Regulation of Heart

6.5.1 Regulation of Cardiac Output

The changes in cardiac output required as per the physiologic conditions are brought about by altering the cardiac rate or stroke volume or both.

6.5.1.1 IntrinsicRegulation

Intrinsic regulation refers to the mechanisms operating within the myocardium to regulate cardiac output. Heart’s inherent ability to vary stroke volume depends on the direct correla­tion between end-diastolic volume and stroke volume.

Fig. 6.4 Regulation of cardiac output. The cardiac output is controlled by intrinsic and extrinsic factors

6.5.1.1.1 HeterometricRegulation

This refers to the mechanism wherein the heart relates the stroke volume according to changes in cardiac muscle fiber length. As more blood returns to the heart, the heart pumps out more blood. The amount of blood pumped by the heart each minute is determined almost entirely by the rate of blood flow into the heart from the veins (venous return). This intrinsic control depends on the length-tension relationship of cardiac muscle, similar to that of skeletal muscle. This intrinsic ability of the heart to adapt to increasing volumes of inflowing blood is called the Frank-Starling mechanism of the heart, in honor of Frank and Starling, two great physiologists of a century ago. According to the Frank- Starling mechanism, the greater the heart muscle is stretched during filling, the greater is the force of contraction and the greater the quantity of blood pumped into the aorta. When an extra amount of blood flows into the ventricles, the cardiac muscle itself is stretched to a greater length causing the release of a greater amount of Ca²+ during systole.

6.5.1.1.2 HomeometricRegulation

Homeometric autoregulation is referred to an intrinsic mech­anism, which allows the heart muscle to adapt to changes both in heart rate (Bowditch effect) and in developed pressure (Anrep effect). The Bowditch effect is an adaptive mecha­nism, wherein an increase in heart rate stimulates inotropy. Calcium is vital for cardiac muscle contraction. Calcium enters the cell during the plateau phase of the cardiac action potential occurring during each contraction. As the heart rate elevates, there is an increase in the number of action potential plateaus. In addition, elevated frequency enhances the amount of calcium entry through L-type calcium channels as well as by slowing channel inactivation. As a result of these processes, there is an increase in the amount of intra­cellular calcium in the myocardium. At excitation, sarcoplas­mic reticulum calcium is released from the terminal cisternae as a result of the increase in intracellular calcium via the L-type membrane channels. Increased intracellular calcium from the sarcoplasmic reticulum results in augmented force of contraction. Additionally, at higher heart rates, the Na⁺/ K⁺-ATPase pumps are unable to keep up with the sodium influx. The increased intracellular Na⁺ reduces the concentra­tion gradient of Na⁺ across the sarcolemma, which reduces the inward movement of Na⁺ down its concentration gradient via the sodium-calcium exchanger, which exchanges three sodium ions for each calcium ion.

The Anrep effect refers to the recovery of the ventricle from transient subendocardial ischemia induced by an abrupt increase in ventricular pressure. Following the reduction in contractility, the coronary bed’s vascular autoregulation redistributes coronary flow to the ischemic regions, causing reactive hyperemia. After an abrupt increase in systolic pres­sure, the ventricle is in a transient state of “decompensation” owing to temporary subendocardial ischemia, which is corrected immediately by a redistribution of coronary blood to the ischemic areas. The decompensation is more severe in coronary insufficiency and left ventricular hypertension. In the healthy heart, the coronary vasodilatation is accompanied by positive inotropism.

6.5.1.2 ExtrinsicRegulation

The cardiac output is regulated depending on the functional requirement of the different parts of the body by factors that are external to the heart. The extrinsic regulation of cardiac output is achieved by neural and endocrine mechanisms. Some ions also influence the cardiac output by affecting heart rate and contractility. The nerves exert their control over the cardiac output to a larger extent on the rate rather than the force of contraction either by direct or through reflex mechanisms.

6.5.1.2.1 Direct Nervous Control

Nervous regulation of the cardiac activity originates in the cardiovascular center present in the medulla oblongata. This region of the brain stem receives input from a variety of sensory receptors and also from higher brain centers, such as the limbic system and cerebral cortex. The cardiovascular center then directs appropriate output by increasing or decreasing the frequency of nerve impulses in both the sym­pathetic and parasympathetic branches of the autonomic ner­vous system (ANS) that abundantly supply the heart, thereby controlling the cardiac activity, especially pumping effective­ness of the heart.

Sympathetic nerves extend from the medulla into the spinal cord, and from the thoracic region of the spinal cord, the sympathetic cardiac accelerator nerves extend out to the SA node, AV node, and most portions of the myocardium. The sympathetic output to the heart affects both contractility and heart rate. Impulses in the cardiac accelerator nerves trigger the release of norepinephrine from the postganglionic sympathetic neurons and act on postsynaptic β1-adrenergic receptors on pacemaker cells and cardiac muscle fibers.

In SA (and AV) node fibers, norepinephrine acts on the β1-adrenoceptor and via the G protein Gs and activates the cAMP-protein kinase A pathway, which has direct action on hyperpolarization-activated cyclin nucleotide-gated channels (HCN channels) and Ca channels. The opening of HCN channels stimulates the diastolic Na⁺ current into the pace­maker cells. The cAMP increases Ca²⁺ current through T-type and L-type Ca²⁺ channels. The net effect of these two changes is an increased rate of diastolic depolarization, so that these pacemakers fire impulses more rapidly; thereby, the diastole shortens and the heart rate increases.

In the contractile fibers throughout the atria and ventricles, norepinephrine enhances positive inotropic effects via pro­tein kinase A and activates the Ca²⁺ entry through the voltage-gated slow Ca²⁺ channels, thereby increasing con­tractility. The net effects of these pathways are contractions that are both stronger and briefer. As a result, a greater volume of blood is ejected during systole. With a moderate increase in heart rate, stroke volume does not decline because the increased contractility offsets the decreased preload. With maximal sympathetic stimulation, however, heart rate may reach 200 beats/min in an adult human. At such a high heart rate, stroke volume is lesser than at rest due to the very short filling time. For given levels of input atrial pressure, the cardiac output can often be increased more than 100% by sympathetic stimulation.

The parasympathetic preganglionic cell bodies originate in the brain stem primarily in the dorsal motor nucleus of the vagus and nucleus ambiguous. Parasympathetic myelinated preganglionic fibers leave the central nervous system via the vagus nerve and travel to terminal ganglia on or near the epicardial surface of the heart, where they form a synapse with short postganglionic neurons in the SA node, AV node, and atrial myocardium. As in the sympathetic nervous sys­tem, ACh is released from preganglionic terminals and binds to and activates nicotinic acetylcholine receptors on postgan­glionic neurons. Parasympathetic nerve impulses reach the heart via the right and left vagus nerves. Parasympathetic output to the heart affects heart rate and, to a much lesser extent, contractility. ACh released by postsynaptic parasym­pathetic neurons binds to M2 muscarinic (i.e., G protein coupled) receptors on pacemaker cells of the SA node and on ventricular myocytes.

In pacemaker cells, ACh acts by three mechanisms:

(1) ACh triggers G protein βγ subunits to directly open inward potassium channels that hyperpolarize the cell and decrease the frequency of action potentials. (2) ACh decreases the diastolic Na⁺ current through HCN channels, thereby reducing the rate of diastolic depolarization. (3) ACh also decreases the Ca²⁺ current through T-type and L-type Ca²⁺ channels, thereby both reducing the rate of diastolic depolarization and making the threshold more positive. The net effect is a reduction in heart rate.

In myocardial cells, ACh exerts minor negative inotropic effect by two mechanisms: (1) Activation of the M2 receptor, via Gαi, inhibits adenylyl cyclase, reducing cAMPi and thereby counteracting the effects of adrenergic stimulation.

(2) Activation of the M3 receptor, via Gαq, stimulates phos­pholipase C, raising Ca²⁺ and thus stimulating nitric oxide synthase. The newly formed nitric oxide (NO) stimulates guanylyl cyclase and increases cGMPi, which inhibits L-type Ca²+ channels and decreases Ca²+ influx.

A continually shifting balance exists between sympathetic and parasympathetic stimulation of the heart, and at rest, parasympathetic stimulation predominates. In humans, the resting heart rate (about 75 beats/min) is usually lower than the autorhythmic rate of the SA node (about 100 beats/min).

ACh released from vagal endings reacts with presynaptic muscarinic receptors on sympathetic nerve endings to reduce the amount of norepinephrine released from sympathetic efferent terminals. In addition to this, transmitters such as neuropeptide Y are also released, which inhibits the release of ACh from vagal nerve endings. At the level of the effector muscle cells, the two antagonistic transmitters oppose one another’s effects via activation of their respective receptors and activation of second messenger systems.

The right and left vagus nerves differentially innervate the SA node. In comparison to the left vagus, stimulation of the right vagus ordinarily has a greater effect in decreasing the firing rate of the SA node (located in the right atrium) and thus decreasing heart rate (negative chronotropy). The nega­tive inotropic effects of the vagus are primarily exerted on the atria where the vagal innervation is relatively rich. Left vagus nerve stimulation inhibits AV conduction and can produce AV block. Thus, vagal fibers have negative chronotropic (rate of contraction), inotropic (force of contraction), and dromotropic (conduction rate) actions on the heart. Vagal stimulation slows the discharge rate of the SA node, slows or blocks AV conduction, and decreases atrial and to a small extent contractility of ventricles. At rest, the vagus nerves exert a continuous or tonic restraint on the heart.

6.5.1.2.2 EndocrineControl

Exercise, excitement, and stress cause the adrenal medulla to release epinephrine and norepinephrine, which increase both heart rate and contractility, thereby enhancing the heart’s pumping effectiveness. Glucagon causes positive inotropic and chronotropic effects acting via cardiac adenylyl cyclase to bring these effects. Additionally, mineralocorticoids, angiotensin II, prostaglandins, insulin, and thyroid hormones have positive inotropic effect on heart.

6.5.1.2.3 ChemicalControl

The relative concentrations of three cations Ca²+, K+, and Na⁺ have a large effect on cardiac function. Elevated levels of K⁺/Na⁺ in blood decrease heart rate and contractility. While excess K⁺ prevents the generation of action potentials, excess Na⁺ prevents Ca²⁺ influx during cardiac action potentials, reducing the force of contraction. A moderate increase in interstitial (and thus intracellular) Ca²⁺ level speeds heart rate and strengthens heartbeat. Oxygen, carbon dioxide, and pH have direct influence on cardiac function via actions on the carotid body and central chemoreceptors. Hypoxia and hypercapnia may depress cardiac contractility and perfor­mance through reduction in calcium sensitivity of contractile proteins. Hypercapnic effects likely occur through decreases in intracellular pH (acidosis). While changes in arterial blood gas composition may directly affect the heart, the reflex responses are likely to predominate.

6.5.2 Regulation of Arterial Blood Pressure

Under normal physiological conditions, arterial blood pres­sure varies; however, immediately it is brought back to nor­mal level because of the presence of well-organized regulatory mechanisms in the body. Whenever the blood pressure undergoes change, nerves and hormones act rapidly to regulate the blood pressure; however, the body utilizes powerful mechanisms involving the kidneys to regulate the blood pressure over long periods. This long-term control of arterial pressure is closely linked with the homeostasis of body fluid volume, which is determined by the balance between the fluid intake and output. Two mechanisms regu­late the arterial pressure:

1. Rapidly acting mechanism operates through nerves and hormones

2. Long-term control of arterial pressure

6.5.2.1 Short-Term Regulation of Blood Pressure

6.5.2.1.1 Neural Regulation of Blood Pressure

Nervous regulation is rapid among all the mechanisms that regulate the arterial blood pressure. Within a few minutes of a pressure change, the nervous system returns it to normal. As the nervous mechanism is rapid in action, it operates only for a short period and hence it is called short-term regulation. The nervous mechanism regulating the arterial blood pres­sure operates through the direct action and reflex mechanism involving vasomotor system.

6.5.2.1.1.1 ReflexMechanism

This involves reflexes that mediate moment-to-moment adjustments in the distribution of blood flow in response to variations in regional or organ function. The cardiovascular reflexes are mediated through the sensory nerves that contin­uously provide the brain with information from the periphery, so that appropriate adjustments in efferent outflow and humoral secretions can be made to maintain blood pressure and meet tissue demands under a variety of physiological conditions.

1. Baroceptor reflex: Baroreceptors are spray-type nerve pressure-sensitive endings that lie in the walls of the arteries, carotid sinus, and aortic arch; they are stimulated when stretched, and the signals from the “carotid baroreceptors” and “aortic baroreceptors” are transmitted through very small Hering’s nerves to the

glossopharyngeal nerves and vagus nerve, respectively, to the tractus solitarius of the medulla of the brain stem. Additionally, secondary signals inhibit the vasoconstrictor center of the medulla and excite the vagal parasympathetic center. The net effects are vasodilation of the veins and arterioles throughout the peripheral circulatory system and decreased heart rate and strength of heart contraction. As a result, when the baroreceptors in the arteries are stimulated by high blood pressure, both peripheral resis­tance and cardiac output are reduced as a result of reflex action. Conversely, low pressure has opposite effects, causing the pressure to rise back toward normal by reflex action.

The baroreceptors respond to rapidly changing pressure than to a stationary pressure. The frequency of impulses generated from baroreceptors is proportional to the blood pressure. Beat-to-beat changes in blood pressure are mon­itored by the brain from the impulses reaching it through aortic and sinus nerves. Increase in arterial pressure increases impulse frequency and a decrease reduces frequency.

The brain responds to an increase in blood pressure by decreasing sympathetic activity and enhancing parasym­pathetic activity. Heart rate and force of contraction are decreased, and hence stroke volume is decreased. Sympa­thetic inhibition causes vasodilatation of arterioles, and peripheral resistance is decreased. All of these effects restore arterial blood pressure to normal. A decrease in blood pressure produces opposite effect to those consid­ered above.

2. Atrial volume receptor reflex: This reflex is initiated by stretch receptors located in the walls of the left and right atria, and these receptors are called volume receptors since atrial volume decides the stretch of the atrial wall. Stretching of the atria also leads to afferent arteriolar dilation in the kidneys and signals the hypothalamus to decrease secretion of antidiuretic hormone. The kidneys’ reduced afferent arteriolar resistance allows the glomeru­lar capillary pressure to increase, which in turn leads to more fluid filtration. The reduction in antidiuretic hor­mone decreases the reabsorption of water from the tubules. Combination of these two effects’ increase in glomerular filtration and decrease in reabsorption of the fluid increases fluid loss by the kidneys and reduces an increased blood volume back toward normal. Addition­ally, atrial stretch caused by increased blood volume also elicits a hormonal effect on the kidneys’ release of atrial natriuretic peptide that adds still further to the excretion of fluid in the urine and return of blood volume toward normal. When blood volume is decreased (hemorrhage), the CNS receives fewer impulses from the volume receptors and CNS reflex increases the sympathetic activ­ity to heart and blood vessels and decreases parasympa­thetic activity. The volume receptor reflex increases thirst sensation (acting through hypothalamus) that helps to increase blood volume, increase ADH secretion and fluid conservation through kidneys, and also activate renin- angiotensin-aldosterone system to conserve sodium.

3. Bainbridge reflex: This reflex operates when the venous return is increased. The stretch receptors of the atria that elicit the Bainbridge reflex transmit their afferent signals through the vagus nerves to the medulla of the brain. Then, vagal and sympathetic nerves send efferent signals back to increase the heartbeat and force of the contraction. This response thereby aids in preventing blood damming in the veins, atria, and pulmonary circulation. This reflex helps to prevent accumulation of blood in veins. Bainbridge reflex causes 40-60% increase in rate.

4. Psychogenic responses: Psychogenic responses originate from conscious perceptions or emotional reactions. They are eliminated by unconsciousness or general anesthesia. They involve neural pathways of the midbrain and fore­brain, including the limbic system and cerebral cortex. Psychogenic responses are often triggered by sensory stimuli. Defense-alarm reaction and vasovagal syncope are two important psychogenic responses that can bring about cardiovascular changes. The defense alarm reaction, also known as fear, fight, or flight response, is an emo­tional response to a threatening situation, physical injury, or trauma. It involves increased sympathetic and decreased parasympathetic activity and includes increased heart rate and stroke volume, vasoconstriction in kidneys, splanchnic organs and skin, vasodilatation in coronary vessel and skeletal muscles, and increased BP. There is enhanced secretion of ADH, angiotensin II, and adrenocorticotropic hormone (ACTH).

The defense alarm reaction (“fear, fight, or flight” response) is an emotional and behavioral response to a threatening situation, physical injury, or trauma. The response involves increased sympathetic activity and decreased parasympathetic activity. There is release of epinephrine and norepinephrine from the adrenal medulla, an increased heart rate, increased stroke volume, vasocon­striction in noncritical organs (kidneys, splanchnic organs, resting skeletal muscle), vasoconstriction in skin, vasodi­lation in coronary vessels and in working skeletal muscle, and increased blood pressure. The cardiovascular responses are enhanced by other circulating hormones, including ADH and angiotensin II. The resulting elevated blood pressure helps to ensure adequate blood flow for the critical organs (exercising skeletal muscles, heart, and brain). During a defense alarm reaction, the baroreceptor reflex is reset by the CNS so that it regulates blood pressure at an elevated level rather than acting to oppose the increased pressure.

Vasovagal syncope (playing dead reaction or playing opossum) is a psychogenic response that occurs in response to certain threatening or emotional situations, wherein the blood pressure decreases and involves a decrease in sympathetic activity and an increase in para­sympathetic activity. These neural changes bring about a vasodilation in the noncritical organs, with a consequent decrease in total peripheral resistance. Heart rate and cardiac output also decrease, so there is a large drop in arterial blood pressure with inadequate blood flow to brain and the animal faints.

5. Chemoreceptor reflex: Carotid bodies located in the bifurcation of each common carotid artery and aortic bodies located in the aortic arch contain peripheral chemoreceptors, which are sensitive to oxygen lack, car­bon dioxide excess, and hydrogen ion excess. The aortic bodies are supplied by the vagus nerve, and the carotid bodies are supplied by a branch of the glossopharyngeal nerve.

The chemoreceptors excite nerve fibers that, along with the baroreceptor fibers, pass through Hering’s nerves and vagus nerves into the vasomotor center of the brain stem. Each carotid or aortic body is supplied with an abundant blood flow through a small nutrient artery, so that the chemoreceptors are always in close contact with arterial blood. The chemoreceptors are activated due to decreased oxygen and an excess accumulation of carbon dioxide as a result of decreased blood flow.

The vasomotor center is stimulated by the signals sent from the chemoreceptors, which raises the arterial pres­sure back to normal. However, until the arterial pressure drops below 80 mmHg, this chemoreceptor reflex is not a potent controller of arterial pressure. As a result, this response becomes crucial at lower pressures to assist in stopping a further drop in pressure.

6.5.2.1.1.2 Regulation by Autonomic Nervous System Sympathetic and parasympathetic neurons influence the car­diovascular system through the release of the neurotransmitters norepinephrine and acetylcholine. In addi­tion, sympathetic nerves affect the cardiovascular system by stimulating the release of epinephrine and norepinephrine from the adrenal medulla.

Epinephrine, norepinephrine, and acetylcholine exert their cardiovascular effects through activating receptor proteins, whether they are working as neurotransmitters or hormones. The receptors activated by epinephrine and norepinephrine act via two types of adrenergic receptors (α and β). The α-adrenergic receptors are subdivided into α1 and α2, which are located in the cell membranes of smooth muscle cells of the arterioles in all organs and in the smooth muscle cells of the abdominal veins. There are three subtypes of β-receptors: β1 (located in cardiac muscle cell), β2 (located in arterioles, particularly in the coronary circulation and in skeletal muscles), and β3, with the first two of these being important in cardiovascular control.

Activation of the α-adrenergic receptors leads to constric­tion of arterioles or veins. Arteriolar vasoconstriction increases the resistance and decreases the blood flow through an organ. If one or more major body organs are vasoconstricted, the total peripheral resistance (TPR) increases, leading to an increase in arterial blood pressure. The increase in arterial pressure increases the driving force for blood flow in all organs of the systemic circulation. In effect, the sympathetic nervous system can vasoconstrict some organs and thereby direct more blood flow to other, non-vasoconstricted organs. Venoconstriction displaces venous blood toward the central circulation, which increases central venous pressure, right ventricular preload, and (by the Starling mechanism) stroke volume.

Acetylcholine activates cholinergic receptors which are of two major types: muscarinic cholinergic receptors and nico­tinic cholinergic receptors. The main cardiovascular effects of acetylcholine are mediated through muscarinic cholinergic receptors located on cardiac, smooth muscle, or endothelial cells. Of the five subtypes of muscarinic receptors, the M2 and M3 receptor subtypes have the greatest cardiovascular importance.

Cardiac muscle cells of the sinoatrial and atrioventricular nodes are densely innervated by postganglionic parasympa­thetic neurons. Atrial cells also receive strong parasympa­thetic innervations, and activation of cardiac M2 receptors has effects basically opposite to those of the activation of β1- adrenergic receptors.

Parasympathetic activation powerfully slows the cardiac pacemakers, decreases cell to-cell conduction velocity, and increases refractory period. Ventricular muscle cells receive very little direct parasympathetic innervations, and hence, parasympathetic activation has only a minor, direct effect on ventricular contractility. However, parasympathetic neurons indirectly act on ventricular muscle cells and release their acetylcholine onto sympathetic neuron terminals, rather than directly onto ventricular muscle cells. This acetylcholine activates muscarinic cholinergic receptors on the sympathetic neuron terminals, which inhibits the release of norepineph­rine from the terminals and thus weakens the effects of sympathetic activity on ventricular cells. Parasympathetic activation can significantly reduce cardiac output by lowering heart rate and reversing the effects of sympathetic stimulation on ventricular contractility. M3 adrenergic receptors are found in the arteries and arterioles all over the body, and acetylcholine causes these blood vessels to enlarge.

6.5.2.1.1.3 VasomotorMechanism

It deals with the maintenance of the diameter of the blood vessels (arteries and arterioles) to maintain blood pressure and thus regulates the blood flow to various organs or tissues according to their demand. These mechanisms regulate blood flow to different organs according to their demand, i.e., shifting of blood from one organ to another on demand, and regulate peripheral resistance which in turn influences the blood pressure.

Vasomotor system includes three components: vasomotor center, vasoconstrictor fibers, and vasodilator fibers.

6.5.2.1.1.3.1 Vasomotor Centre

Vasomotor center is bilaterally situated in the reticular for­mation of medulla oblongata and the lower part of the pons and includes vasoconstrictor and vasodilator centers. This center receives sensory signals through vagus and glossopharyngeal nerves. By its output signals, it regulates the activities of both the vasoconstrictor or vasodilator center. Vasoconstrictor and vasodilator centers show reciprocal inhi­bition. These centers are controlled by higher neurons from hypothalamus and cerebral cortex and also from sensory impulses from the peripheral organs and chemical composi­tion of blood.

1. Vasoconstrictor area and vasoconstrictor fibers

Vasoconstrictor center is extended from the middle pons to upper spinal cord. Vasoconstrictor fibers are projected through the sympathetic nervous system. Under normal circumstances, the sympathetic vasoconstrictor nerve fibers in the vasoconstrictor region continuously transmit impulses that maintain a partial state of blood vessel contraction known as sympathetic vasoconstrictor tone. Small arteries, big arterioles, and veins are all innervated by sympathetic nerves (thoracolumbar output). They pro­vide peripheral resistance and function to maintain the tonus of the arterioles, thus regulating BP. On the other hand, the capillaries and precapillary sphincters are free from sympathetic innervations. The venules have fewer adrenergic fibers than large veins, which themselves are less richly innervated than the arterioles. Sympathetic innervation to veins helps to change the volume of veins by constriction/dilatation, thus regulating BP by altering the volume of the circulatory system. The neurotransmit­ter of the sympathetic nerves is the norepinephrine. Sym­pathetic stimulation also causes the release of epinephrine from adrenal medulla.

Both epinephrine and norepinephrine act through α- and β-receptors on blood vessels. NEP excites mainly α-receptors and causes vasoconstriction. By its action on α1-adrenergic receptors, it causes vasoconstriction in arterioles of all organs of the body. Epinephrine acts both on α- and β-adrenergic receptors. Its action on α-adrenergic receptors in cutaneous and renal arterioles causes vasoconstriction. Epinephrine causes vasodilata­tion in the cardiac and skeletal muscles via its effect on β-receptors. Neuropeptide Y potentiates the vasoconstric­tor effect of adrenergic receptors in primates.

All vasoconstrictor fibers are sympathetic fibers, and these fibers are in tone. Without using vasodilator fibers, the vasoconstrictor or vasodilator effect can be created by simply changing the tone of the vasoconstrictor. Vasocon­striction results from sympathetic fibers in the veins being stimulated.

2. Vasodilator area and vasodilator fibers

Vasodilator center is located medially in the floor of the ventricles of the medulla oblongata, but close to the vaso­constrictor area, and inhibits the vasoconstrictor area pro­ducing vasodilatation. Vasodilator fibers are of three types, the parasympathetic fibers, sympathetic cholinergic fibers, and antidromic fibers. These fibers do not exert tonic activity on blood vessels.

Parasympathetic vasodilator fibers: These are the cranio­sacral outflow as chorda tympani (branch of facial nerve), glossopharyngeal, vagus, and pelvic nerves.

The neurotransmitter of these fibers is acetylcholine, which acts through the cholinergic muscarinic M3-type receptors, which are found on the endothelial cells and on the smooth muscle cells of most arterioles. M3 receptors are innervated by parasympathetic fibers in the coronary circulation and in the external genitalia and by sympathetic cholinergic fibers in skeletal muscles. The stimulation of M3 receptors on the endo­thelial cells both causes vasodilatation and releases nitrous oxide from endothelial cells. This nitrous oxide causes vasodilatation by altering the arterial smooth muscles. Stimulation of these fibers results in vasodilatation in coronary vessels, tongue, salivary gland, external genitalia, bladder, and rectum.

Sympathetic cholinergic vasodilator fibers: They are lim­ited to the arterioles of active skeletal muscles and cause anticipatory increase in blood flow even before exercise to overcome fatigue (in dogs and cats). Sym­pathetic cholinergic fiber-innervated cholinergic mus­carinic M3 receptors are stimulated by acetylcholine and cause cutaneous vasodilatation.

Antidromic fibers: These fibers originate from dorsal roots of spinal cord and show bidirectional conduction of impulses. The antidromic fibers divide at their periph­eral end, one branch supplying the receptors of the skin or muscle and the other to the nearby arterioles. The receptor is sensitive to trauma, heat, cold, and frostbite. When the receptor is triggered, the impulse travels in the opposite direction (antidromic) to the affected blood artery and causes vasodilation. The response is known as the “axon reflex” because it only affects the sensory nerve and its blood vessel branch.

3. Sensory area

Sensory area is in the nucleus of tractus solitarius, which is situated in the posterolateral part of medulla and pons. This area receives sensory impulses via glossopharyngeal and vagal nerves from the periphery, particularly from the baroreceptors. Sensory area in turn controls the vasocon­strictor and vasodilator areas.

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Unique Cardiovascular Feature in Giraffe

Giraffes exhibit unique cardiovascular features. An adult full-grown giraffe may be around 5-6 m tall, and due to their long necks, their brains may be 1.6 m above their hearts. Further, standing giraffes have exception­ally high blood pressures in their legs and feet due to their tall columns of blood. Giraffes possess a remark­ably well-developed left ventricle and maintain unusu­ally high systemic aortic blood pressures. Their mean aortic pressure on standing/at rest is about 220 Hg in contrast to about 100 mmHg in most other mammals.

As the giraffe lowers its head to the ground, arterial blood pressure at the level of the heart is reduced considerably, thereby maintaining a relatively constant blood flow to the brain. Further, the ability of the giraffe to regulate pressure and flow in peripheral vessels other than those to the head is also particularly very crucial for renal functioning.

6.5.2.1.1.3.2 VasomotorReflexes

These are of two types:

1. Pressor reflex: When the blood pressure falls to less than normal, the impulse frequency passing through the buffer nerves decreases, which stimulates cardio accelerator and vasoconstrictor centers of the medulla, the stimulation of which increases BP to normal level.

2. Depressor reflex: This reflex produces a fall in blood pressure. A rise in blood pressure above normal causes increased sensory impulse frequency through buffer nerves to the medullary vasomotor centers, where it causes inhibition of vasoconstrictor and sympathetic cen­ter but stimulates vagal center. These effects result in vasodilatation and decreased heart rate to establish normal blood pressure.

6.5.2.1.2 EndocrineRegulation

The epinephrine and norepinephrine released from sympa­thetic system and adrenal medulla activate adrenergic receptors on the cardiac muscle cells and on the endothelial or smooth muscle cells of blood vessels, act through α-receptors, and cause arteriolar vasoconstriction. Resistance to blood flow is increased, and total peripheral resistance increases. The hormones also cause blood to be pushed to the central circulation, an increase in ventricular preload, and venoconstriction (α-receptor activation). The hormones also cause the heart’s receptors to contract more quickly and forcefully, increasing the volume of the stroke. The increase in preload, stroke volume, and total peripheral resistance raises blood pressure. There are several different hormones that have an impact on blood pressure.

The following hormones cause an increase in blood pressure:

Adrenaline: Adrenaline is secreted by the adrenal medulla and is also released by sympathetic postganglionic nerve endings. Through its effects on the heart and blood vessels, adrenaline controls blood pressure. It increases systolic pressure by increasing the heart rate and cardiac output. By lowering the total peripheral resistance, it lowers diastolic pressure. Adrenaline causes constriction of blood vessels through α-receptors. It also causes dilata­tion of blood vessels through β2 receptors in some areas of the body like skeletal muscle, liver, and heart. So, the total peripheral resistance is reduced leading to decrease in diastolic pressure.

Noradrenaline: Noradrenaline is secreted by the adrenal medulla. It is also released by sympathetic postganglionic nerve endings. Because of its overall vasoconstrictor impact, noradrenaline causes a rise in diastolic pressure. It has stronger effects on blood vessels than on the heart. It causes constriction of all blood vessels throughout the body via α-receptors. Noradrenaline increases the total peripheral resistance, increases diastolic pressure, and causes slight increase in the systolic pressure by increas­ing the force of contraction of heart.

Thyroxine: Thyroxine secreted from thyroid gland increases systolic pressure but decreases diastolic pressure. It increases the systolic pressure by increasing cardiac out­put due to increase in the blood volume and force of contraction of the heart. Thyroxine has indirect action on diastolic pressure. Large quantities of metabolites are pro­duced during increased metabolic activity induced by thyroxine. These metabolites cause vasodilatation, leading to decrease in peripheral resistance. It causes decrease in diastolic pressure.

Aldosterone: Aldosterone, secreted from adrenal cortex, causes retention of sodium and water and thereby increases the ECF fluid volume and blood volume, leading to increase in blood pressure.

Vasopressin: Vasopressin produced by the supraoptic nucleus of hypothalamus has vasoconstrictor and antidiuretic effect. However, the physiological level of ADH in plasma is too low to produce vasoconstriction and its physiological role is related to long-term regulation of BP brought about by water reabsorption from the kidneys. In hemorrhage, large amounts of ADH are released, which brings about vasoconstriction.

Angiotensins: Angiotensins II, III, and IV obtained from angiotensinogen cause constriction of systemic arterioles and elevate blood pressure.

Serotonin (5-hydroxytryptamine): Serotonin is present in highest concentration in blood platelets and in the gastro­intestinal tract, where it is found in the enterochromaffin cells and the myenteric plexus. It is also found within the brain and spinal cord. It increases the blood pressure by vasoconstriction.

Endothelin (ET): Endothelin (ET), a21-amino acidpolypep- tide produced primarily by the vascular endothelium, is a potent vasoconstrictor that has three isoforms of which ET1 is most prominent that causes vasoconstriction and vascularization, induces the release of norepinephrine and serotonin during the regulation of vascular tone, and participates in the redistribution of blood flow during exercise. ET1 functions in a paracrine and autocrine fash­ion in pulmonary and systemic arteries and veins. Endothelins are produced by stretching of blood vessels. These peptides act by activating phospholipase, which in turn activates prostacyclin and thromboxane A2. These two substances cause the constriction of blood vessels and increase the blood pressure.

Thromboxane A2 (TXA2): Thromboxane A2 released from platelets causes vasoconstriction, especially when blood vessels become traumatized or ruptured.

Vasoactive intestinal polypeptide: Vasoactive intestinal polypeptide (VIP) is secreted in the stomach and small intestine. A small amount of this hormone is also secreted in large intestine. VIP is a vasodilator and causes dilata­tion of peripheral blood vessels and decrease in blood pressure.

Atrial natriuretic factor (ANF): Atrial natriuretic factor is a peptide hormone having 24-28 amino acids. Stretching of atria due to increased blood volume stimulates its release. It acts on kidney tubules and favors increased GFR and decreased Na⁺ reabsorption (natriuresis), diuresis, and vasodilatation. By its inhibitory action, it modulates the activity of renin, aldosterone, and ADH. Neuropeptide Y has direct vasoconstrictor property and regulates the release of atrial natriuretic factor and angiotensin II. It potentiates the effects of norepinephrine as well as vaso­constrictor actions of serotonin and K⁺, whereas it inhibits renin release. It provides moment-by-moment regulation of blood pressure and blood flow.

Histamine: Histamine is secreted in nerve endings of hypo­thalamus, limbic cortex, and other parts of cerebral cortex. Histamine is also released from mast cells and basophils during allergic conditions, inflammation, or damage. His­tamine causes vasodilatation and decreases blood pressure.

Prostaglandins: Prostaglandins are local hormones, synthesized by vascular endothelium from arachidonic acid. The prostaglandin PGE2 and prostacyclin (PGI2) are potent vasodilators.

Nitric oxide (endothelium-derived relaxing factor) (EDRF): Nitric oxide is released by the vascular endothelium and brain. It is synthesized from arginine and brain nitric oxide synthase. 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.

Adenosine: Adenosine released during tissue anoxia stimulates adenosine A2 receptors, activates cAMP mech­anism, and results in profound vasodilatation. ADP and ATP cause release of nitrous oxide from endothelial cells and act on P2 receptors. The nitrous oxide as a vasodilator substance causes vasodilation.

Bradykinin: Bradykinin is a vasoactive peptide causing func­tional hyperemia of the salivary glands and the pancreas, and its activity includes stimulation of nitric oxide synthase. Bradykinin is produced in blood during conditions like inflammation. During such conditions, the enzyme in the blood called kallikrein is activated. It acts on α2-globulin to form kallidin, which is converted into bradykinin. Bradykinin is a vasodilator substance and causes reduction in blood pressure.

6.5.2.1.3 Local Control of Blood Flow (Control of Capillaries)

1. Myogenic theory of autoregulation (pressure

autoregulation): Blood supply to organs is maintained almost constant even when arterial pressure changes. When blood pressure rises, the blood vessels dilate due to increased pressure and stretch the vascular smooth muscles surrounding the vessel, which contract because of stretching, and when pressure decreases, these muscles relax. In addition, when perfusion pressure (arteriovenous pressure difference) is increased above normal, additional blood flows through the organ due to increased pressure, which accelerates removal of metabolic products and increases oxygen delivery to the tissues. Hence, the con­centration of vasodilator metabolic products decreases. These two mechanisms help to maintain normal blood flow even when arterial pressure is increased or decreased. Pressure regulation is important to maintain blood supply to brain, heart, and kidneys.

2. Metabolic theory of autoregulation: Capillaries regulate the local blood supply to tissues according to the need of the tissues. Metabolic control of blood flow is the most important local control mechanism as it matches the blood flow in a tissue to the metabolic rate of the tissue, and it is stimulated by chemical changes within the tissue. An increase in tissue blood flow in response to increased meta­bolic rate is called active hyperemia. When the metabolic rate of a tissue increases, its consumption of oxygen increases, and there is an increased rate of production of metabolic products, including carbon dioxide, adenosine, and lactic acid. Also, some potassium ions (K⁺) escape from rapidly metabolizing cells, and these ions accumulate in the interstitial fluid. Therefore, as the metabolism of a tissue increases, the interstitial concentration of oxygen decreases, and the interstitial concentrations of metabolic products and K⁺ increase. All these changes relax the arteriolar smooth muscle; thereby, the arterioles and precapillary sphincters dilate, vascular resistance decreases, total capillary surface area for diffusional exchange increases, and more blood flows through the tissue, and hence more O₂ is delivered and accumulated metabolic products are removed. Reactive hyperemia refers to a temporary increase in blood flow to above normal in a tissue after a period of restricted blood flow. Autoregulation of blood flow is also a metabolic control phenomenon.

6.5.2.2 Long-Term Regulation of Blood Pressure

Kidneys play a vital role in the long-term regulation of arterial blood pressure. Slow blood pressure changes cause the nervous system to become accustomed to the new pres­sure and lose sensitivity to the changes. It cannot regulate the pressure anymore. In such conditions, the renal mechanism operates efficiently to regulate the blood pressure. Hence, it is called long-term regulation. Kidneys regulate arterial blood pressure by two ways:

1. By regulation of ECF volume

2. Through renin-angiotensin mechanism

6.5.2.2.1 Regulation of Extracellular Fluid Volume

When the blood pressure increases, kidneys excrete large quantities of water and salt, particularly sodium, by means of pressure diuresis and pressure natriuresis. Even a slight increase in blood pressure doubles the water excretion. Because of diuresis and natriuresis, there is a decrease in ECF volume and blood volume, which in turn brings the arterial blood pressure back to normal level. The reabsorption of water from renal tubules increases as blood pressure drops. This in turn raises cardiac output, blood volume, and ECF volume, restoring blood pressure.

6.5.2.2.2 Renin-Angiotensin Mechanism

In response to decreases in blood pressure, cells in the juxtaglomerular apparatus of the kidney produce an enzyme, renin. Renin acts on angiotensinogen, an α2-globulin produced by the liver and released into the circulation, and this results in the production of angiotensin I, a decapeptide. Angiotensin I is further hydrolyzed to angiotensin II, an octapeptide, by angiotensin-converting enzyme. Angiotensin II stimulates the zona glomerulosa to produce mineralocorticoid aldosterone released from adrenal cortex and conserves body sodium and water. The vasoconstriction and sodium conservation elevate blood pressure to normal. Angiotensin II also increases periph­eral resistance of the blood vascular system by causing vaso­constriction of smooth muscle of the blood.

6.6