Afterload and Its Components

October 21, 2015 Cardiology, Critical Care, Physiology and Pathophysiology, Respirology No comments , , , , , , , , , , ,


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Afterload in the intact heart reflects the resistance that the ventricle must overcome to empty its contents. It is more formally defined as the ventricular wall stress that develops during systolic ejection. Wall stress (σ), like pressure, is expressed as force per unit area and, for the left ventricle, may be estimated from Laplace relationship:

σ = (P x r)/(2 x h) [Laplace Equation]

where P is ventricular pressure, r is ventricular chamber radius, and h is ventricular wall thickness. Thus, ventricular wall stress rises in response to a higher pressure load (e.g., hypertension) or an increased chamber size (e.g., a dilated left ventricle). Conversely, as would be expected from Laplace relationship, an increase in wall thickness (h) serves a compensatory role in reducing wall stress, because the force is distributed over a greater mass per unit surface area of ventricular muscle.

Components of Afterload

The forces that contribute to ventricular afterload can be identified by their relationship to the variables in the Laplace equation. The component forces of ventricular afterload include end-diastolic volume (EDV/preload), pleural pressure, vascular impedance, and peripheral vascular resistance.

Pleural Pressure

Since afterload is a transmural wall tension, it will be influenced by the pleural pressure surrounding the heart. Therefore, negative pressure surrouding the heart will impede ventricular emptying by opposing the inward movement of the ventricular wall during systole. This effect is responsible for the transient decrease in systolic blood pressure that occurs during the insiratory phase of spontaneous breathing. When the inspiratory drop in systolic pressure is greater than 15 mm Hg, the condition is called "pulsus paradoxus" (which is a misnomer, since the response is not paradoxical, but is an exaggeration of the normal response).

Conversely, positive pressures surrounding the heart will promote ventricular emptying by facilitating the inward movement of the ventricular wall during systole. When intrathoracic pressure rises during a positive-pressure breath, there is a transient rise in systolic blood pressure, reflecting an increase in the stroke output of the heart. The inspiratory rise in blood pressure during mechanical ventilation is known as "reverse pulsus paradoxus". The "unloading" effect of positive intrathoracic pressure is the basis for the use of positive-pressure breathing as a "ventricular assist" maneuver for patients with advanced heart failure.


Vascular impedance is the force that opposes the rate of change in pressure and flow, and it is expressed primarily in the large, proximal arteries, where pulsatile flow is predominant. Impedance in the ascending aorta is considered the principal afterload force for the left ventricle, and impedance in the main pulmonary arteries is considered the principal afterload force for the right ventricle. Vascular impedance is a dynamic force that changes frequently during a single cardiac cycle, and it is not easily measured in the clinical setting.


(Systemic) vascular resistance is the force that opposes non-pulsatile or steady flow, and is expressed primarily in small, terminal blood vessels, where non-pulsative flow is predominant. About 75% of the vascular resistance is in arterioles and capillaries. In the beginning of arterioles, although the blood pressure is still pulsatile, the vascular smooth muscles have autoregulation function so the blood flow is steady. Becasue the flow is steady, the mean arterial pressure had been created to equal the "average" arterial pressure during a cardac cycle, under which the amount of blood flow per time is the same. So the relationship between SVR, MAP, and CO is:

SVR = (MAP – RAP) / CO

Similarly, the relationship between PVR, PAP, and CO is:

PVR = (PAP – LAP) / CO

However, SVR and PVR are not considered to be accurate representations of the resistance to flow in the pulmonary and systemic circulations. Because vascular impedance is not easily measured, vascular resistance is often used as a clinical measure of ventricular afterload. But animal studies have shown a poor correlation between direct measures of ventricular wall tension (true afterload) and the calculated vascular resistance. This is consistent with the notion that vascular impedance is the principal afterload force for ventricular emptying. However, the contribution of vascular resistance to afterload cannot be determined with the SVR and PVR because these parameters do not represent the actual resistance to flow in the circulatory system.

Determinants of Myocardial Oxygen Consumption



Myocyte contraciton is the primary factor determining myocardial oxygen consumption (MVO2) above basal levels. Therefore, factors that enhance tension development by the caridac muscle cells, the rate of tension development, or the number of tension generating cycles per unit time will increase MVO2. For example, doubling heart rate approximately doubles MVO2 because ventricular myocytes are generating twice the number of tension cycles per minute. Increasing inotropy also increases MVO2 because the rate of tension development is increased as well as the magnitude of tension, both of which result in increased ATP hydrolysis and oxygen consumption. Increasing afterload, because it increases tension development, also increases MVO2. Increasing preload (e.g., ventricular end-diastolic volume) also increases MVO2; however, the increase is much less than what might be expected because of the LaPlace relationship.

The LaPlace relationship has been discussed above. If we substitute ventricular end-diastolic volume/EDV for ventricular radius, we get below new LaPlace equation:

Screen Shot 2016-07-18 at 1.16.30 PMThis relationship indicates that a 100% increase in venticular volume (V) incrases wall tension (T) by only 26%. In contrast, increasing intraventricular pressure (P) by 100% increases wall tension by 100%. For this reason, wall tension, and therefore MVO2, is far less sensitive to changes in ventricular volume than pressure.

Physiologic Adapations and Maladaptations in Heart Failure

October 20, 2015 Cardiology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , , , , ,

Basic Concepts


The concept of preload in the intact heart was described by physiologists Frank and Starling a century ago. The preload can be though of as the amount of myocardial stretch at the end of diastole, just before contraction. Measurements that correlate with myocardial stretch, and that are often used to indicate the preload on the horizontal axis, are the ventricular end-diastolic volume (EDV).


Afterload in the intact heart reflects the resistance that the ventricle must overcome to empty its contents. It is more formally defined as the ventricular wall stress that develops during systolic ejection. Wall stress (σ), like pressure, is expressed as force per unit area and, for the left ventricle, may be estimated from Laplace relationship:

σ = (P x r)/(2 x h)

where P is ventricular pressure, r is ventricular chamber radius, and h is ventricular wall thickness. Thus, ventricular wall stress rises in response to a higher pressure load (e.g., hypertension) or an increased chamber size (e.g., a dilated left ventricle). Conversely, as would be expected from Laplace relationship, an increase in wall thickness (h) serves a compensatory role in reducing wall stress, because the force is distributed over a greater mass per unit surface area of ventricular muscle.

Pathophysiology of Heart Failure

The pathophysiology of heart failure is complex and must be understood at multiple levels. Traditionally, research has focused on the hemodynamic changes of the failing heart, considering the heart as an isolated organ. However, studies of the failing heart have emphasized the importance of understanding changes at the cellular level and the neuro-hormonal interactions between the heart and other organs of the body.

Hemodynamic Changes

From a hemodynamic standpoint, heart failure can arise from worsening systolic or diastolic function or, more frequently, a combination of both.

Systolic Dysfunction

In systolic dysfunction, the isovolumic systolic pressure curve of the pressure-volume relationship is shifted downward (A). This reduce the stroke volume of the heart with a concomitant decrease in cardiac output. To maintain cardiac output, the heart can respond with three compensatory mechanisms:

1.Increased return of blood to the heart (preload) can lead to increased contraction of sarcomeres. In the pressure-volume relationship, the heart operates at a' instead of a, and stroke volume increases, but at the cost of increased end-diastolic pressure (D).

2.Second, increase release of catecholamines can increase cardiac output by both increasing the heart rate and shifting the systolic isovolumetric curve to the left (C).

3.Cardiac muscle can hypertrophy and ventricular volume can increase, which shifts the diastolic curve to the right (B).

Screen Shot 2015-10-18 at 7.15.43 PMAlthough each of these compensatory mechanisms can temporarily maintain cardiac output, each is limited in its ability to do so, and if the underlying reason for systolic dysfunction remains untreated, the heart ultimately fails.

Diastolic Dysfunction

Screen Shot 2015-10-18 at 8.49.51 PMIn diastolic dysfunction, the position of the systolic isovolumic curve remains unchanged (contractility of the myocytes is preserved). However, the diastolic pressure-volume curve is shift to the left, with an accompanying increase in left ventricular end-diastolic pressure and symptoms of heart failure. Diastolic dysfunction can be present in any disease that causes decreased relaxation, decreased elastic recoil, or increased stiffness of the ventricle.

Neurohormonal Changes

After an injury to the heart, increased secretion of endogenous neurohormones and cytokines is observed. Initially, increased activity of the adrenergic system and the renin-angiotensin system provides a compensatory response that maintains perfusion of vital organs. However, over time these changes can lead to progressive deterioration of cardiac function.

Sympathetic Nervous System

Increased sympathetic activity occurs early in the development of heart failure. Elevated plasma norepinephrine levels cause increased cardiac contractility and an increased heart rate that initially help maintain cardiac output. However, continued increases lead to increased preload (as a result of venous vasoconstriction) and afterload (from arterial vasoconstriction), which can worsen heart failure. In addition, sympathetic hyperactivity causes deleterious cellular changes.


Reduced renal blood pressure stimulates the release of renin and increases the production of angiotensin II. Both angiotensin II and sympathetic activation cause efferent glomerular arteriolar vasoconstriction, which helps maintain the glomerular filtration rate despite a reduced cardiac output. Angiotensin II stimulates aldosterone synthesis, which leads to sodium resorption and potassium excretion by the kidneys. However, a vicious circle is initiated as continued hyperactivity of the renin-angiotensin system leads to severe vasoconstriction, increased afterload, and further reduction in cardiac output and glomerular filtration rate.


Heart failure is associated with increases release of vasopressin from the posterior pituitary gland. Vasopressin is another powerful vasoconstrictor that also promotes reabsorption of water in the renal tubules (collecting ducts).

Cytokines and Others

Heart failure is associated with the release of cytokines and other circulating peptides. Cytokines are a heterogeneous family of proteins that are secreted by macrophages, lymphocytes, monocytes, and endothelial cells in response to injury. The interleukins (ILs) and tumor necrosis factor (TNF) are the two major groups of cytokines that may have an important pathophysiologic role in heart failure. Upregulation of the gene responsible for TNF with an acompanying increase in circulating plasma levels of TNF has been found in patients with hear failure. TNF appears to have an important role in the cycle of myocyte hypertrophy and cell death (apoptosis). Preliminary in vitro data suggest that IL-1 may accelerate myoctye hypertrophy. Another peptide important for mediating some of the pathophysiologic effects observed in heart failure is the potent vasoconstrictor endothelin, which is released from endothelial cells. Preliminary data have suggested that excessive endothelin release may be responsible for hypertension in the pulmonary arteries observed in patients with left ventricular heart failure. Endothelin is also associated with myocyte growth and deposition of collagen in the interstitial matrix.

Cellular Changes

Pathophysiologic chanages at the cellular level are very complex and include changes in Ca2+ handling, adrenergic receptros, contractile apparatus, and myocyte structure.

Ca2+ Handling

In heart failure, both delivery of Ca2+ to the contractle apparatus and reuptake of Ca2+ by the sarcoplasmic reticulum are slowed. Decreased levels of messenger ribonucleic acid (mRNA) for the specialized Ca2+ release channels have been reported by some investigators. Similarly, myocytes from failing hearts have reduced levels of mRNA for the two sarcoplasmic reticulum proteins phospholamban and Ca2+-ATPase.

Changes of Adrenergic Receptors

Two major classes of adrengeric receptors are found in the human heart. Alpha1-adrenergic receptors are important for induction of myocardial hypertrophy; levels of alpha1 receptors are slightly increased in heart failure. Heart failure is associated with significant beta-adrenergic receptor desensitization as a result of chronic sympathetic activation. This effect is mediated by downregulation of beta1-adrenergic receptors, downstream uncoupling of the signal transducton pathway, and upregulation of inhibitory G proteins. All of these changes lead to a further reduction in myocyte contractility.

Contractile Apparatus

Cardiac myocytes cannot proliferate once they have matured to their adult form. However, these is a constant turnover of the contractile proteins that make up the sarcomere. In response to the hemodynamic stresss associated with heart failure, angiotensin II, TNF, norepinephrine, and other molecules induce protein synthesis via intranuclear mediators of gene activity. This causes myoctye hypertrophy with an increase in sarcomere numbers and a re-expression of tetal and neonatal forms of myosin and troponin. Activation of this primitive program results in the development of large myocytes that do not contract normally and have decreased ATPase activity.

Myocyte Structure Changes

The heart enarges in response to continued hemodynamic stress. Changes in myocardial size and shape associated with heart failure are collectively referred to as left ventricular remodeling. Several tissue is associated with myocyte loss via a process of necrosis, apoptosis (programmed cell death). Unlike the process of necrosis, apoptotic cells initially demonstrate decreased cell volume without disrutpion of the cell membrane. However, as the apoptotic process continues, the myocyte ultimately dies, and "holes" are left in the myocardium. Loss of myocytes places increased stress on the remaining myoctes. The process of apoptosis is accelerated by the proliferative signals that stimulate myocyte hypertrophy such as TNF. Although apoptosis is a normal process that is essential in organs made up of proliferating cells, in the heart apoptosis initiates a vicious circle whereby cell death causes increased stress that leads to hypertrophy and further acceleraton of apoptosis.

A second tissue change observed in heart failure is an increased amount of fibrous tissue in the interstitial spaces of the heart. Collagen deposition is due to activation of fibroblasts and myocyte death. Endothelin release leads to interstitial collagen deposition. The increase in connective tissue increase chamber siffness and shifts the diastolic pressure-volume curve to the left.

Finally, heart failure is associated with gradual dilation of the ventricle. Myocyte "slippage" as a result of activation of collagenases that disrupt the collagen network may be responsible for this process.

The Regulation of Circulation (Heart, Neurohormons, Local)

February 19, 2015 Cardiology, Physiology and Pathophysiology No comments , , , , , , ,

Screen Shot 2015-02-01 at 3.47.09 PMHeart is innervated by both sympathetic and parasympathetic divisions of the autonomic nervous system. Release of norepinephrine from postganglionic sympathetic nerves activates β1-adrenoceptors in the heart, notably on the sion-atrial (SA) node, atrioventricular (AV) node, His-Purkinje conductive tissue, and atrial and ventricular contractile tissue. In response to stimulation of sympathetic nerves, the heart rate (chronotropy), rate of transmission in the cardiac conducive tissue (dormitory), and the force of ventricular contraction (inotropy) are increased.

On the other hand, release of acetylcholine from postganglionic parasympathetic (vagus) nerves activates nicotinic receptors in the heart, notably on the SA and AV nodes and atrial muscle. In response to stimulation of the vagus nerve, the heart rate, the rate of transmission through the AV node, and atrial contractility are reduced.

Besides, there are adrenergic and cholinergic receptors on autonomic nerve terminals that modulate transmitter release from nerve endings. For example, releases of acetylcholine from vagal nerve terminals inhibits the release of norepinephrine from sympathetic nerve terminals, so this enhance the effects of vagal nerve activation on the heart.

The Cardiac Cycle

Detail here,

The Cardiac Output

Predictably, changes in cardiac output that are called for by physiologic conditions can be produced by changes in cardiac rate, or stroke volume, or both.

End-diastolic ventricular volume, in health person it is usually about 130 mL.

End-systolic ventricular volume, in health person it is usually about 50 mL.

Ejection fraction = stroke volume/end-diastolic ventricular volume, in health person it is usually about 65%.

The cardiac rate is controlled primarily by the autonomic nerves, with sympathetic stimulation increasing the rate and parasympathetic stimulation decreasing it. Stroke volume is also determined in part by neural input, with sympathetic stimuli making the myocardial muscle fibres contract with greater strength at any given length and parasympathetic stimuli having the opposite effect. When the strength of contraction increases without an increase in finer length, more of the blood that normally remains in the ventricles is expelled.

Isometric contractions and the effect of muscle length on resting tension and active tension development

Isometric contractions and the effect of muscle length on resting tension and active tension development

The force of contraction of cardiac muscle also depends on its preloading and its afterlaoding. These factors are illustrated in the figure on the left. A muscle strip is stretched by a load (the preload) that rests on a platform. The initial phase of the contraction is isometric; the elastic component in series with the contractile element is stretched, and tension increases until it is sufficient to lift the load. The tension at which the load is lifted is the afterload. The muscle then contracts isotonically without developing further tension. In vivo, the preload is the degree to which the myocardium is stretched before it contracts and the afterload is the resistance against which blood is expelled.

PS: Muscle

Cardiac muscle has cross-striations, but it is functionally syncytial and, although it can be modulated via the autonomic nervous system,  it can contract rhythmically in the absence of external innervation owing to the presence in the myocardium of pacemaker cells that discharge spontaneously.

Muscular contraction involves shortening of the contractile elements, but because muscles have elastic and viscous elements in series with the contractile mechanisms, it is possible for contraction to occur without an appreciable decrease in the length of the whole muscle. Such a contraction is called isometric. Contraction against a constant load with a decrease in muscle length is isotonic. Note that because work is the product of force times distance, isotonic contractions do not work, whereas isometric contractions do not. In other situations, muscle can do negative work while lengthening against a constant weight.

Length-Tension Relationships

Isometric Contractions

The influence of muscle length on the behavior of the cardiac muscle during isometric contraction is illustrated in Figure 2-8. The top panel shows the experimental arrangement for measuring muscle force at rest and during contraction at three different lengths. The middle Panel shows time records of muscle tensions recorded at each of the three lengths in response to an external stimulus, and the bottom panel shows a graph of the resting and peak tension results plotted against muscle length.

The first important fact illustrated in Figure 2-8 is that force is required to stretch a resting muscle to different lengths. This force is called the resting tension. The lower curve in the graph in Figure 2-8 shows the resting tension measured at different muscle lengths and is referred to as the resting length-tension curve. When a muscle is stimulated to contract while its length is held constant, it develops an additional component of tension called active or developed tension. The total tension exerted by a muscle during contraction is the sum of the active and resting tensions.

The second important fact illustrated in Figure 2-8 is that the active tension developed by the cardiac muscle during the course of an isometric contraction depends very much on the muscle length at which the contraction occurs. Active tension development is maximal at some intermediate length referred to as Lmax. Little active tension is developed at very short or very long muscle lengths. Normally, the cardiac muscle operates at lengths well below Lmax so that increasing muscle length increases the tension developed during an isometric contraction.

Description of isotonic and after loaded contractions within the constraints of the cardiac muscle length-tension diagram

Description of isotonic and after loaded contractions within the constraints of the cardiac muscle length-tension diagram

Isotonic Contractions

During what is termed isotonic contraction (the load is fixed), a muscle shortens against a constant load. A muscle contracts isotonically when it develops sufficient tension to lift a fixed weight such as 1-g load shown in Figure 2-9. Such a 1-g weight placed on a resting muscle will result in some specific resting muscle length, which is determined by the muscle’s resting long-tension curve. If the ends of the muscle were to be fixed between two immoveable objects and the muscle were to be activated at this fixed length, it would contract isometrically and be capable of generating a certain amount of tension, for example, 4.5 g as indicated by the dashed line in the graph in Figure 2-9. A contractile tension of 4.5 g obviously cannot be generated if the muscle is allowed to shorten and actually lift the 1-g weight. When a muscle has contractile potential in excess of the tension required to move the load, it will shorten. Thus, in an isotonic contraction, muscle length decreases at constant tension, as illustrated by the horizontal arrow from point 1 to point 3 in Figure 2-9. As the muscle shortens, however, its contractile potential inherently decreases, as indicated by the downward slope of the peak isometric tension curve in Figure 2-9. There exists some short length at which the muscle is capable of generating only 1 g of tension, and when this length is reached, shortening must cease. Therefore, the peak isometric curve on a cardiac muscle length-tension diagram also establishes the limit on how far muscle shortening can proceed with different loads.

Figure 30-5 illustrate three important factors that alter cardiac output, including  preload, and contractility, heat rate, and afterload. It should be always remembered in mind that cardiac out is the result of the integrated control of those mechanisms discussed below.


Preload affects the cardiac output by Frank-Starling law. For the heart the length of the muscle fibres (preload) is proportional to the end-diastolic volume. When the muscle is stretched, the developed tension increases to a maximum and then declines as stretch becomes more extreme. Figure 5-18 show the principle of Frank-Starling law.Length-tension relationship for cardiac muscle Several factors can affect the cardiac output via preload, including,

1.An increase in intrapericardial pressure limits the extent to which the ventricle can fill.

2.A decrease in ventricular compliance limits the extent to which the ventricle can fill. This condition consists of increase in ventricular stiffness produced by myocardial infarction, infiltrative disease, and so on.

3.Atrial contractions (the “atrial kick”) aid ventricular filling. Especially in elderly people the atrial kick contribute significantly to the ventricular filling.

4.Factors affecting the amount of blood returning to the heart likewsie change the ventricular filling during diastole. For instance, an increase in total blood volume increases venous return. Constriction of the veins reduces the size of the venous reservoirs, decreasing venous pooling and thus increasing venous return. An increase in the normal negative intrathoracic pressure increase the pressure gradient along which blood flows to the heart, where a decrease impedes venous return. Standing decreases venous return, and muscular activity increases it as a result of the pumping action of skeletal muscle.

Someone summarised the factors affecting ventricle filling, including 1.the filling pressure of blood returning to the heart and artia;2.the ability of the AV valves to open fully;and 3.the ability of the ventricular wall to expand passively with little resistance (compliance).


The ANS affects the contractility directly via neurotransmitters, with sympathetic nerves increasing the contractility and parasympathetic nerves decreasing it.

Circulating neurohormonals affects heart contractility in the same way like the ANS, with catecholamines increasing the contractility and acetylcholine decreasing it.

Change of heart rate and rhythm also contribute to contractility as discussed below.

Heart Rate

Heart increases the cardiac out obviously because the cardiac out equals the stroke multiplying the heart rate (CO = SV * HR). Heart rate is influenced by ANS directly. Circulating neurohormones also contribute to the accelerate or decelerate the heart rate. However, if the heart rate is too fast, the time used to ventricular filling is compromised, and as a result the ventricular end-diastolic volume is reduced, which causes: 1.preload is compromised; 2.the heart starts to eject blood while the ventricle is not properly filled enough.

Changes in cardiac rate and rhythm also affect myocardial contractility, know as the force-frequency relation. Ventricular extrasystoles condition the myocardium in such a way that the next succeeding contraction is stronger than the preceding normal contraction. This postextrasystolic potentiation is independent of ventricular filling, since it occurs in isolated cardiac muscle and is due to increased availability of intracellular Ca2+. Also while the heart rate increases, the myocardial contractility increases, although the increment is relatively small.


Figure 2-9 shows a complex type of muscle contraction that is typical of the way cardiac muscle cells actually contract in the heart. This is called an after loaded isotonic contraction, in which the load on the muscle at rest (the preload) and the load on the muscle during contraction (the total load) are different. In the example of Figure 2-9, the preload is equal to 1 g, and because an additional 2-g weight (the afterload) is engaged during contraction, the total load equals 3 g.

Because preload determines the resting muscle length, both contractions shown at top of Figure 2-9 begin from the same length. Because of the different loading arrangement, however, the after loaded muscle must increase its total tension to 3 g before it can shorten. This initial tension will be developed isometrically and can be represented as going from point 1 to point 4 on the length-tension diagram. Once the muscle generates enough tension to equal the total load, its tension output if fixed at 3 g and it will now shorten isotonically because its contractile potential still exceeds its tension output. This isotonic shortening is represented as a horizontal movement on the length-tension diagram along the line from point 4 to point 5. As in any isotonic contraction, shortening must cease when the muscle’s tension-producing potential is decreased sufficiently by the length change to be equal to the load on the muscle.

So, it is very clear that the afterload limits the degree at which the cardiac muscle can shorten maximally.

Systemic Regulation by Nuerohumoral Agents

Many circulating substances affect the vascular system. The vasodilator regulators include kinins, VIP (vasoactive intestinal polypeptide), and ANP (atrial natriuretic peptide/natriuretic hormones). Circulating vasoconstrictor hormones include vasopressin, norepinephrine, epinephrine, and angiotensin II.


Two related vasodilator peptides called kinins are found in the body. One is the nonapeptide bradykinin, and the other is the decapeptide lysylbradykinin, also known as kallidin. The action of both kinins resemble those of histamine. They are primarily paracrines, although small amounts are also found in the circulating blood. They cause contraction of visceral smooth muscle, but they relax vascular smooth muscle via NO, lowering blood pressure. They also increase capillary permeability, attract leukocytes, and cause pain upon injection under the skin.

They are formed during active secretion in sweat glands, salivary glands, and the exocrine portion of the pancreas, and they are probably responsible for the increase in blood flow when these tissues are actively secreting their products.

Vasoactive Intestinal Peptide

Also known as the vasoactive intestinal polypeptide or VIP is a peptide hormone containing 28 amino acidresidues. VIP is neuropeptide that belongs to a glucagon/secretin superfamily, the ligand of class II G protein-coupled receptors.[1] VIP is produced in many tissues of vertebrates including the gut, pancreas, and suprachiasmatic nuclei of the hypothalamus in the brain.[2][3] VIP stimulates contractility in the heart, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gall bladder.

Natriuretic Hormones

There is a family of natriuretic peptides involved in vascular regulation, including  atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). ANP and BNP are secreted by the heart, where the muscle cells in the atria and, to a lesser extent, in the ventricles contain secretory granules. They are also present in human brain. They are released in response to hypervolemia. ANP secretion is increased when ECF volume is increased and the atria are stretched. BNP secretion is increased when the ventricles are stretched.

PS: ANP secretion is also increased by immersion in water up to the neck, a procedure that counteracts the effect of gravity on the circulation and increases central venous and consequently atrial pressure.

ANP and BNP circulate, whereas CNP acts predominantly in a paracrine fashion. In general, these peptides antagonise the action of various vasoconstrictor agents and lower blood pressure due to relax vascular smooth muscle in arterioles and venules. Natriuretic hormones have other actions including to increase the permeability of capillary, leading to extravasation of fluid and a decline in blood pressure.

In the brain, ANP is present in neurons, and an ANP-containing neural pathway projects from the anteromedial part of the concerned with neural regulation of the cardiovascular system. ANP’s effects are generally opposite to those of angiotensin II. BNP and CNP in the brain probably have similar function as ANP.

In the kidneys, ANP and BNP also serve to coordinate the control of vascular tone with fluid and electrolyte homeostasis. Specifically, ANP and BNP in the circulation act on the kidneys to increase fluid and Na+ excretion and injected CNP has a similar effect. They appear to produce this effect by dilating afferent arterioles and relaxing mesangial cells. Both of these actions increase glomerular filtration. In addition, they act on the renal tubules to inhibit Na+ reabsorption.

PS: ANP: atrial natriuretic peptide (ANP), BNP: brain natriuretic peptide, and CNP: C-type natriuretic peptide.

Circulating Vasoconstrictors

Vasopressin is a potent vasoconstrictor, but when it is injected in normal individuals, there is a compensating decrease in cardiac output, so that there is little change in blood pressure. Vasopressin’s main function is to regulate the ECF volume, see

Norepinephrine has a generalized vasoconstrictor action, whereas epinephrine dilates the vessels in skeletal muscle and the liver, see

Angiotensin II has a generalized vasoconstrictor action of angiotensin converting enzyme (ACE) on angiotensin I, which itself is liberated by the action of renin from the kidney on circulating angiotensinogen. See for the factors affecting production of Angiotensin II.

Urotensin-II, a polypeptide first first isolated from the spinal cord of fish, is present in human cardiac and vascular tissue. It is one of the most potent mammalian vasoconstrictors known, and is being explored for its role in a large range of different human disease states. For example, levels of both urotensin-II and its receptor have been shown to be elevated in hypertension and heart failure, and may be marker of disease in these and other conditions.

Local Regulation


See thread The Autoregulation of Renal Blood Flow

Vasodilator Metabolites

The metabolic changes that produce vasodilation include, in most tissues, decreases in O2 tension and pH. These changes cause relaxation of the arterioles and pre capillary sphincters.

A local fall in O2 tension, in particular, can initiate a program of vasodilatory gene expression secondary to production of hypoxia-inducible factor-1α (HIF-1α), a transcription factor with multiple targets.

Increased in CO2 tension and osmolality also dilate the vessels. The direct dilator action of CO2 is most pronounced in the skin and brain.

A rise in temperature exerts a direct vasodilator effect, and the temperature rise in active tissues (due to the heat of metabolism) may contribute to the vasodilation.

K+ is another substance that accumulates locally, and has demonstrated dilator activity secondary to the hyperpolarization of vascular smooth muscle cells.

Lactate may also contribute to the dilation.

In injured tissues, histamine released from damaged cells increases capillary permeability. Thus, it is probably responsible for some of the swelling in areas of inflammation.

Adenosine may play a vasodilator role in cardiac muscle but not in skeletal muscle. It also inhibits the release of norepinephrine.

Local Vasoconstriction

Injured arteries and arterioles constrict strongly. The constriction appears to be due in part to the local liberation of serotonin from platelets that stick to the vessel wall in the injured area. Injured veins also constrict.

A drop in tissue temperature causes vasoconstriction, and this local response to cold plays a part in temperature regulation.