Mechanisms Controlling Blood Flow and Arterial Pressure

Mechanisms Controlling Blood Flow and Arterial Pressure

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Mechanisms Controlling Blood Flow and Arterial Pressure

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Claire E Sears

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Barbara Casadei

The key word to consider when thinking about the control of blood flow and arterial blood pressure (ABP) is ‘integration’. The body has developed a large number of integrated homeostatic mechanisms in order to keep ABP and flow at around constant levels, with the aim of maintaining adequate perfusion of the vital organs both at rest and in situations where there is a change in environment or workload. Maintenance of normal ABP is mainly dependent on the balance between cardiac output and peripheral vascular resistance (PVR), related by the equation: Mean ABP = Cardiac output × PVR There is integration between central control by the nervous system and local control in the tissues, and here we summarize the key mechanisms involved. Autoregulation is the process by which blood flow is maintained constant despite changes in ABP (Figure 1). This process is crucial for two main reasons: one is to keep a constant supply of nutrients for the continuing function of the tissues, and the other is to control capillary pressure, as

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its increase could lead to excessive fluid filtration and hence depletion of plasma volume. Autoregulation, of course, can never be perfect, and so in practice it can be said that it limits the tendency for an increase in pressure to increase flow. The regulation is, however, of sufficient efficiency that there is only about a 10ml/min increase in flow over a 70 mmHg pressure change. Resistance vessels play an important role in the regulation of local blood flow and capillary pressure (Figure 2). Poiseuille’s equation tells us that resistance is governed by the fourth power of the radius of the vessel, so small changes in radius have a profound effect on flow. The founding work that has led to the establishment of these principles can be

traced back to William Harvey’s discovery of the circulation of the blood in the 1600s, but one of the key pieces of evidence comes from Bayliss (1902) who was the first to describe autoregulation. He noted that in the dog a rise in ABP was associated with a decrease in hind limb volume. There are two main processes involved in autoregulation. (1) A metabolic process, which regulates the tight coupling between blood flow and tissue metabolism. (2) A myogenic process, which modulates blood vessel response to a change in intravascular pressure. Sometimes the myogenic and metabolic processes will exist in conflict with one another, but mostly they are in balance, although the dominance between the two

Schematic structure of an arterial blood vessel and key equations concerned with the control of blood pressure and flow ������������� ���������������� ����������������� ����� ������������

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Claire E Sears is a Royal Society Dorothy Hodgkin Research Fellow in the Department of Cardiovascular Medicine, University of Oxford. Her interests include the role of nitric oxide in the control of cardiac contractility and the development of pacemaker currents in ventricular tissue in heart disease.

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Barbara Casadei is a Senior Research Fellow of the British Heart Foundation and an Honorary Consultant in the Department of Cardiovascular Medicine, University of Oxford. Her interets include the free radical control of myocardial excitability.

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processes differs in different vascular beds, depending on function. For example, in dependent limbs, where gravitational effects are of obvious importance, the myogenic response of skin and subcutaneous vessels is particularly strong and prevents the gravity-induced increase in capillary pressure from affecting fluid volume. In contrast, in the heart, which is largely protected from gravitational effects, the emphasis is on providing sufficient blood flow to match the high metabolic demand. As a general rule, in times of low or decreasing flow, priority is given to metabolic effects, whilst myogenic effects become relatively more important when flow (and pressure) are high. The metabolic response It is thought that the matching of blood flow to metabolic demand depends upon an accumulation of vasodilator metabolites, either due to their reduced washout or their increased production. These metabolites then cause arteriolar vasodilatation and hence increase perfusion and oxygen supply. Oxygen concentration is thought to be a crucial factor. Experiments in the 1960s in coronary blood vessels showed that blood flow increased after release of an occlusion and then gradually fell back to control levels. The experiment was repeated with deoxygenated blood and in this case hyperaemia was sustained even after release of the occlusion until O 2 was re-introduced. However, the position and nature of the oxygen sensor has not been established. Wherever and however O2 is sensed, it is thought that hypoxia in times of low flow leads to production of anaerobic vasodilator metabolites. However, hypoxia may also act as a direct vasodilator by causing a fall in the ratio of ATP/ADPi, which results in KATP channels opening and relaxation of vascular smooth muscle. In addition, the direct effect of O2 cannot explain sustained metabolic responses – measurements with an O2-sensitive electrode show that after the removal of an occlusion PO2 rises back to control levels long before the reactive hyperaemia falls off. Various candidates have been suggested: H+, K+, lactic acid, ADP, AMP and adenosine. No one candidate is accepted as ‘the vasodilator metabolite’, and in fact it seems likely that different metabolites play different roles in different vascular beds. In the coronary circulation, adenosine

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has emerged as the most likely vasodilator metabolite. It is produced when AMP, accumulating as a result of increased ATP breakdown, is dephosphorylated by cell membrane enzyme 5´-nucleotidase, and is broken down by adenosine deaminase. Its mechanism of action is via A2 receptors and enzyme-induced increases in cAMP (Figure 3). Consistent with this idea, cardiac muscle hypoxic vasodilatation is abolished by the highly selective adenosine blocker 8-phenyltheophylline in the anaesthetized dog. However, adenosine production is not exactly correlated with tissue O 2 level, suggesting that other metabolites may be involved. In skeletal muscle, adenosine receptor antagonists and adenosine deaminase have little effect on exercise hyperaemia. In this tissue, potassium seems a better candidate. Indeed, raised K+ increases its conductance in vascular smooth muscle, causing hyperpolarization and hence relaxation. However, the rise in K+ is only transient so sustained hyperaemia must again involve other metabolites. Other possible metabolites include calcitonin gene-related peptide (CGRP). This has been implicated in the metabolic response of cerebral vessels where capsaicin, which depletes CGRP in nerves, markedly attenuates metabolic responses in the cerebral pial artery. As a vasodilator candidate, a neurotransmitter such as CGRP has certain attractive properties: the response is fast and acts in a feed-forward manner by the same stimulus that causes vasoconstriction, i.e. the action potential. Other vasodilators may be important under certain circumstances, for example, in the presence of inflammation, various autacoids are released. Histamine, prostaglandin E2, bradykinin and platelet-activating factor all cause vasodilatation as well as increasing postcapillary venular permeability to aid access of leucocytes and antibodies to a site of infection or damage. Most vasodilators are thought to work through activation of the 2nd messengers cAMP and cGMP (Figure 3). Production of cGMP leads to PKG activation, which may result in relaxation of vascular smooth muscle due to activation of K+ channels and subsequent hyperpolarization. There may also be enhanced Ca2+ extrusion caused by stimulation of the sarcoplasmic Ca2+ pump. Cyclic AMP is also thought to stimulate the Ca2+ pump and to open ATP-sensitive and Ca 2+-

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activated K+ channels, while PKA may phosphorylate and inactivate myosin light chain kinase.

The myogenic response In 1902, Bayliss (see earlier) noted a secondary rise in blood volume in the dog hind limb when the clamp on the aorta was released. This is known as reactive hyperaemia and refers to the regulation of flow and pressure in a vessel in response to changes in intramural pressure. The immediate mechanical effect of raising internal pressure is distension of the vessels and a decrease in resistance, and this is followed in most arterioles and some arteries by a contractile response. As already mentioned, this is of particular importance in orthostasis. The interesting question concerning the myogenic response is the nature and position of the pressure sensor that effects this action. Currently, it is believed that wall stress is sensed, resulting in the opening of stretch-activated channels. That wall stress instead of stretch per se is sensed is supported by data showing that the autoregulatory response persists after vessels have been constricted by application of noradrenaline. It is thought that stretch causes depolarization of vascular smooth muscle cells via stretch-activated cation channels, and this may result in the activation of voltagedependent Ca2+ channels. Indeed, stretch has been shown to increase [Ca 2+] i in vascular smooth muscle cells and findings indicate that dihydropyridine Ca2+ channel blockers abolish or at least dramatically attenuate myogenic responsiveness, whilst Ca2+ channel openers enhance it. Stretch-activated cation channels may be regulated by forces transmitted through the cytoskeleton, with transduction possibly occurring via integrins. Consistent with this hypothesis, integrin-binding peptides inhibit myogenic tone in skeletal muscle arterioles. A role for second messengers has also been implicated, particularly in autoregulation of the cerebral and renal circulations. Here, stretch is thought to lead to phospholipase C activation, resulting in IP3 and diacylglycerol production, and arachidonic acid release. Arachidonic acid is converted by cytochrome p450 to 20-hydroxy eicosatetraenoic acid (20-HETE). 20-HETE is an inhibitor of

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Simplified schematic showing some of the intracellular pathways involved in smooth muscle relaxation ��������������������������������� �� ���������������������������� ������������������� ������������������������ ������������������������ ������������������������������������� ������������������������������������� ������������������������ ������������������������ I���������������������������������� I���������������������������������� I���������������I������������������� �������������� ����������������������������� ������������������������������������������� ��������������������������������� �� �������������������������������������� ������������������������������������

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KCa channels (possibly via protein kinase C or tyrosine kinase). It constricts arterioles at nanomolar levels and is released in a pressure-dependent manner. Its key role has been demonstrated in vivo where inhibition of 20-HETE production impairs renal blood flow autoregulation. Both mRNA and protein for 20-HETE

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biosynthesis have been localized to vascular smooth muscle cells. Interestingly, in the cerebral circulation the effects of 20-HETE may be regulated by arachidonic acid. This is converted to epoxyeicosatrienoic acid (EET), which stimulates KCa channels. Inhibition of KCa channels causes depolarization of the membrane potential and vasoconstriction.

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Relaxation occurs when intracellular calcium activates KCa channels.

Tubulo-glomerular feedback The kidney is the single most important organ in the control of blood volume and ABP, and it has its own autoregulatory processes. In the kidney, autoregulation

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maintains near constant flow via stretchactivated channels. In addition, tubuloglomerular feedback (TGF) regulates the tone of the afferent arteriole, with the negative feedback control signals coming from the macula densa cells of the distal nephron. In response to an increase in NaCl concentration or fluid flow, the afferent arteriole constricts. Some studies suggest that an important mediator of TGF is ATP, which is thought to stimulate a ligand-gated Ca2+ channel via P2 purinoceptors. This depolarizes smooth muscle cells in the afferent arteriole. Renal interstitial fluid ATP concentrations are correlated with changes in renal vascular resistance in response to alterations in renal arterial pressure. In addition, normal autoregulatory responses are impaired by the presence of blockers of P2 purinoceptors. Another potential molecule involved in the signalling between the macula densa and the afferent arteriole is 20-HETE. In support of this theory, experimental TGF is enhanced by the 20-HETE precursor arachidonic acid and is blocked by inhibition of 20-HETE. There are also signalling mediators that are thought to act to dampen the TGF mechanism, such as angiotensin II (via AT1 receptors) and nitric oxide.

Control of blood flow and pressure by the vascular endothelium Endothelial cells are well placed to be effectors of blood flow control as they are the interface between blood and smooth muscle. The key experiment showing the role of the endothelium in the regulation of vascular tone was carried out by Furchgott (1980), who noted that the relaxation induced in strips of precontracted aorta by acetylcholine (ACh) did not occur when the vessel endothelium was removed by rubbing the insides of the vessels. He determined that ACh was working via the production of a relaxant factor because when two vessel strips were put together and ACh was added to only one strip, the other relaxed. This relaxant factor he called endothelium-derived relaxing factor (EDRF), which has, of course, since been identified as nitric oxide (NO). In blood vessels, NO is synthesized from the precursor L-arginine by the endothelial isoform of the NO synthase enzyme (eNOS). Once produced, NO

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readily diffuses from endothelial cells to smooth muscle cells where it activates the enzyme guanylate cyclase, leading to an increase in intracellular cGMP and activation of protein kinase G. This results in vasodilatation via a decrease in [Ca2+]i (through the inhibition of Ca2+ influx and Ca2+ release from the sarcoplasmic reticulum, coupled with stimulation of Ca2+ extrusion across the plasma membrane and back into the sarcoplasmic reticulum) and activation of potassium channels (Figure 3). Many locally released factors effect vasodilatation through the production of NO, for example, bradykinin, adenosine, histamine, serotonin, substance P and ACh. However, NO is also constitutively released by the vascular endothelium and the most important physiological stimulus for its production is shear stress. An increase in blood velocity through arteries and arterioles increases shear stress, leading to NO release and vasodilatation. This mechanism appears to be of particular importance at high flow rates and provides continuous control of arterial diameter at rest and during hyperaemia. Nitric oxide is also thought to be an important ‘brake’ on the myogenic response. Infusion of cat gastrocnemius muscle arteries with L-NMMA increased resistance by 65%, showing a basal release of NO, while NOS inhibition led to an enhanced myogenic response. The endothelium also produces other vasodilating factors, such as prostacyclin, which promotes vasodilatation by increasing smooth muscle cell cAMP levels, and also has an important role to play in limiting platelet aggregation and adhesion. Among the vasoconstrictor factors produced by the endothelium one of the most potent is endothelin-1, which is released in response to factors such as angiotensin, vasopressin, thrombin and adrenaline. Endothelin-1 acts via two types of receptors found on vascular smooth muscle cells, Eta and Etb. These receptors are thought to be coupled to phospholipase C via a G-protein and subsequent production of IP3 (Figure 3). Application of endothelin-1 to arterial smooth muscle cells causes a rapid transient increase in [Ca2+]i. In addition, endothelin-1 receptor activation also causes activation of phospholipase D and A 2 and changes in arachidonic acid

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metabolism. Various endothelin receptor antagonists are under development in the pharmaceutical industry, and evidence indicates that their infusion in vivo causes a sustained fall in PVR, suggesting that, like NO, endothelin-1 may be tonically released. There are cross-links between the various vasodilator and vasoconstrictor pathways, for example, endothelin-1 mRNA expression is also affected by vasodilator factors, e.g. NO, prostacyclin and ANP. It is thought that an imbalance of NO and endothelin may play an important role in cardiovascular disease.

Hormonal mechanisms The principal hormones involved in raising arterial blood pressire (ABP) are: • adrenaline and noradrenaline • angiotensin II • atrial natriuretic factors. Adrenaline and noradrenaline These are secreted from the adrenal medulla in response to sympathetic stimulation. They cause vasoconstriction and an increase in cardiac output through increases in heart rate and cardiac inotropy. Vasoconstriction is mediated mainly by α1A adrenergic receptors on the vascular smooth muscle cells, acting via the G q pathway and the second messengers IP3 and DAG. Also involved are α2C in arterial contraction and venous vasoconstriction. The vasculature also contains β1 and β2 adrenergic receptors, which mediate vasodilatation via the Gs protein and are of particular importance in the skeletal and coronary circulations. Angiotensin II A fall in ABP stimulates the renin– angiotensin system in the kidney, which acts to inhibit Na+ excretion, stimulates thirst and causes vasoconstriction to help return ABP back to normal levels. Renin is released by the granular cells of the renal juxtaglomerular apparatus in response to a decrease in renal perfusion pressure, an increase in sympathetic nerve activity (in response, for example, to a fall in arterial blood pressure, see section on Neural control) or the release of prostacyclin (which occurs when the macula densa cells sense a fall in the NaCl content of the tubular fluid). Renin is a proteolytic enzyme which cleaves

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PHYSIOLOGY

Summary of the principal mechanisms involved in the control of blood pressure via the arterial baroreflex ����������������

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angiotensinogen to angiotensin I. This is further cleaved by the angiotensinconverting enzyme (ACE) on the surface of endothelial cells to produce the vasoactive peptide angiotensin II, which mediates vasoconstriction as well as smooth muscle cell proliferation, aldosterone secretion and sodium retention. ACE also breaks down bradykinin (a vasodilator) to inactive peptides. There are also local tissue renin– angiotensin systems (RAS), e.g. in the vasculature all components of RAS appear to be present with the exception of renin. Angiotensin II acts via angiotensin type 1 and type 2 receptors. AT1 receptors mediate most of the physiological actions of angiotensin II (vasoconstriction, growth, etc.) whereas stimulation of AT2 receptors promotes, at least in vitro, vasodilatation, growth inhibition and apoptosis. Thus, angiotensin II is not only important as a vasoconstrictor, but appears to be critical in vascular remodelling. Atrial natriuretic factors These peptides are secreted by atrial and ventricular myocytes during cardiac hypertrophy. Release is triggered by atrial stretch (via mechano-sensitive ion channels), adrenergic stimulation via α 1A receptors and endothelin via its ETA receptor subtype. The atrial natriuretic

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peptide is a vasodilator (caused by the activation of guanylate cyclase) and an important regulator of salt and water excretion.

Neural control Autonomic reflexes work alongside local mechanisms to minimize fluctuations in mean ABP (Figure 4). Unlike hormonalmediated regulation of ABP, neural reflexes are fast and regulate ABP on a ‘beat-to-beat’ basis. Instances in which the neural control of ABP is crucial include postural changes and haemorrhage. The ‘high pressure’ arterial baroreflex has its sensors embedded in the wall of the carotid arteries and aortic arch. These unmyelinated nerve endings are stretch receptors and sense changes in transmural pressure. An increase in ABP increases their firing frequency and activates the reflex, resulting in a rapid increase in vagal tone (within one beat), followed by a reduction in sympathetic nerve discharge. The resulting effect is a reduction in cardiac output and sympathetic vasoconstrictor tone, both of which lead to a reduction in ABP. Conversely, a fall in ABP decreases the tonic firing of the arterial baroreceptors, resulting in a reduction in cardiac parasympathetic tone followed by an increase in sympathetic

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activity to the heart and blood vessels. These changes in autonomic nerve activity result in an increase in cardiac output and PVR. Furthermore, increased sympathetic activity to the venules displaces blood to the thoracic great veins, increasing end diastolic volume, whereas stimulation of renal sympathetic nerves causes renin release, angiotensin II production and aldosterone secretion. Thus, in the face of hypotension, the resulting tachycardia, vasoconstriction and fluid retention work together to restore ABP. Vasoconstriction effected by the sympathetic nervous system is mostly mediated by α 1A adrenergic receptors on vascular smooth muscle cells, and its functional importance is greatest in the microcirculation. α2C (linked to Gi/o), on the other hand, are potently activated by circulating adrenaline. It is worth noting that the vasculature (particularly coronary and skeletal muscle) also contains β1 and β 2 adrenergic receptors, which when stimulated exert a vasodilating influence. Furthermore, arteriolar vasoconstriction results in a reduction in capillary pressure, leading to increased absorption of interstitial fluid into the circulation, which in turn causes blood volume expansion, increased left ventricular preload and thus cardiac output. u

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