Regulation Of Blood Flow

As discussed in Chapter 10, the flow of blood through a vascular bed depends on the pressure gradient across it and its resistance to flow. Because arterial and venous pressures are normally maintained within narrow limits, regulation in flow through an organ is achieved by changing the internal diameter of the major resistance vessels, that is, the arterioles. Vascular resistance within many organs is regulated by systems that are intrinsic to the organ, as well as by extrinsic influences, such as the autonomic nerves and hormones. Intrinsic and extrinsic influences at times may act to induce similar changes in blood flow. At other times, they must oppose one another and balance the needs of the organ with the needs of the entire body.

For most organs, blood flow is normally regulated to ensure the adequate delivery of oxygen (O2), which is usually the rate-limiting metabolite delivered by the blood. Two vascular elements contribute to the regulation of O2 delivery to metabolically active tissues: arterioles and precapillary sphincters. Although the arterioles govern the convection (or bulk flow) of O2 to the organ by regulating blood flow, the precapillary sphincters modulate the diffusive exchange of O2 by regulating the number of capillaries open to perfusion and hence the surface area available for O2 exchange. Thus, in some tissues, both arterioles and precapillary sphincters will dilate when O2 demand increases. As a result of these vascular responses, O2 supply and demand are matched. The mechanisms responsible for this matching are intrinsic to the tissue and no neural or endocrine influence is involved. The intrinsic ability of a tissue to regulate blood flow is usually defined in terms of the intensity of vasoregulatory phenomena such as pressure flow autoregulation, active (functional) hyper-emia, and reactive hyperemia.

The most extensively studied and characterized intrinsic vasoregulatory phenomenon in most organs is pressure flow autoregulation. This term refers to the ability of a tissue to maintain a relatively constant blood

Pressure (mmHg)

FIGURE 2 Relation between blood flow and arterial pressure. The phenomenon of autoregulation illustrates the ability of an organ to maintain a relatively constant blood flow over a wide range of arterial pressures. In this example, the autoregulatory range lies between 60 and 140 mm Hg.

Pressure (mmHg)

FIGURE 2 Relation between blood flow and arterial pressure. The phenomenon of autoregulation illustrates the ability of an organ to maintain a relatively constant blood flow over a wide range of arterial pressures. In this example, the autoregulatory range lies between 60 and 140 mm Hg.

flow over a wide range of arterial pressures. The phenomenon of autoregulation is illustrated in Fig. 2, which demonstrates that arterial pressure must be reduced below a value of 60 mm Hg before blood flow is significantly compromised. Similarly, increases in arterial pressure above a normal value of 100 mm Hg do not profoundly affect blood flow until arterial pressure exceeds 140 mm Hg. This ability of the tissue to autoregulate blood flow requires that arterioles dilate at low arterial pressures, whereas the vessels must constrict in order to maintain flow when arterial pressure is increased. Although many organs (heart, brain, kidney, intestine, and skeletal muscle) exhibit pressure flow autoregulation, the intensity of this phenomenon varies between tissues, with the more metabolically active organs often exhibiting more precise control of blood flow when arterial pressure is changed.

A second vasoregulatory phenomenon that is generally attributed to intrinsic control of blood flow is active

FIGURE 3 The phenomenon of active hyperemia. An organ is being perfused at a constant arterial pressure. As the rate of metabolism of the organ increases, blood flow increases to deliver the additional O2 needed to meet the metabolic needs.

FIGURE 3 The phenomenon of active hyperemia. An organ is being perfused at a constant arterial pressure. As the rate of metabolism of the organ increases, blood flow increases to deliver the additional O2 needed to meet the metabolic needs.

(or functional) hyperemia. Figure 3 shows that blood flow to an organ tends to be proportional to its metabolic activity. Hence, when an organ becomes active, this leads to an increased metabolic demand and blood flow rises in an effort to deliver more of the O2 and nutrients needed to sustain the increased level of activity. In some tissues (e.g., myocardium), increasing blood flow is the only means for enhancing O2 delivery to more active tissue because opening additional capillaries to facilitate diffusive O2 exchange is not possible. (In myocardium, nearly all capillaries are open under resting conditions and there are no closed capillaries in reserve.) However, other organs, like skeletal muscle and intestine, are able to meet the increased O2 demand associated with enhanced organ function (exercise and nutrient absorption, respectively) by increasing both blood flow (arteriolar dilation) and the number of perfused capillaries (precapillary sphincter dilation).

The third phenomenon that supports the existence of intrinsic blood flow control mechanisms is called reactive hyperemia. As shown in Fig. 4, when an artery supplying an organ is occluded temporarily, a transient increase occurs in blood flow above the preocclusion level after release of the arterial occlusion. The longer the occlusion, the larger and longer the subsequent increase in blood flow when the occlusion is released. It would appear that the previously ischemic tissue is attempting to repay the blood flow debt that was incurred during the occlusion periods. Clearly, the repayment of this O2 or blood flow debt is made possible by a progressively more intense dilation of the arterioles as the ischemic duration increases.

The responses associated with the three intrinsic vasoregulatory phenomena described above are consistent with mechanisms geared toward regulating either blood flow and/or the delivery of O2 (or some other critical nutrient). However, the possibility has been raised that these phenomena are linked more closely to stretch-related events that are intrinsic to smooth muscle. The myogenic theory invokes a role for arte-riolar wall tension, rather than blood flow, as the controlled variable in the vasculature. This concept evolved from observations that vascular smooth muscle contracts in response to stretch and relaxes when smooth muscle tension is reduced. According to the law of LaPlace, T = P x r, where T is the vessel wall tension, P is the pressure, and r is the radius of the vessel. If T is indeed the controlled variable in arterioles, then one would expect the vessel to dilate (r increases) when pressure is reduced, whereas the opposite would occur when pressure is increased, that is, r must fall in order to maintain a constant T. These properties of smooth muscle may well explain why vascular resistance falls in response to a reduction in arterial pressure

FIGURE 4 The phenomenon of reactive hyperemia. An organ is being perfused at a constant arterial pressure. Blood flow is stopped for 20, 40, and 60 sec. Note that blood flow increased transiently on release of each occlusion. Also note that the magnitude and duration of the hyperemic response increased with the duration of arterial occlusion.

FIGURE 4 The phenomenon of reactive hyperemia. An organ is being perfused at a constant arterial pressure. Blood flow is stopped for 20, 40, and 60 sec. Note that blood flow increased transiently on release of each occlusion. Also note that the magnitude and duration of the hyperemic response increased with the duration of arterial occlusion.

(pressure flow autoregulation), as well as the sudden vasodilation observed in tissues after release of a temporary arterial occlusion (reactive hyperemia). Indeed, there is strong evidence that myogenic responses occur in the vasculature of organs like the intestine. However, the importance of myogenic factors in the regulation of blood flow appears to diminish when the metabolic demands of the organ are increased (e.g., in the intestine after ingestion of a meal). Thus, it would appear that metabolic factors can override the myogenic mechanism when the nutritive needs of the tissue are increased.

The metabolic theory has been proposed to explain the tight coupling of blood flow to tissue metabolism. This mechanism is particularly attractive as an explanation for the active hyperemia observed in a number of organs. Many metabolites are known to be vasoactive. Among those thought to be important for regulating vascular resistance are carbon dioxide (CO2), H+, O2, K+, and adenosine. Of these, all but O2 relax smooth muscle and act as vasodilators. An increased O2 tension is generally associated with vascular smooth muscle contraction, whereas reducing O2 tension will relax smooth muscle. The vasoactive properties of molecular O2 and metabolites such as adenosine may provide the link that exists between metabolism and blood flow for conditions like pressure flow autoregulation, reactive hyperemia, and active hyperemia. If blood flow is suddenly increased in response to an elevation in mean arterial pressure, the increased flow will promote the washout of vasodilatory products of metabolism, such as adenosine, and it will increase the O2 tension around arterioles. The increased tissue Po2, coupled with the decline in the concentration of vasodilator metabolites, will induce smooth muscle contraction, increase vascular resistance, and reduce blood flow until the normal balance between blood flow, metabolite concentration, and tissue Po2 is once again achieved.

The metabolic theory can also explain reactive and active hyperemias. If the metabolic activity and O2 consumption of an organ are increased, tissue PO2 will decrease and the levels of metabolites (adenosine) will increase. This will result in dilation of both arterioles and precapillary sphincters. The resulting increases in blood flow and the number of perfused capillaries will then enhance both the convective and diffusive delivery of O2 to the more active tissue. Finally, if an artery perfusing an organ is occluded, ongoing metabolic activity without blood flow will result in a decrease in tissue Po2 and an accumulation of vasodilator metabolites. As a consequence of these changes, the arterioles will already be dilated when the occlusion is released and blood flow will rapidly increase above the preocclusion level (reactive hyperemia). The increased flow or hyperperfusion will be temporary, gradually subsiding as tissue PO2 and vasodilator metabolite concentrations return to their normal values.

Adenosine has received considerable attention as a metabolic vasodilator. When flow is too low to meet the O2 requirements of a tissue, adenosine triphosphate (ATP) breakdown exceeds its synthesis. Adenosine, an end product of ATP degradation, can readily exit cells and enter the interstitial fluid, which bathes vascular smooth muscle. Adenosine causes smooth muscle to dilate by stimulating A2-adenosine receptors on the smooth muscle cell. On restoration of blood flow, adenosine production is diminished and that which was released is quickly degraded or washed away. Although adenosine is thought to contribute to metabolic control of blood flow, it cannot explain phenomena such as pressure flow autoregulation because this occurs in some tissues even when A2 receptors are completely blocked.

Extrinsic Control

Although intrinsic mechanisms normally ensure that an organ will receive a blood supply adequate to meet its metabolic needs, in many instances blood flow through particular organs serves a purpose other than simply supplying nutrients and removing metabolites. Under those circumstances, blood flow regulation is often mediated via extrinsic pathways such as the autonomic nervous system or circulating hormones. Norepineph-rine is the principal neurotransmitter released at sympathetic nerve terminals. Inasmuch as norepinephrine is a potent vasoconstrictor in some vascular beds (skin and intestine), its release from sympathetic nerve terminals can exert a profound influence on blood flow. Most vascular beds are innervated by adrenergic nerves; however, the density of innervation varies markedly between organs. For example, the arterioles of the skin are heavily innervated by sympathetic fibers, whereas

Clinical Note

Organic nitrates such as glycerol trinitrate and that these agents act on vascular smooth isosorbide dinitrate have long been used in muscle by releasing and/or mimicking the actions the treatment of angina. It is now recognized of NO.

innervation to the coronary arterioles is quite sparse. As might be expected, mild to moderate activation of the skin's sympathetic nerves will markedly increase vascular resistance and decrease skin blood flow, as illustrated in Fig. 5. Various vascular beds also differ in their density of receptors for vasoactive hormones such as epinephrine and angiotensin II. Thus, release of these hormones can greatly alter the distribution of blood flow. Under such circumstances, flow will be diverted from those beds with high receptor density, such as skin and intestines, to those beds whose vessels have fewer receptors, such as the coronary artery.

Parasympathetic neural influences on blood flow have received less attention than sympathetic influences because only a small proportion of the arterioles in the body receive parasympathetic fibers. However, in tissues such as the salivary glands and intestines, stimulation of cholinergic fibers can elicit intense vasodilation. Ace-tylcholine, a neurotransmitter released at cholinergic nerve terminals, is known to produce a vasodilatory response that is endothelium dependent; that is, when the endothelial lining in small arteries is rubbed away, the vessels will no longer relax in response to acetylcholine. The apparent mediator of this endothelium-dependent vasodilator response to acetylcholine is nitric oxide

Sympathetic Nerve Stimulation Frequency —►

FIGURE 5 The response of vascular resistance to sympathetic nerve stimulation. As the frequency of stimulation is increased, vascular resistance increases.

(NO). NO is synthesized in endothelial cells via the oxidation of the amino acid, L-arginine, by an enzyme called NO synthase. Inhibition of this enzyme by stable analogs of L-arginine causes a rise in mean arterial pressure and a reduction in blood flow in different vascular beds, suggesting that the NO produced by endothelial cells exerts a tonic inhibitory influence on arteriolar resistance. Endothelial cell-derived NO appears to diffuse to the underlying smooth muscle in arterioles, where it activates the enzyme guanylyl cyclase, which in turn generates the vascular smooth muscle relaxant, cyclic guanosine monophosphate. In addition to acetylcholine, agents such as bradykinin, substance P, and adenosine diphosphate, as well as an increased shear stress on the wall of blood vessels, lead to an increase in production of NO by endothelial cells.

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