Department of Physiology: CVS Physiology-Review & Illustrations

Heart

Conducting System of the Heart: Animation 1, Animation 2

Myocardial Cells: Now that you have a good understanding of the basic features of the heart, we will look at how the heart fulfills its role as a central pump within the circulatory system. In order to do this we must first examine the basic cell types within the heart. There are two principal types of myocardial cells: contractile cells, which have similar features to skeletal muscle cells and nodal/conducting cells that have features similar to nerve cells. Let's look at each cell type separately.
The contractile cells are considered to be the real muscle cells of the heart and form most of the walls of the atria and ventricles. They have similar features and contract in almost the same way as skeletal muscle fibers. (You may wish to review the skeletal muscle section).
The contractile cells of the heart contain the same contractile proteins actin and myosin arranged in bundles of myofibrils surrounded by a sarcoplasmic reticulum. They differ from skeletal muscle by having only one nucleus but far more mitochondria. In fact, one-third of their volume is taken up by mitochondria. These cells are extremely efficient at extracting oxygen; they extract roughly 80% of the oxygen from the passing blood—about twice the amount of other cells. The cells are much shorter, are branched, and are joined together by special structures called intercalated discs. These structures contain tight junctions that bind the cells together, while gap junctions allow for the movement of ions and ion currents between the myocardial cells. Because of the gap junctions, the myocardial cells of the heart can conduct action potentials from cell to cell without the need for nerves. As we will see, this is an extremely important feature of the heart as a whole.
The second type of cells found in the heart is nodal or conducting cells. These cells contract very weakly because they contain very few contractile elements (myofibrils). These special cells are able to spontaneously generate action potentials without the help of nervous input like regular neurons. Along with this special property of self-excitability, they can also rapidly conduct the action potentials to atrial and ventricular muscle. Thus, these specialized cells provide a self-excitatory system for the heart to generate impulses and a transmission system for rapid conduction of the impulses throughout the heart.
Although nearly all of the cells in the heart can spontaneously generate action potentials, the sinoatrial node (or SA node) is generally the site of origin. The SA node is located in the upper posterior wall of the right atrium, and it is the first area to spontaneously depolarize, producing an action potential; this is why it is called the pacemaker of the heart (see figure). From here, the action potential travels through the atria to the atrial-ventricular node (AV node) and then to the Bundle of His. From the Bundle of His, the action potential travels through the Purkinje Fibers and then to the ventricular muscle.
Cardiac muscle cells metabolism: They are elongated, branching cells that contain one, or occasionally two, centrally located nuclei. Cardiac muscle cells contain actin and myosin myofilaments organized to form sarcomeres. The actin and myosin myofilaments are responsible for muscle contraction, and their organization gives cardiac muscle a striated appearance. Smooth sarcoplasmic reticulum of cardiac muscle has no dilated cisternae (calcium ion stores) as in skeletal muscle.
Cardiac muscle has more mitochondria than skeletal muscle does, reflecting its greater dependence on oxygen for its energy metabolism. Although the weight of the heart mass represents merely 1 % of the body weight (in adults), the myocardium consumes app. 10 % of the total body oxygen consumption. The heart is a typical aerobic organ with a minimal ability to work under oxygen debt. The heart relies almost exclusively on aerobic respiration. As a result, cardiac muscle cannot operate effectively for long without oxygen. When a normal heart is beating, it gets energy as the mitochondria break down fatty acids (stored as lipid droplets) and glucose (stored as glycogen) (figure). If the oxygen supply is suﬃcient, the dominant fuel is represented by fatty acids which are predominantly utilized and they cover 50-70% of the total energy demands myocardium, and glucose which covers the remnant 30 %. Lactate is utilized as an energy substrate under the condition of increased muscular activity, during which the lactate concentration in blood augments rapidly. Ketone bodies and amino acids are utilized exclusively under special pathological conditions (e.g. in diabetic ketoacidosis). They participate in ATP production by more than 10 %. These aerobic reactions can occur only when oxygen is readily available. In addition to obtaining oxygen from the coronary circulation, cardiac muscle cells maintain their own sizable reserves of oxygen. In these cells, oxygen molecules are bound to the heme units of myoglobin molecules. Normally, the combination of circulatory supplies plus myoglobin reserves is enough to meet the oxygen demands of the heart, even when it is working at maximum capacity. This is in contrast to skeletal muscle, which can contract for prolonged periods by carrying out anaerobic respiration. Cardiac muscle is much more adaptable and readily switches metabolic pathways to use whatever nutrients are available; including lactic acid generated by skeletal muscle activity. Consequently, the real danger of an inadequate blood supply to the myocardium is not lack of nutrients, but lack of oxygen. When a region of heart muscle is oxygen-starved (as during a heart attack), the ischemic cells (ischemic = blood deprived) begin to metabolize anaerobically, producing lactic acid. The rising H⁺ level that results raises intracellular Ca²⁺, damaging mitochondria and hindering cardiac cells’ ability to produce ATP. High levels of intracellular H⁺ and Ca²⁺ also cause the gap junctions (which are usually open) to close, isolating the damaged cells and forcing action potentials to find alternate routes to the cardiac cells beyond them. This may lead to fatal arrhythmias.

Adenosine triphosphate (ATP) provides the energy for cardiac muscle contraction, and, as in other tissues, ATP production depends on oxygen availability. Under resting conditions, most of the ATP produced in cardiac muscle is derived from the metabolism of fatty acids. During heavy exercise, however, cardiac muscle cells use lactic acid as an energy source.

SA Node Action Potential: Although the cause for spontaneous generation of the action potential is still controversial, several characteristics of the SA node are generally considered to be responsible for its self-excitability. Recall from the previous page that Na⁺ ions are moving into the cell, down their concentration gradient. In fact, the Na⁺ permeability is slightly higher here than in other cells. This will make the inside of the cell more positive (depolarized) over time. Ca⁺⁺ are similar to Na⁺—they are also trying to move into the cell and will also depolarize the cell. The animation shows the movement of Na⁺ and Ca⁺⁺ into an SA nodal cell, producing an initial depolarization of the membrane. We have not yet created an action potential.

Although the movement of both Na⁺ and Ca⁺⁺ into the cell causes a depolarization, the main cause of the spontaneous action potential is the movement of K⁺. Recall that K⁺ are trying to leave the inside of the cell down their concentration gradient. By itself, this will make the inside more negative (a hyperpolarization). But you do not want this to happen if you want to depolarize the cell. Instead, the potassium permeability of the SA node cells decreases over time (that is, less K+ leak out). In addition, since the Na+/K+ pump is always pumping K+ into the cell, both of these factors will cause these cells to depolarize.

Because Na⁺ and Ca⁺⁺ are flowing into the cell and K+ build up inside, the membrane potential of the SA nodal cells depolarizes from –60 mV to –40 mV (the threshold of these cells). Consequently, the SA nodal cells do not have a stable "resting" membrane potential like neurons or muscle cells. This slow depolarization is completely spontaneous and is called the pacemaker potential. The pacemaker potential, as we will see, is responsible for setting the pace of the heartbeat, and any alteration to it will affect the heart rate.

Once the membrane potential depolarizes to threshold (–40 mV), special voltage-gated Ca⁺⁺ channels will open. Ca⁺⁺ will rapidly flow in, producing the depolarization phase of the SA node action potential (see animation). These Ca⁺⁺ channels will begin closing at roughly the same times as voltage-gated K+ channels begin to open, allowing K⁺ out to repolarize the cell. Once the cell has returned to its lowest value of roughly –60 mV, the pacemaker potential will begin depolarizing the cell and the sequence will repeat itself. Later, we will see that this influx of Ca⁺⁺is important during the contraction of the heart.

NOTES: Drugs That Block Calcium Channels: Various chemical agents, such as nifedipine and verapamil, block voltage-gated Ca ²⁺ channel–blocking agents prevent the movement of Ca²⁺ through voltage-gated Ca²⁺ channels into the cell; for that reason, they are called calcium channel blockers. Some calcium channel blockers are widely used to treat various cardiac disorders, including tachycardia and certain arrhythmias. Calcium channel blockers slow the development of the pacemaker potential and thus reduce the heart rate. If action potentials arise prematurely within the SA node or other areas of the heart, calcium channel blockers reduce that tendency. Calcium channel blockers also reduce the amount of work performed by the heart because less Ca²⁺ enters cardiac muscle cells to activate the contractile mechanism. On the other hand, epinephrine and norepinephrine increase the heart rate and its force of contraction by opening voltage-gated Ca²⁺ channels.

Propagation of action potential: You should notice that the sequence of events is similar to the generation of a neuronal action potential, yet there are some important differences in terms of ions and their movements.

Once the action potential is generated at the SA node, it travels throughout the heart in a highly coordinated manner (see animation). From the SA node, the action potential spreads throughout the atrial muscle, causing it to contract. From the atria, the action potential travels to the ventricles. However, the atria are electrically isolated from the ventricles by a fibrous tissue. Therefore, the action potential cannot jump directly down to the ventricles. The action potential must first travel through the atrio-ventricular (AV) node. Once through the AV node, the action potential travels through each branch of the Bundle of His down to the apex of the heart. From here, the action potential propagates through the Purkinje Fibers, which rapidly distribute the action potential to the ventricular muscle, which then contracts.

The SA node has one of the slowest conduction speeds. The action potential speeds up through the atrial muscle to ensure that this muscle contracts simultaneously. With the SA node at the top of the heart, the action potential and, consequently, the contraction of the muscle move from the top down. This ensures that the blood is forced down into the ventricles. The AV node slows the conduction speed in order to ensure that the atria have finished contracting before the ventricles contract. The action potential must now reach the base of the heart rapidly. It does this through the Bundle of His, which conducts the action potential at a very fast rate. It is important for the action potential to reach the apex of the heart to contract first so the blood can be forced up and out through the valves at the top of the ventricles. The Purkinje fibers then spread the action potential throughout the ventricular muscle so it contracts from the apex upward.

Electrocardiogram (ECG): We have seen how the action potential is generated and how it spreads through the heart to initiate contraction. Since body fluids are good conductors of electricity and the heart sits in the middle of this conducting fluid, when the action potential passes through various parts of the heart, the electrical current can spread to the surface of the body. If electrodes are placed on the skin around the heart, electrical potentials generated by the heart can be recorded. Such a recording during the cardiac cycle is called the electrocardiogram (ECG). Let's have a closer look at a typical ECG.
As shown in the figure, the P wave represents the electrical activity in the heart associated with the depolarization of the atrial muscle leading to their contraction. The large QRS complex is produced by the depolarization of the ventricular muscle just prior to its contraction. The T wave is a result of the repolarization of the ventricular muscle as it relaxes. Notice that there is no wave associated with the repolarization of the atrial muscle. This event, which does occur, is obscured by the much larger QRS complex. While it is not important to understand all of the intervals shown at right, you should be familiar with those discussed above.

Cardiac axis (download this file and open it with this program)

Cardioversion is a procedure for delivering an electrical shock to the heart via paddles or electrodes to convert a pathologically in creased heart rate (tachycardia) or other arrhythmia to a normal rhythm. It does this by causing all of the cardiac muscle cells to

contract simultaneously. This brief interruption to the arrhythmia gives the SA node an opportunity to regain control over the pacing of the heart.

Medullary control of the cardiovascular system: This is achieved by cardiovascular centers (CVC) that are located in the medulla oblongata. The outputs from the CVC are sympathetic and parasympathetic nerve fibers. Both types of these fibers are under tonic discharge. CVC (figure) consist of:

The cardioacceleratory center projects to sympathetic neurons in the T 1 –T 5 level of the spinal cord. These preganglionic neurons, in turn, synapse with postganglionic neurons in the cervical and upper thoracic sympathetic trunk. From there, postganglionic fibers run through the cardiac plexus to all parts of the heart and innervate the SA and AV nodes, with a strong representation to the ventricular muscle, and coronary arteries. The sympathetic nerves are distributed to all parts of the heart.

The cardioinhibitory center sends impulses to the parasympathetic dorsal vagus nucleus in the medulla, which in turn sends inhibitory impulses to the heart via branches of the vagus nerves. Most parasympathetic postganglionic motor neurons lie in ganglia in the heart wall and their fibers project most heavily to the SA and AV nodes and to lesser extent to the muscle of the two atria, and far very few to the ventricular muscle.

The parasympathetic division opposes sympathetic effects and effectively reduces heart rate when a stressful situation has passed. Because vagal innervation of the ventricles is sparse, parasympathetic activity has little or no effect on cardiac contractility. Under resting conditions, both autonomic divisions continuously send impulses to the SA node of the heart, but the dominant influence is inhibitory. For this reason, the heart is said to exhibit vagal tone, and heart rate is generally slower than it would be if the vagal nerves were not innervating it. Cutting the vagal nerves results in an almost immediate increase in heart rate of about 25 beats/min, reflecting the inherent rate (100 beats/min) of the pacemaking SA node.

The vasomotor center (VMC) that controls the diameter of blood vessels. The vasomotor center transmits impulses at a fairly steady rate along sympathetic efferents called vasomotor fibers. These fibers exit from the T 1 through L 2 levels of the spinal cord and innervate the smooth muscle of blood vessels, mainly arterioles. As a result, the arterioles are almost always in a state of moderate constriction, called vasomotor tone. These sympathetic nerves release norepinephrine from their endings that interacts with α-adrenergic receptors on the smooth muscle cells to cause contraction and thus arteriolar constriction.

Autonomic Effects on the Heart and Blood Vessels (see figure)

CVC are subjects of various stimuli that modify their activities. In general, stimuli that increase the heart rate also increase blood pressure, whereas those that decrease the heart rate lower blood pressure. However, there are exceptions, such as the production of reflex hypotension (baroreceptor induced) and tachycardia by stimulation of atrial stretch receptors and the production of hypertension and reflex bradycardia (baroreceptor induced) by increased intracranial pressure.

There are descending tracts to the CVC from the cerebral cortex (particularly the limbic cortex) that relay in the hypothalamus. These fibers are responsible for the blood pressure and heart rate changes produced by emotions such as sexual excitement and anger (figure). Heart rate varies with respiration, heart rate increase during inspiration and decreases during expiration which result from variations in vagal tone that affect the SA node and it is commonly seen in children and in athlete (figure). Inhalation temporarily suppresses vagal activity, causing an immediate increase in heart rate. Exhalation then decreases heart rate and causes vagal activity to resume. Pain usually causes a rise in blood pressure via afferent impulses in the reticular formation converging in the vasomotor center. However, prolonged severe pain may cause vasodilation and fainting (figure). The activity in afferents from exercising muscles probably exerts a similar pressor effect via pathway to the VMC. The pressor response to stimulation of somatic afferent nerves from exercising muscles is called the somatosympathetic reflex. Baroreceptor (figure) are stretch receptors located in the carotid sinuses (dilations in the internal carotid arteries, which provide the major blood supply to the brain), in the aortic arch, and in the walls of nearly every large artery of the neck and thorax. These receptors are high-pressure receptors. Baroreceptors are also located in the walls of the right and left atria at the entrance of the superior and inferior venae cavae and the pulmonary veins, as well as in the pulmonary circulation. These receptors are low-pressure receptors (atrial “Bainbridge” reflex) (figure). The low-pressure baroreceptors are involved with the regulation of blood volume. The blood volume determines the mean pressure throughout the system, in particular in the venous side where most of the blood is held. The low-pressure baroreceptors have both circulatory and renal effects; they produce changes in hormone secretion, resulting in profound effects on the retention of salt and water; they also influence intake of salt and water. An increase in systemic arterial pressure causes the walls of the arterial regions to stretch. When stretched, high-pressure baroreceptors send a rapid stream of inhibitory impulses along sensory nerve fibers to the cardiovascular center causing inhibition of the vasomotor and cardioacceleratory centers while stimulation of cardioinhibitory center. A fall in pressure below the normal range, by contrast, causes a decrease in the frequency of action potentials produced by these sensory nerve fibers and consequently causing excitation of the vasomotor and cardioacceleratory centers while inhibition of cardioinhibitory center. Although baroreceptors respond to short-term changes in blood pressure, they quickly adapt to prolonged or chronic episodes of high or low pressure. Peripheral chemoreceptors act principally to detect variation of the oxygen concentration in the arterial blood, whilst also monitoring arterial carbon dioxide and pH. They are located in the aortic body and carotid body, on the transverse aortic arch and on the common carotid artery, respectively.

The Cardiac Cycle (figure): The cardiac cycle consists of all of the mechanical, electrical, and valvular events taking place in the heart during a single contraction. An understanding of the relationship between all of these events is important in order to understand how the heart functions as a pump. A simplified look at the cardiac cycle is shown at right.

The cardiac cycle has two primary phases (systole and diastole) that can be divided into several smaller phases that we will see on the next page. As we work through the cycle, it will be important to pay attention to the ECG, the pressure changes (remember that in order for blood to flow, there must be a pressure gradient from high to low between two areas), the volume in the ventricle, and the activity of the valves.

Keeping these things in mind, let's have a closer look at the cardiac cycle.

Each of the five steps of the cardiac cycle is summarized below, while the animation shows how they fit together. Note that we are looking at events on the left side of the heart.

Step 1—Atrial systole. This first phase of the cycle begins with the depolarization of the atria (P wave in the ECG). The atria contract. Atrial pressure is greater than ventricular pressure. The AV (mitral) valve opens and blood flows into the ventricle. Ventricular volume increases slightly (this is the end diastolic volume). Most of the blood (70–80%) enters the ventricles when they relax (during late ventricular diastole) and not when the atria contract (atrial systole), which contributes roughly 20–30% to ventricular filling (see figure & animation). Blood flows passively into the ventricles when the pressure in the atria exceeds that in the ventricles. This pressure gradient begins during late ventricular diastole, when the ventricles are relaxing, and continues until the atria have finished contracting.

Step 2—Isovolumetric ventricular contraction (also called early ventricular systole). This begins with the ventricles depolarizing (QRS complex) then contracting. Ventricular pressure increases rapidly (above atrial but below aortic pressures). The mitral valve closes. No change in ventricular volume.

Step 3—Ventricular systole (also called ejection period). The ventricles are still contracting, but now ventricular pressure is above aortic. The aortic valve opens. Blood flows into the aorta, and ventricular volume decreases. In order for blood to be ejected from the heart, the pressure in the ventricles must be greater than the pressure in the aorta (see animation). When the pressure in the left ventricle rises above 80 mmHg (which is the pressure in the aorta), the aortic valve opens. Immediately, blood pours out of the ventricles, while the pressure continues to increase to 120 mmHg. The period during which the ventricles empty blood into the aorta is known as the ejection period.

Step 4—Early ventricular diastole (also called isovolumetric relaxation phase). Ventricular pressure falls below aortic pressure, and the aortic valve closes. Some blood remains in the ventricles (end systolic volume). Ventricular pressure continues to fall. No change in ventricular volume.

Step 5—Late ventricular diastole. Ventricular pressure drops below atrial pressure. The mitral valve opens, and blood flows into the ventricle. Ventricular volume increases. P wave begins, and the cycle repeats.

Heart Sounds: The opening of heart valves is a slowly developing process and produces no sound. However, when they close, the vanes of the valves and the surrounding fluid vibrate under the influence of sudden pressure differences, producing sounds that travel in all directions through the chest. The first heart sound is produced (indirectly) by the closure of the AV valves; it is of low pitch and of relatively long duration. The second heart sound is produced (indirectly) by the closing of the aortic and pulmonary semilunar valves; this is of high pitch and of relatively smaller duration (see animation . A third heart sound sometimes occurs in the middle of diastole. This is caused by blood flowing with rumbling motion into the almost filled ventricles; it is difficult to hear with a stethoscope.

Normal heart sound (listen)

Benign murmur (listen)

S3 heart sound (listen)

S4 heart sound (listen)

Split S1 sound (listen)

Split S2 sound (listen)

splits1 & 2 sound (listen)

Mechanical Performance of the Heart: We will now examine the heart from the point of view of a pump. We will look at how much blood it can pump at rest or during exercise, how to calculate how much it pumps, and the mechanisms that control its pumping capacity.

Cardiac output (CO) is the amount of blood each ventricle can pump in one minute. At rest, the cardiac output is roughly 5 liters (1.3 gallons) of blood every minute. During vigorous exercise, this can increase up to 20 l/min (5.2 gallons/min) in a normal individual and up to 35 to 40 l/min (10 gallons/min) in a highly trained athlete. This is a remarkable amount considering the athlete has the ability to fill the equivalent of a small automobile gas tank in about 1 minute (about the same length of time as a gas pump). Figure shows the distribution of the cardiac output to different parts of the body.

Cardiac Output:

As already mentioned, cardiac output (CO) is the amount of blood pumped by each ventricle in one minute. CO can be calculated using equation: CO = HR x SV. Heart rate (HR) is the number of times the heart beats in one minute, and stroke volume (SV) is the amount of blood pumped by one ventricle during one contraction/heartbeat.

At rest, the heart rate is 70 beats per minute (bpm) and the stroke volume is roughly 70 ml/beat. Using equation 5, a CO of roughly 5 l/min is determined. During exercise, CO increases dramatically in order to supply the working muscles with more oxygen and nutrients. This increase in CO is achieved by increasing HR, SV, or both (see animation).

We will now examine how the body controls HR and SV to meet the demands of the exercising muscle. We will begin by looking at the control of heart rate.

The Control of Heart Rate: We saw in the nervous system module that the autonomic nervous system (ANS) exerts a powerful control over heart rate and force of contraction.

This is because the heart is innervated by both the parasympathetic nervous system (PSYN) and the sympathetic nervous system (SYN). The parasympathetic nerves are distributed mainly to SA and AV nodes and to a lesser extent to atrial and ventricular muscles. Sympathetic nerves are distributed to the same areas but with a stronger innervation to the ventricular muscle.

The PSYN will decrease heart rate by affecting both the SA node and AV node and will (to a lesser extent) decrease the force of contraction of the heart. The SNS, on the other hand, will have the opposite effect, increasing the heart rate and force of contraction (see animation). Using the animation, move the slider labeled "PSYN Activity" to slow heart rate. Increasing heart rate above 100 bpm involves shutting off the PSYN activity and increasing activity from the SYN to the heart. Move the "SYN Activity" slider to do this. If all these influences from the ANS were removed, the heart would beat at its own natural rhythm of roughly 100 bpm. Yet, the resting heart rate of a normal individual is roughly 70 bpm. Why this difference? The answer is quite interesting: in an individual at rest, there is constant activity from the PSYN keeping the heart rate slowed to roughly 70 bpm!. Remember that the PSYN is continually activated at rest to keep the heart beating at roughly 70 bpm. This phenomenon is called vagal tone since the vagus nerve transmits the signals from the PSYN to the heart. When there is no activity from either the PSYN or SYN (as shown at right) the heart will beat at its intrinsic rate of 100 bpm. Slowing the heart rate from this intrinsic rate involves activity from the PSYN.

In order to change the heart rate, you must change the pacemaker potential of the SA nodal action potential. You will recall that the pacemaker potential is a result of Na⁺ and Ca⁺⁺ leaking in and K⁺ permeability decreasing. This causes a gradual depolarization to threshold (–40 mV) that will fire the action potential. If the rate of depolarization of the pacemaker potential is changed, then the heart rate will also change. Let's now examine the exact mechanism through which each division of the ANS affects the heart. The pacemaker potential is altered by the parasympathetic nervous system (PSYN). When the neurons of the PSYN to the heart are activated, they release the neurotransmitter acetylcholine (ACh) onto the SA and AV nodes. The ACh causes K⁺ channels to open, letting more K⁺ out of the cell. This will do two things: The membrane potential will hyperpolarize, and the slope of the pacemaker potential will decrease (see animation). This means the membrane potential will take longer to reach threshold and heart rate will slow down.

What we have just seen is how the PSYN slows the heart rate by directly affecting the pacemaker potential of the SA node. The PSYN will also affect the AV node in a similar manner—by the release of acetylcholine onto cells in this region.

But why would you want to do that? After all, the SA node is the pacemaker and it sets the heart rate—right? Don't forget that the action potential has to travel through the AV node on its way to the ventricles; in fact, it slows down in this region to ensure the atria have finished contracting before the ventricles begin contracting.

If the heart rate is decreased further, then the action potential conduction through the AV node must also decrease to ensure the atria have finished contracting before the ventricles contract.

The sympathetic nervous system (SYN) has the opposite effect on the SA and AV nodes; it increases heart rate. In order to increase heart rate, threshold must be reached faster, which requires increasing the slope of the pacemaker potential (see animation). This is accomplished by the neurotransmitter norepinephrine (and also by the hormone epinephrine, also known as adrenaline). Epinephrine, released by nerves of the SYN onto the SA node, will cause the opening of Na+ and Ca⁺⁺ channels, allowing more of these ions to enter SA nodal cells. When these ions enter the cell, they will cause a more rapid depolarization. Consequently the pacemaker potential will reach threshold quicker and the heart rate will increase.

Control of Stroke Volume: Recall that stroke volume is the amount of blood pumped by one ventricle in one contraction. SV = EDV-ESV

End Diastolic Volume (EDV), as the name implies, is the amount of blood in the ventricle at the end of diastole—or just before it contracts. You may recall this from the cardiac cycle. This is usually 120 ml when at rest.

End Systolic Volume (ESV), as the name implies, is the amount of blood in the ventricle at the end of systole—or just after it contracts. This is usually 50 ml at rest. The difference of these two values gives you the amount of blood ejected, or the stroke volume. In this example it would be 70 ml.

Any change in end diastolic volume (EDV) or end systolic volume (ESV) will change stroke volume (SV). Any change to SV will change cardiac output (CO). You will notice that any change in either the EDV or ESV will change the stroke volume. Since the force of contraction of the heart determines stroke volume, whatever factors can change the force of contraction will change the stroke volume (and consequently the cardiac output). Three things can alter the stroke volume:

1. Input from the autonomic nervous system—either the PSYN or the SYN
2. EDV and preload
3. ESV

Let's have a look at each one.

The PSYN will decrease the force of contraction of the heart by releasing acetylcholine (ACh) onto the cardiac muscle. This will decrease the amount of Ca⁺⁺ entering the muscle cells. Since Ca⁺⁺ are essential for muscle contraction, the decrease in Ca⁺⁺ will decrease the force of contraction. This will decrease the stroke volume. The SYN will do the opposite by releasing norepinephrine onto muscle cells. This will increase the amount of Ca⁺⁺ entering the cells, leading to a more forceful contraction and an increase in stroke volume.

Preload is the "load" on the heart just before it contracts, and it is directly related to the end diastolic volume (EDV). This load comes from the blood in the ventricle that stretches the muscle of the heart. The more blood in the ventricle (the higher the EDV), the more "load" there is on the heart muscle just before it contracts. This stretching will cause special Ca⁺⁺ channels in the cardiac muscle cells to open, allowing Ca⁺⁺ into the cell. The more Ca⁺⁺ in the muscle cell, the more forcefully it will contract during systole, causing more blood to be ejected. The more blood ejected, the lower the end systolic volume and the higher the stroke volume.

This mechanism, which occurs in the heart even without any nervous system input, is called the Frank-Starling Law of the Heart. An animated example of the Frank-Starling Law is provided at right. Click on each button to see the effects of different end diastolic volumes on the stroke volume. Essentially, this law states that an increase in end diastolic volume (EDV) will cause an increase in stroke volume (SV), and vice versa, due to the mechanisms outlined on the previous page.

Increasing the end diastolic volume (EDV) means filling the heart with more blood before it contracts. Since blood returns to the heart by the veins, one way to increase EDV is to "squeeze" the veins much like you would a tube of toothpaste. As we will see in the next module, the veins contain 70% of the total blood volume of the body. Since the veins have valves, which ensure blood flows in one direction, squeezing the veins will increase the venous return of blood to the heart, which will increase EDV.

One way to squeeze the veins, to increase venous return, is by activating the SYN. The SYN innervates smooth muscle located in the walls of the veins. This muscle forms a ring around the inside of the vessel wall. When this muscle contracts, it causes the veins to constrict and, with the help of valves, squeezes blood back to the heart. This will increase venous return, causing an increasing EDV and leading to an increase in SV, which will then increase CO (see animation).

Another way of changing the EDV is by exercising the muscles. The repeated contraction and relaxation of skeletal muscle can also squeeze veins. Since many veins run between large groups of muscle, dynamic forms of exercise like running, swimming, or cycling can repeatedly squeeze veins, pumping the blood back to the heart. This "muscle pump" can consequently increase end diastolic volume (EDV), which, through the Frank-Starling Law, will increase stroke volume and consequently cardiac output. In this way, the activity of exercise itself increases cardiac output, which helps to deliver more blood to the exercising muscle.

In summary: The figure summarizes the main factors that determine CO.

ventricular pressure–volume loop (see figure)

NOTES: Blockage of β1-adrenergic receptors in the heart reduces heart rate and contractility and delays atrioventricular (AV) conduction. Blockage of β2 receptors causes arteriolar vasoconstriction (including the coronary arteries) and bronchoconstriction, so agents that act selectively on β1 receptors (e.g., atenolol) are used to treat cardiovascular disease. These so-called cardioselective β1 blockers are
used to reduce myocardial oxygen (O2) demand in angina and myocardial infarction (MI), to control hypertension, to depress AV nodal conduction in atrial fibrillation and atrial flutter, and to prevent ventricular fibrillation during the first 2 years following a
myocardial Infraction (MI).

Effect of extracellular ion Concentration: The ions that affect cardiac muscle function are the same ions (K⁺, Ca²⁺, and Na⁺) that influence membrane potentials in other electrically excitable tissues. However, cardiac muscle responds to these ions differently than nerve or skeletal muscle tissue does. For example, the extracellular levels of Na⁺ rarely deviate enough from normal to significantly affect cardiac muscle function.

Excess K⁺ (hyperkalemia) in cardiac tissue causes the heart rate and stroke volume to decrease. A twofold increase in extracellular K⁺ results in heart block, which is the loss of action potential conduction through the heart. The excess K⁺ in the extracellular fluid causes partial depolarization of the resting membrane potential, resulting in reduced amplitude of action potentials and, because of the reduced amplitude, a decreased rate at which action potentials are conducted along cardiac muscle cells. As the conduction rates decrease, ectopic action potentials can occur. In many cases, partially depolarized cardiac muscle cells spontaneously produce action potentials because the membrane potential reaches threshold. Elevated blood levels of K⁺ can produce enough ectopic action potentials to cause fibrillation. The reduced action potential amplitude also results in less Ca²⁺ entering the sarcoplasm of the cell; thus, the strength of cardiac muscle contraction lessens. Although the extracellular concentration of K⁺ is normally small, a reduction in extracellular K⁺ (hypokalemia) causes the resting membrane potential to become hyperpolarized; as a consequence, it takes longer for the membrane to depolarize to threshold. Ultimately, the reduction in extracellular K⁺ results in a decrease in heart rate. The force of contraction is not affected, however.

A rise in the extracellular concentration of Ca²⁺ (hypercalcemia) produces a greater force of cardiac contraction because of a higher influx of Ca²⁺ into the sarcoplasm during action potential generation. Elevated plasma Ca²⁺ levels have an indirect effect on heart rate because they reduce the frequency of action potentials in nerve fibers, thus reducing sympathetic and parasympathetic stimulation of the heart. Generally, elevated blood Ca²⁺ levels lower the heart rate. A low blood Ca²⁺ level (hypocalcemia) increases the heart rate, although the effect is imperceptible until blood Ca²⁺ levels are reduced to approximately one-tenth of their normal value. The reduced extracellular Ca²⁺ levels cause Na⁺ channels to open, which allows Na⁺ to diffuse more readily into the cell, resulting in depolarization and action potential generation. However, reduced Ca²⁺ levels usually cause death due to tetany of skeletal muscles before they decrease enough to markedly influence the heart’s function.

Vascular System

Blood vesseles-Interactive Physiology 1

Blood vesseles-Interactive Physiology 2

Blood vesseles-Interactive Physiology 3

Physiological variations of BP:

1. Age Arterial blood pressure increases as age advances.
2. Sex In females, up to the period of menopause, arterial pressure is 5 mm Hg, less than in males of same age. After menopause, the pressure in females becomes equal to that in males of same age.
3. Body Built Pressure is more in obese persons than in lean persons.
4. Diurnal Variation In early morning, the pressure is slightly low. It gradually increases and reaches the maximum at noon. It becomes low in evening.
5. After Meals Arterial blood pressure is increased for few hours after meals due to increase in cardiac output.
6. During Sleep Usually, the pressure is reduced up to 15 to 20 mm Hg during deep sleep. However, it increases slightly during sleep associated with dreams.
7. Emotional Conditions During excitement or anxiety, the blood pressure is increased due to release of adrenaline.
8. After Exercise After moderate exercise, systolic pressure increases by 20 to 30 mm Hg above the basal level due to increase in rate and force of contraction and stroke volume. Normally, diastolic pressure is not affected by moderate exercise. It is because, the diastolic pressure depends upon peripheral resistance, which is not altered by moderate exercise. After severe muscular exercise, systolic pressure rises by 40 to 50 mm Hg above the basal level. But, the diastolic pressure reduces because the peripheral resistance decreases in severe muscular exercise.
9. Gravity: In an upright position, BP in the arteries below the heart level is increased, and that in the arteries above the heart level is decreased by 0.77 mm Hg for each cm of vertical distance below or above the heart. Thus, routine
measurement of BP should be performed with the artery at the heart level.

Determinants of systemic blood pressure: MAP is proportional to cardiac output and vascular resistance. Factors that increase cardiac output or vascular resistance increase MAP. To understand specific determinants of blood pressure indices, it is necessary to interpret a patient’s vital signs.

Systolic blood pressure has three determinants:

1. SV. Increased SV increases systolic blood pressure and pulse pressure.
2. Aortic compliance. If compliance is low, the SV produces a large systolic blood pressure. Aortic compliance is not physiologically regulated but declines gradually in older persons. Systolic blood pressure typically increases 1 mm Hg for each year after age 60. This increase results from the loss of tissue elasticity in the aorta and atherosclerotic change in arterial walls.
3. Diastolic blood pressure. The absolute value of systolic blood pressure must be interpreted with respect to diastolic blood pressure because this is the baseline pressure before systole. For this reason, pulse pressure is also observed to assess SV.

Diastolic blood pressure has three determinants:

1. Vascular resistance is the main determinant of diastolic blood pressure. Blood flow through the circulation continues throughout diastole, although ventricular ejection is over. Flow is sustained because the arterial pressure exceeds the venous pressure. In addition, the elastic aorta stores energy during systole that is imparted to arterial blood during diastole. Diastolic blood pressure is determined by the size of arteriolar resistance encountered by blood flow. Higher arteriolar resistance (vasoconstriction) increases diastolic blood pressure.
2. Runoff of blood from the aorta. Diastolic blood pressure decreases if blood flow into the circulation during diastole is reduced. In aortic valve insufficiency, the aortic pressure rapidly decreases during diastole because backflow of blood into the left ventricle reduces forward flow into the circulation. This also occurs when a patent ductus arteriosus is present.
3. Diastolic time interval. Aortic pressure decreases with time between heart beats because blood continues to flow into the circulation from the aorta throughout diastole. The measured diastolic blood pressure is lower when the HR is slow because more time elapses between beats. Diastolic blood pressure is higher at faster HRs because there is less time for a decline in aortic pressure between beats. Figure illustrates the effect of altered HR on diastolic blood pressure.

Regulation of arterial blood pressure: Arterial blood pressure varies even under physiological conditions. However, immediately it is brought back to normal level because of the presence of well-organized regulatory mechanisms in the body. Body has four such regulatory mechanisms to maintain the blood pressure within normal limits (see figure) and these are:

A. Nervous mechanism or short-term regulatory mechanism
B. Renal mechanism or long-term regulatory mechanism
C. Hormonal mechanism
D. Local mechanism.
E. Vascular mechanisms.

A summary of the mechanisms are in the following:

Sensors:

1. Arterial baroreceptors: located in the aortic arch and carotid sinus; relay information to the integrator via CN IX (glossopharyngeal) and CN X (vagus)
2. Cardiopulmonary receptors (low-pressure baroreceptors): located in atria, pulmonary artery and vein, and vena cavae; atrial receptors are sensitive to atrial wall tension.
3. Chemoreceptors: located in aortic and carotid bodies; monitor blood gases

Integrator: Brainstem medulla oblongata contains the cardiovascular control center and is organized into three functional regions:

1. Vasomotor center: vasoconstricts when active
2. Cardioacceleratory center: increases heart rate (HR) and cardiac inotropy
3. Cardioinhibitory center: slows HR

Effectors:

1. Sinoatrial and atrioventricular nodes: control HR
2. Myocardium: contractile strength determines cardiac output (CO)
3. Veins: vasoconstriction forces blood toward the heart and preloads the ventricles
4. Resistance vessels: vasoconstriction limits output from the arterial tree and raises systemic vascular resistance (SVR)
5. Adrenal medulla: releases epinephrine and norepinephrine into the circulation

Response: To keep mean arterial pressure (MAP) stable, and MAP = CO x SVR. CO = HR x stroke volume:

1. Low MAP: Increase HR, Increase inotropy, Increase venoconstriction, Increase total peripheral resistance
2. High MAP: Decrease HR, Decrease inotropy, Decrease venoconstriction, Decrease total peripheral resistance.

A. Nervous mechanism or short-term regulatory mechanism: This mechanism operates through the action of vasomotor center in the regulation of blood pressure. Short-term regulation (within seconds) is achieved by reflexes integrated at cardiovascular centers of the medulla, and their output travels via autonomic fibers to the heart and vascular smooth muscle and the afferent fibers of this reflex arc involve the baroreceptors, chemoreceptors and higher brain centers. Figure shows the ranges of BP at which short-term neural controls operate. Although nervous mechanism is quick inaction, it operates only for a short period and then it adapts to the new pressure.Vasomotor center regulates the arterial blood pressure by causing vasoconstriction or vasodilatation. However, its actions depend upon the impulses it receives from other structures such as baroreceptors, chemoreceptors, low-pressure baroreceptors (atrial “Bainbridge” reflex), higher centers and respiratory centers. Among these structures, baroreceptors and chemoreceptors play a major role in the short-term regulation of blood pressure. A summary of arterial Blood pressure regulation is shown in figure. When arterial blood pressure rises rapidly, baroreceptors are activated and send stimulatory impulses to nucleus of tractus solitarius through glassopharyngeal and vagus nerves. Now, the nucleus of tractus solitarius acts on both vasoconstrictor area and vasodilator areas of vasomotor center. It inhibits the vasoconstrictor area and excites the vasodilator area. Inhibition of vasoconstrictor area reduces vasomotor tone. Reduction in vasomotor tone causes vasodilatation, resulting in decreased peripheral resistance. Simultaneous excitation of vasodilator center increases vagal tone. This decreases the rate and force of contraction of heart, leading to reduction in cardiac output. These two factors, i.e. decreased peripheral resistance and reduced cardiac output bring the arterial blood pressure back to normal level. When blood pressure decreases, or the occlusion of common carotid arteries decreases the pressure in carotid sinus, this causes inactivation of baroreceptors. Now, there is no inhibition of vasoconstrictor center or excitation of vasodilator center. Therefore, the blood pressure rises. Information regarding blood pressure within the range of 50 to 200 mm Hg (mean arterial pressure) reaches the vasomotor center through the carotid baroreceptors. Information about the blood pressure range of 100 to 200 mm Hg goes through aortic baroreceptors. Both carotid and aortic baroreceptors are stimulated by the rising pressure than the steady pressure and their response depends upon the rate of increase in the blood pressure.

♠ i. Regulating Blood Pressure by the Baroreceptor Reflex (see figure): Baroreceptors are stretch receptors found in the carotid body, aortic body and the wall of all large arteries of the neck and thorax. Baroreceptors entered the medulla (tractus solitarius). Respond progressively at 60-180 mm Hg. It is extremely important that blood pressure be maintained at relatively constant levels. The cardiovascular system uses the Baroreceptor reflex to regulate blood pressure. In order to better understand how it does this, we must understand how to calculate blood pressure. Blood pressure can be calculated by using equation Mean BP = CO x Total peripheral resistance (TPR).

Notice that increasing either cardiac output or total peripheral resistance will increase pressure and vice versa. The baroreceptor is a perfect example of a negative feedback mechanism. Recall from module 1 that a feedback loop relies on a set point (normal blood pressure value of 120/80), control center (cardiovascular center in the brain stem), effector (the heart and blood vessels), controlled variable (blood pressure), and sensors (baroreceptors). The baroreceptor reflex relies on special stretch receptors called baroreceptors located in the walls of the aortic arch and carotid sinuses. These receptors are sensitive to any stretching of the wall of these blood vessels. An increase in blood pressure will stretch the vessel walls, and activating these receptors will send an action potential to the cardioregulatory and vasomotor centers in the medulla oblongata. These centers will then take the appropriate steps to return blood pressure to normal by changing the heart rate, the force of contraction, and the diameter of blood vessels.

A sudden increase in blood pressure will dilate almost all blood vessels. The walls of these vessels will stretch, activating the baroreceptors in the arotic arch and carotid sinus. As the pressure increases, the baroreceptors will increase the frequency of action potentials sent to the cardioregulatory center and vasomotor center in the brain stem. In order to return blood pressure to normal, cardiac output and total peripheral resistance must be decreased. Recall: Blood Pressure = CO x TPR. Also: Cardiac Output = HR x Stroke Volume. The cardioregulatory center will activate the parasympathetic nervous system and will shut down the sympathetic nervous system. The result is a drop in heart rate and force of contraction (decreasing stroke volume and, consequently, cardiac output). The vasomotor center will cause vasodilation of most blood vessels (decreasing total peripheral resistance). Blood pressure will then return to normal (see figure).

♠ ii. Regulating Blood Pressure by the Chemoreceptors are the receptors giving response to change in chemical constituents of blood. Peripheral chemoreceptors inﬂuence the vasomotor center. Peripheral chemoreceptors are sensitive to lack of oxygen, excess of carbon dioxide and hydrogen ion concentration in blood. Whenever blood pressure decreases, blood ﬂow to chemoreceptors decreases, resulting in decreased oxygen content and excess of carbon dioxide and hydrogen ion. These factors excite the chemoreceptors, which send impulses to stimulate vasoconstrictor center. Blood pressure rises and blood ﬂow increases. Chemoreceptors play a major role in maintaining respiration rather than blood pressure. Vasomotor center is also controlled by the impulses from the two higher centers in the brain.

♠ iii. CNS ischemic response: Ischemia to the medulla oblongata causes an elevated blood pressure. This response called the central nervous system (CNS) ischemic response (figure B). The CNS ischemic response does not play an important role in regulating blood pressure under normal conditions. It functions primarily in response to emergency situations, such as when blood flow to the brain is severely restricted or when blood pressure falls below approximately 50 mm Hg. Reduced blood flow results in decreased oxygen, increased carbon dioxide, and reduced pH within the medulla oblongata. Neurons of the vasomotor center are strongly stimulated. As a result, the vasomotor center stimulates vasoconstriction, and blood pressure rises dramatically. The increase in blood pressure that occurs in response to CNS ischemia increases blood flow to the CNS provided the blood vessels are intact. The so called Cushing reaction (figure A) is a special type of CNS ischemic response that results from increased pressure of the cerebrospinal fluid around the brain in the cranial vault. For instance, when the cerebrospinal fluid pressure rises to equal the arterial pressure, it compresses the whole brain as well as the arteries in the brain and cuts off the blood supply to the brain. This initiates a CNS ischemic response that causes the arterial pressure to rise. The results of such reflex is the Cushing`s triad “bradycardia (PR ↓), BP ↑, respiratory rate ↓”, in opposite to what seen in shock “tachycardia (PR ↑), BP ↓, respiratory rate ↑”. However, if severe ischemia lasts longer than a few minutes, metabolism in the brain fails because of the lack of oxygen. The vasomotor center becomes inactive, and extensive vasodilation occurs in the periphery as vasomotor tone decreases. Prolonged ischemia of the medulla oblongata leads to a massive decline in blood pressure and ultimately death.

♠ iv. Influence of higher brain centers: Reflexes that regulate blood pressure are integrated in the medulla oblongata of the brain stem. Although the cerebral cortex and hypothalamus are not involved in routine controls of blood pressure, these higher brain centers can modify arterial pressure via relays to the medullary centers. For example, the fight-or-flight response mediated by the hypothalamus has profound effects on blood pressure. Even the simple act of speaking can make your blood pressure jump if the person you are talking to makes you anxious.

♠ v. Hypothalamus and temperature regulation: Hypothalamic control over cutaneous (skin) arterioles for the purpose of temperature regulation takes precedence over control that the cardiovascular center has over these same vessels for the purpose of blood pressure regulation. As a result, blood pressure can fall when the skin vessels are widely dilated to eliminate excess heat from the body, even though the baroreceptor responses are calling for cutaneous vasoconstriction to help maintain adequate total peripheral resistance.

Summary of short-term regulation of blood pressure: In most circumstances throughout the day, the baroreceptor reflex is the most important short-term regulatory mechanism for maintaining blood pressure. The adrenal medullary mechanism plays a role during exercise and emergencies. The chemoreceptor mechanism is more important when blood oxygen levels are reduced, such as at high altitudes or when carbon dioxide is elevated or pH is reduced. Thus, it is more important in emergency situations. The CNS ischemic response is activated only in rare, emergency conditions when the brain receives too little oxygen.

Cardiovascular response during dynamic exercise by bicycle ergometer for 25 years old athletic male under normal environmental condition at 225 m/min is shown in figure:

B. Renal mechanism or long-term regulatory mechanism: Unlike short-term controls of blood pressure that alter peripheral resistance and cardiac output, long-term controls (requiring minutes to days) alter blood volume (figure). Renal mechanisms mediate long-term regulation. Although baroreceptors respond to short-term changes in blood pressure, they quickly adapt to prolonged or chronic episodes of high or low pressure. This is where the kidneys step in to restore and maintain blood pressure homeostasis by regulating blood volume.

Direct mechanism: The direct renal mechanism alters blood volume independently of hormones. When either blood volume or blood pressure rises, the rate at which fluid filters from the bloodstream into the kidney tubules speeds up. In such situations, the kidneys cannot reabsorb the filtrate rapidly enough, and more of it leaves the body in urine. As a result, blood volume and blood pressure fall. When blood pressure or blood volume is low, water is conserved and returned to the bloodstream, and blood pressure rises. As blood volume goes, so goes the arterial blood pressure.
Indirect mechanism: The kidneys can also regulate blood pressure indirectly via the renin-angiotensin-aldosterone mechanism. When blood pressure or blood volume is low, the kidneys release renin. Renin enzymatically cleaves angiotensinogen, a plasma protein made by the liver, converting it to angiotensin I. In turn, angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II which stimulates intense vasoconstriction, promoting a rapid rise in systemic blood pressure. Angiotensin II also stimulates release of aldosterone and ADH, which act in long-term regulation of blood pressure by enhancing blood volume, and stimulate thirst center via hypothalamus.
ACE activity is associated with the capillary endothelium in various body tissues, particularly the lungs. Angiotensin II acts in four ways to stabilize arterial blood pressure and extracellular fluid volume (figure):

It stimulates the adrenal cortex to secrete aldosterone, a hormone that enhances renal reabsorption of sodium. As sodium moves into the bloodstream, water follows, which conserves blood volume. In addition, angiotensin II directly stimulates sodium reabsorption by the kidneys.
It stimulates the posterior pituitary to release ADH, which promotes more water reabsorption by the kidneys.
It triggers the sensation of thirst by activating the hypothalamic thirst center. This encourages water consumption, ultimately restoring blood volume and so blood pressure.
It is a potent vasoconstrictor, increasing blood pressure by increasing peripheral resistance.

C. Hormonal Mechanism for Regulation of blood pressure: Hormones also help regulate blood pressure, both in the short term via changes in peripheral resistance and in the long term via changes in blood volume.

Adrenal medulla hormones: During periods of stress (figure & figure), the adrenal gland releases epinephrine and norepinephrine (NE) to the blood. Both hormones enhance the sympathetic response by increasing cardiac output and promoting generalized vasoconstriction.
Antidiuretic hormone (ADH, Vasopressin). Produced by the hypothalamus, It stimulates the kidneys to conserve water. Its secretion is inhibited in response to atrial distention. It is not usually important in short-term blood pressure regulation. However, when blood pressure falls to dangerously low levels (as during severe hemorrhage), much more ADH is released and helps restore arterial pressure by causing intense vasoconstriction (high levels of ADH has a vasoconstrictor effect).
Atrial natriuretic peptide (ANP): The atria muscles of the heart produce the hormone ANP, which leads to a reduction in blood volume and blood pressure. It is released in response to atrial stretch (low-pressure baroreceptors) and a variety of other signals induced by hypervolemia. ANP is secreted in response to:
Atrial distention, stretching of the vessel walls
Sympathetic stimulation of β-adrenoceptors
Angiotensin-II
Endothelin, a potent vasoconstrictor

ANP:

Antagonizes aldosterone and stimulate the kidneys to excrete more sodium and water from the body, reducing blood volume.
It also inhibits renin secretion, thereby inhibiting the renin-angiotensin-aldosterone system.
It also causes generalized vasodilation.

Antidiuretic hormone (ADH, Vasopressin): Produced by the hypothalamus, It stimulates the kidneys to conserve water. Its secretion is inhibited in response to atrial distention. It is not usually important in short-term blood pressure regulation. However, when blood pressure falls to dangerously low levels (as during severe hemorrhage), much more ADH is released and helps restore arterial pressure by causing intense vasoconstriction (high levels of ADH has a vasoconstrictor effect).

Other hormones: Hormones which increase the blood pressure such as serotonin thyroxin. Hormones which decreases the blood pressure such as vasoactive intestinal polypeptide (VIP), bradykinin, prostaglandin, acetylcholine, histamine, brain Natriuretic peptide.

Thyroxin:
• It increases the systolic pressure but decreases the diastolic pressure
• It increases systolic pressure, by increasing the force of contraction of heart and cardiac output
• Due to production of different metabolites vasodilation occurs
• Due to which peripheral resistance educed and it decreases the diastolic pressure
Vasoactive intestinal polypeptide (VIP):
• It is secreted in stomach and small intestine
• It is a vasodilator and help in decreasing blood pressure
Bradykinin:
• It is produced in blood during the condition like inflammation
• In such conditions an enzyme kallikrein is activated which is later on converted into Bradykinin
• It is a vasodilator and help in decreasing blood pressure
Prostaglandins:
• It is secreted from all tissues of the body
• It is a vasodilator and help in decreasing blood pressure
Histamine:
• It is secreted in nerve endings of the hypothalamus and cerebral cortex
• It also causes vasodilation of blood vessels

D. Local mechanism for regulation of blood pressure: In addition to nervous, renal and hormonal mechanisms, some local substances also regulate the blood pressure. The local substances regulate the blood pressure by vasoconstriction or vasodilatation.

1 . Local vasoconstrictors: Local vasoconstrictor substances are derived from vascular endothelium. These substances are called endothelium-derived constricting factors (EDCF). Common EDCF are endothelins (ET), which are peptides. Three types of endothelins ET1, ET2 and ET3 are identified so far. Endothelins are produced by stretching of blood vessels. These peptides act by activating phospholipase, which in turn activates prostacyclin and thromboxane A. These two substances cause constriction of blood vessels and increase the blood pressure.

2. Local vasodilators: Local vasodilators are of two types :A. Vasodilators of metabolic origin. B. Vasodilators of endothelial origin.

Vasodilators of Metabolic Origin: Vasodilators of metabolic origin are carbon dioxide, lactate, hydrogen ions and adenosine.

Vasodilators of Endothelial Origin: Are Nitric oxide (NO) is an endotheliumderived relaxing factor (EDRF). It is synthesized from arginine. Nitric oxide synthesis is stimulated by acetylcholine, bradykinin, VIP, substance P and platelet breakdown products. As nitric oxide is a vasodilator, deficiency of this leads to constant vasoconstriction and hypertension. Other functions of nitric oxide are penile erection with vasodilatation and engorgement of corpora cavernosa, activation of macrophages in brain, destruction of cancer cells and relaxation of smooth muscles of gastrointestinal tract.

E. Vascular mechanisms: A fall in capillary pressure causes fluid to be absorbed by osmosis from the interstitial compartment into the circulation, thus increasing the blood volume and pressure. Conversely, when the capillary pressure rises too high, fluid moves out of the circulation into the interstitial spaces, reducing the blood volume and pressure.

Autoregulation: Local regulation of blood flow: Autoregulation is the automatic adjustment of local blood flow to each tissue in proportion to the tissue’s requirements at any instant independent of control by nerves or hormones.

These intrinsic control mechanisms may be classed as metabolic (chemical) or myogenic (physical) (figure).

Myogenic (physical) controls: Fluctuations in systemic blood pressure would cause problems for individual organs. These myogenic responses keep tissue perfusion fairly constant despite most variations in systemic pressure. Fortunately, vascular smooth muscle prevents these problems by responding directly to passive stretch (caused by increased intravascular pressure) with increased tone, which resists the stretch and causes vasoconstriction. Reduced stretch promotes vasodilation and increases blood flow into the tissue.
Metabolic (chemical) controls: When blood flow is too low to meet a tissue’s metabolic needs, oxygen levels decline and metabolic products accumulate. These changes serve as autoregulation stimuli that lead to automatic increases in tissue blood flow. The metabolic factors that regulate blood flow are (many of them act directly to relax vascular smooth muscle):

Low oxygen levels, and increases in H+ (from CO2 and lactic acid),
K+,
Adenosine,
Histamine,
Prostaglandins, and
Increased local temperature.

Other causes constriction of blood vessels such as:

Locally released platelet serotonin, thromboxane A2, and
Decreased local temperature.
Some may act by causing vascular endothelial cells to release endothelium-derived relaxing factors (EDRF) such as nitric oxide (NO), prostaglandins and endothelium-derived hyperpolarizing factor, as well as vasoconstricting factors such as endothelin, superoxide and thromboxanes play an influential role in the maintenance and regulation of vascular tone and the corresponding peripheral vascular resistance. nitric oxide. Nitric oxide (NO) is a powerful vasodilator which acts via a cyclic GMP second-messenger system that, through a variety of mechanisms, acts to lower the cytoplasmic Ca2+ concentration (figure). NO is quickly destroyed and its potent vasodilator effects are very brief. Even so, NO is the major player in controlling local vasodilation, often overriding sympathetic vasoconstriction when tissues need more blood flow. Many different stimuli act on the endothelial cells to produce NO. NO is synthesized from arginine in a reaction catalyzed by nitric oxide synthase (NO synthase, NOS). Three isoforms of NOS have been identified: NOS 1, found in the nervous system; NOS 2, found in macrophages and other immune cells; and NOS 3, found in endothelial cells. NOS 1 and NOS 3 are activated by agents that increase intracellular Ca2+ concentrations, including the vasodilators acetylcholine and bradykinin. The NOS in immune cells is not activated by Ca2+ but is induced by cytokines. The NO that is formed in the endothelium diffuses to smooth muscle cells, where it activates soluble guanylyl cyclase, producing cyclic 3,5-guanosine monophosphate (cGMP), which in turn mediates the relaxation of vascular smooth muscle. NO is inactivated by hemoglobin. When flow to a tissue is suddenly increased by arteriolar dilation, the large arteries to the tissue also dilate. This flow-induced dilation is due to local release of NO. Products of platelet aggregation also cause release of NO, and the resulting vasodilation helps keep blood vessels with an intact endothelium patent. This is in contrast to injured blood vessels, where the endothelium is damaged at the site of injury and platelets therefore aggregate and produce vasoconstriction. Penile erection is also produced by release of NO, with consequent vasodilation and engorgement of the corpora cavernosa. This accounts for the efficacy of drugs such as Viagra, which slow the breakdown of cGMP.
The endothelium also releases potent vasoconstrictors, including the family of peptides called endothelins, which are among the most potent vasoconstrictors known. Normally, NO and endothelin release from endothelial cells are in a dynamic balance, but this balance tips in favor of NO when blood flow is too low for metabolic needs. The net result of metabolically controlled autoregulation is immediate vasodilation of the arterioles serving the capillary beds of the “needy” tissues and dilation of their precapillary sphincters. Blood flow to the area rises temporarily, allowing blood to surge through the true capillaries and become available to the tissue cells.
Inflammatory chemicals (such as histamine, kinins, and prostaglandins) released in injury, infection, or allergic reactions also cause local vasodilation. Inflammatory vasodilation helps the defense mechanisms clear microorganisms and toxins from the area, and promotes healing.
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 active or exercise 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.

Endothelium: The structural characteristics of the blood vessels vary by region. However, the entire circulatory system, from the heart to the smallest capillary, has one structural component in common: a smooth, single-celled layer of endothelial cells (endothelium) that is in contact with the flowing blood. Capillaries consist only of endothelium and associated extracellular basement membrane, whereas all other vessels have one or more layers of connective tissue and smooth muscle. Endothelial cells have a large number of functions, which are summarized for reference in the following.

Functions of Endothelial Cells:

Serve as a physical lining that blood cells do not normally adhere to in heart and blood vessels
Serve as a permeability barrier for the exchange of nutrients, metabolic end products, and ﬂuid between plasma and interstitial fluid; regulate transport of macromolecules and other substances
Secrete paracrine agents that act on adjacent vascular smooth muscle cells, including vasodilators such as prostacyclin and nitric oxide (endothelium-derived relaxing factor [EDRF]), and vasoconstrictors such as endothelin-1
Mediate angiogenesis (new capillary growth)
Play a central role in vascular remodeling by detecting signals and releasing paracrine agents that act on adjacent cells in the blood vessel wall
Contribute to the formation and maintenance of extracellular matrix
Produce growth factors in response to damage
Secrete substances that regulate platelet clumping, clotting, and anticlotting
Synthesize active hormones from inactive precursors
Extract or degrade hormones and other mediators
Secrete cytokines during immune responses
Influence vascular smooth muscle proliferation in the disease atherosclerosis

Age-related cardiovascular changes: Aging results in gradual changes in heart function, which are minor under resting conditions but become more significant in response to exercise or age-related diseases. Under resting conditions, the mechanisms that regulate the heart compensate effectively for most of the age-related changes.

Hypertrophy of the left ventricle is a common age-related change. This appears to result from a gradual increase in the pressure in the aorta, against which the left ventricle must pump blood, and a gradual increase in the stiffness of cardiac muscle tissue. The elevated aortic pressure results from a gradual reduction in arterial elasticity, leading to increased stiffness of the aorta and other large arteries. Myocardial cells accumulate lipids, and the number of collagen fibers increases in cardiac tissue. These changes make the cardiac muscle tissue stiffer and less compliant. The increased volume of the left ventricle can sometimes result in higher left atrial pressure and increased pulmonary capillary pressure. This can cause pulmonary edema and a tendency for older people to feel out of breath when they exercise strenuously. The maximum heart rate gradually declines, as can be roughly predicted by the following formula: Maximum heart rate = 220 - Age of individual. The rate at which cardiac muscle breaks down ATP increases, and the rate of Ca²⁺ transport decreases. The maximum rate at which cardiac muscle can carry out aerobic respiration also decreases. In addition, the degree to which epinephrine and norepinephrine can increase the heart rate declines. These changes lead to longer contraction and relaxation times for cardiac muscle and a decrease in the maximum heart rate. Both the resting and maximum cardiac outputs slowly decline as people age; by 85 years of age, the cardiac output may have decreased by 30–60%. Age-related changes also occur in the connective tissue of the heart valves. The connective tissue becomes less flexible, and Ca²⁺ deposits increase. The result is an increased tendency for the heart valves to function abnormally. The aortic semilunar valve is especially likely to become stenosed, but other heart valves, such as the bicuspid valve, may become either stenosed or incompetent. The atrophy and replacement of cells of the left bundle branch and a decrease in the number of SA node cells alter the electrical conducting system of the heart and lead to a higher rate of cardiac arrhythmias in elderly people. The enlarged and thickened cardiac muscle, especially in the left ventricle, requires more oxygen to pump the same amount of blood pumped by a younger heart. This change is not significant unless the coronary circulation is diminished by coronary artery disease. However, the development of coronary artery disease is age-related, as is congestive heart disease. Approximately 10% of elderly people over 80 have congestive heart failure, and a major contributing factor is coronary artery disease. Because of age-related changes in the heart, many elderly people are limited in their ability to respond to emergencies, infections, blood loss, and stress. Exercise has many beneficial effects on the heart. Regular aerobic exercise improves the heart’s functional capacity at all ages, provided the person has no other conditions that cause the extra workload on the heart to be harmful.