved in the outoregulation of coronary blood flow.
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Arterial supply:

Immediately after aorta leaves left ventricle, it gives right and left coronary arteries.
The left coronary artery passes under the left auricle and divides into two branches:
The anterior interventricular artery; travels down the anterior interventricular sulcus toward the apex. It gives smaller branches to the interventricular septum and anterior walls of both ventricles. Clinically, this vessel is also called the left anterior descending (LAD) artery.
The circumflex artery; continues around the left side of the heart in the coronary sulcus. It supplies blood to the left atrium and posterior wall of the left ventricle.
The right coronary artery supplies the right atrium, continues along the coronary sulcus under the right auricle, and then gives two branches:
The marginal artery supplies the lateral aspect of the right atrium and ventricle.
The posterior interventricular artery travels down the corresponding sulcus and supplies the posterior walls of both ventricles.
An interruption of the blood supply to any part of the myocardium can cause necrosis within minutes. A fatty deposit or blood clot in the coronary artery can cause a myocardial infarction (MI). The coronary circulation has a defense against such an occurrence by mean of the anastomoses where two arteries come together and combine their flow to supply distal tissue. Thus, if one artery becomes obstructed, blood continues to reach myocardial tissue through the alternative route. The most important anastomoses is the point at which the circumflex artery and right coronary artery meet on the posterior side of the heart; they combine their blood flow into the posterior interventricular artery. Another is the meeting of the anterior and posterior interventricular arteries at the apex of the heart.
Venous Drainage:
Venous Drainage refers to the route by which blood leaves an organ. After flowing through capillaries of the myocardium, a bout 20% of the coronary blood empties directly from small veins into the right ventricle. The other 80% return to the right atrium by:
The great cardiac vein.
The middle cardiac vein.
The coronary sinus; collects blood from the upper veins and smaller cardiac veins. It passes across the posterior aspect of the heart in the coronary sulcus and empties blood into the right atrium.


Factors affecting the coronary blood flow:
The coronary blood flow is affected by four types of factors:

Metabolic factors:

The coronary blood flow is regulated mainly by the metabolic needs of the heart (metabolic autoregulation). Any increase in metabolic activity leads to a parallel increase in coronary blood flow. This is induced by coronary vasodilation. Coronary vasodilation during high metabolic activity is caused by:
Local hypoxia, hypoxia is a strong coronary vasodilator.
Adenosine is a strong coronary vasodilator released by cardiac cells. It is probably the main coronary vasodilator during high cardiac activity.
Lactic acid, Hypercapnia, Endothelial-derived relaxing factor (EDRF), increased extracellular K+ level, Prostaglandins, Histamine, and H+ ion.
All these factors are released during the normal metabolic reactions of the myocardial cells causing some degree of coronary vasodilation. With increased metabolic activity they are released in higher amounts leading to more dilation. During low activity periods of the heart, the amount of released metabolites decreases. This leads to coronary vasoconstriction and reduction in coronary blood flow.

Mechanical factors:

The phase of the cardiac cycle: The left ventricle gets its blood supply mainly during diastole. The highest coronary flow occurs during the isometric relaxation phase. During the isometric contraction phase, the left ventricular myocardial fibers squeeze the coronary vessels between them, stopping the blood flow in them.
The aortic pressure: As the aortic pressure is the perfusion pressure for the coronary blood flow, acute changes in aortic blood pressure are accompanied with parallel changes in the coronary blood flow. However, if the change is long lasting, the tone of the coronary vessels is readjusted to maintain adequate coronary flow regardless of the pressure level (autoregulation of the coronary blood flow).
The heart rate: An increase in the heart rate influences the coronary blood flow in two opposite ways:
It decreases the diastolic period, so decreasing the coronary blood flow.
It increases the metabolic activity, so increasing the coronary blood flow.
A decrease in heart rate decreases the metabolic activity and decreases the amount of vasodilator metabolites.

Nervous factors:

Sympathetic stimulation has a direct vasoconstrictor effect on the coronary vessels by stimulating the α-adrenergic receptors. In vivo, however, sympathetic stimulation increases the metabolic activity of the heart which has a strong dilator effect on the coronaries. So, the net effect of sympathetic stimulation is coronary vasodilation.
Parasympathetic vagal stimulation dilates the coronaries, but because it decreases the heart rate, metabolic activity decreases and coronary flow decreases.


Hormonal factors:
Noradrenaline is secreted by the sympathetic nerves and the adrenal medulla. It is a strong vasoconstrictor of the coronaries by stimulating the α-adrenergic receptors.
Adrenaline is secreted by the adrenal medulla during the alarm response. It stimulates the α- receptors as well as the metabolic activity of the heart leading to coronary vasodilation.
Vasopressin (also called antidiuretic hormone - ADH). It is a hormone secreted by the posterior pituitary gland in response to hypovolemia or plasma hypertonicity. It is a strong vasoconstrictor of all vessels including the coronaries. It acts on blood vessels only when found in high concentrations. In lower concentrations, it acts only on the kidney to conserve water.
Angiotensin II is formed during hypotension, hypovolemia, hyponatremia or renal ischemia. It is a powerful constrictor of vessels including the coronaries.

Coronary anastomoses and angiogenesis:

With sudden occlusion of a coronary artery, the small anastomoses dilate within few seconds (metabolic autoregulation). These vessels supply about 15% of the basal blood supply to the ischemic area. Angiogenesis is stimulated by the severe local hypoxia. New vessels appear and start to allow blood flow after 8-24 hours. After 24-48 hours, the blood flow to the ischemic area reaches 30-40% of the basal level. Angiogenesis continues at a lower rate afterwards to take the flow back to the normal basal level in about one month. Further increase in local blood flow occurs by more angiogenesis if the metabolic needs of the heart are increased.

CHARACTERISTICS OF CORONARY CIRCULATION:

It is a very short, very rapid circulation.
It is a very rich circulation. The heart weighs about 320 gm {~ 0.5% ofthe body weight), and receives 200 mL blood/min (~ 4% of the cardiacoutput). There is one capillary for each myocardial fiber.
It is the only circulation where blood flow occurs mainly during diastole.
It is regulated mainly by the amount of metabolites released from thecardiac muscle cells (metabolic autoregulation), not by autonomic nervesupply.
High capillary permeability, the lymph from the heart contains 4%proteins.
Very low venous O2 reserve. So, any increase in the metabolic activity ofthe heart should be accompanied by a parallel increase in coronary bloodflow.

OXYGEN CONSUMPTION OF THE HEART:

The normal heart, during rest, consumes 25 mL O2 /min {8 mL/100 gm/min). This is the "resting O2 consumption". It may increase up to 150 mL/min with maximum exertion. The metabolic reactions in the heart are mostly aerobic. That is why the cardiac performance is rapidly and seriously deteriorated in hypoxia.

OXYGEN SUPPLY TO THE HEART

The O2 content of arterial blood is 19.5 mL/dL. So, the coronary blood flow (200 mL/rain) supplies the heart with 39 mL O2 /min. This is called the "resting total Oj supply" to the heart. The heart normally extracts 12.5 mL O2 /dL of coronary blood supply, i.e. an O2 extraction coefficient of 65%.
When the metabolic activity of the heart increases, the heart can extract up to 15.5 mL O2 /dL of coronary blood supply, i.e. an O2 extraction coefficient of 80%. The maximum volume of O2 that can be extracted by the heart from the coronary blood flow is called the "effective O2 supply" to the heart ( 150 mL).


under nonphysiological conditions, e.g. coronary atherosclerosis where coronary vessels can not dilate to the normal maximal limits, the increase in the coronary blood flow does not match the metabolic activity he heart and an increase in heart rate results in coronary insufficiency.

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Lect. 19
The cerebral circulation
Objectives:
Explain the mechanisms by which blood flow to the brain is regulated.
The cerebral circulation is maintained in response to changes in arterial blood pressure. (Explain how).
Physiologic anatomy:
The brain is supplied by the internal carotid and vertebral arteries, which form the circle of Willis. From each side of the circle arise three cerebral arteries; anterior, middle and posterior. They run along the convex surface of the cerebral hemispheres to supply the cerebral cortex and send deep branches to supply the subcortical structures. With the exception of the circle of Willis, there is no anastomosis between the intracranial arteries, but some anastomoses exist between the smaller arterioles. Still, these anastomoses are inadequate to nourish the brain tissue when an arterial branch is occluded. That is why the cerebral arteries are considered functionally as end-arteries. The superficial and deep veins drain the cerebral blood into the large venous sinuses which exist between the folds of the dura mater. The venous sinuses are prevented from collapse by the tough structure of the dura and the attachment of their walls to the bones of the skull. The cerebral venous blood is drained from the sinuses by the jugular veins, mainly the internal jugular in man.
In contrast to the arterial supply, the cerebral venous system contains plenty of anastomoses between the superficial and deep veins, and between the intra- and extracranial veins. That is why occlusion of the internal jugular veins does not arrest the cerebral venous return, even if it is bilateral.
The brain is highly vulnerable to damage by hypoxia or ischemia. This is because of three factors:
The high metabolic rate of the brain (7kcal/kg/hr) compared with thatof the whole body (1 kcal/kg/hr).
The metabolic reactions of the brain are all aerobic.
The lack of significant energy stores in the brain. Glucose is the mainmetabolic substrate of the brain, yet the glycogen content of the brain (1.6 g/kg) meets its metabolic needs for only two minutes.

Autoregulation of the cerebral blood flow:

A sudden rise in the arterial blood pressure (ABP) leads to transient increase in the cerebral blood flow. If the rise in pressure is maintained, autoregulation mechanisms operate to restore the cerebral blood flow back to its normal basal level within 1-2 minutes. The cerebral blood flow is autoregulated in the blood pressure range of 70-140 mmHg in normal persons or up to 180 mmHg in hypertensive persons. The cerebral blood flow is regulated in response to a rise in ABP by the following mechanisms:
Myogenic vasoconstrictor response; caused by the increased tension in the vascular wall.
Metabolic vasoconstriction response; caused by washing out the vasodilator metabolites released by brain metabolism.
Neurosympathetic response; sympathetic stimulation constricts the cerebral blood vessels.
A fall in the ABP leads to the opposite mechanisms with a resultant vasodilation to maintain a constant blood flow rate.
Control of the cerebral blood flow:
Three main control mechanisms regulate and adjust the cerebral blood flow:


Nervous control:
The cerebral blood vessels receive sympathetic nerve supply from the cervical division of the sympathetic nervous system. It constricts the large and intermediate arteries during sympathetic activity. Under ordinary conditions, the vasoconstrictor effect of the sympathetic nerves on cerebral vessels is overridden by the autoregulation mechanisms. However, sympathetic cerebral vasoconstriction is strong and is very important in the following conditions:
In severe muscular exercise when arterial blood pressure rises to very high levels. Vasoconstriction of the large and intermediate vessels protects the small vessels and prevents their rupture.
After rupture of a small cerebral vessel, e.g. cerebral stroke, subdural hematoma or brain tumour. Sympathetic reflexes cause severe constriction of the large arterial supply to limit the intracranial bleeding.

Metabolic control:

The blood flow to the brain is regulated mainly by its own metabolism. The cerebral vessels are characterized by being extremely sensitive to hypoxia, hypercapnia and acidosis, which produce marked vasodilation of the cerebral vessels and increase the cerebral blood flow. Hypercapnia increases the H2CO3 and H+ levels in blood. CO2 has no direct vasodilator effect. It is the H+ ion produced by the hypercapnia which dilates the vessels.

Physical control: (by the intracranial pressure)

The intracranial cavity has a fixed volume because it is enclosed in the rigid bones of the skull. It contains the brain, whose volume is approximately 1500 mL, plus 75 mL of blood and 75 mL of cerebrospinal fluid (CSF). Because the brain tissue and fluids are incompressible, the total volume of the blood, the CSF and the brain is constant at any time. It follows that:
Any rise in the intracranial pressure compresses the cerebral vessels and reduces the cerebral blood flow. A drop in the intracranial pressure expands (dilates) the vessels and increases the cerebral blood flow.
Any change in the venous pressure immediately causes a similar change in the intracranial pressure which influences the cerebral blood flow.

The brain is very richly supplied with blood. In a normal adult male, the brain weighs about 1.5 kg (2% of body weight) and receives about 750 mL of blood/min (14% of the cardiac output). The cerebral blood flow is not uniform in all parts of the brain. The average blood flow in the gray matter is about six times that of the white matter. The largest blood flow per gram is in the inferior colliculus of the midbrain (1.8 mL/g/min), followed by the sensorimotor cortex (1.4 mL/g/min). The least blood flow is in cerebral white matter (0.2 mL/g/min).

VARIATIONS IN THE TOTAL AND REGIONAL CEREBRAL BLOOD FLOW

Total cerebral blood flow increases in hypoxia, hypercapnia and acidosis. It decreases during deep, quiet, slow-wave sleep.
Regional blood flow in the brain varies during different physiological or pathological conditions. The following are examples:
Quiet thinking during rest increases the blood flow in the prefrontal association area.
Voluntary clinching of the right hand increases the blood flow in the hand area of the left sensorimotor cortex.
Looking at a luminous object increases the blood flow in the visual occipital cortex.
In an epileptic focus, the blood flow increases during the epileptic seizure but decreases in other pans of the brain. In between seizures, the blood flow decreases in the epileptic focus but remains normal in other parts.
In manic depressive patients, there is a general decrease in the cortical blood flow when the patients are depressed.


On standing from the supine position, the arterial pressure in the head area drops to 65 mmHg. The cerebral blood flow decreases by 20%, but the O2 supply remains unaffected due to increased O2 extraction coefficient. If standing is accompanied with muscular exercise, cerebral blood flow is maintained at the basal level (750 mL/min).

For example, if the body is accelerated upwards, gravitational forces act toward the feet (positive gravity), i.e. blood moves toward the feet. The arterial pressure at the level of the head decreases which tends to decrease the cerebral blood flow. This is compensated to a large extent by the drop in venous pressure which decreases the intracranial pressure→ less compression of the blood vessels→ vasodilation → increase in the blood flow back toward the normal level.
On acceleration downwards (negative gravity), the opposite reactions occur to prevent marked increase in the cerebral blood flow.

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Cardiovascular / Physiology / Prof. Dr. Najeeb /2012

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