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Thismechanism is particularly important in vascular responses toinflammatory stimuli, as well as in parasympathetic-mediatedvasodilation in the genital system and lower gastrointestinaltract (vessels in other regions are not innervated by the parasympathetic nervous system). In addition, many substancesthat directly act on smooth muscle cells to produce constriction (for example, norepinephrine) also release endothelialNO. This simultaneous release and action of NO results in adampened response to vasoconstrictors in healthy vessels, asopposed to vessels in which the endothelium has beendamaged. Many of the same stimuli that release NO alsorelease prostacyclin (PGI2) from endothelial cells, a vasodilator metabolite of arachidonic acid.
Although prostacyclin isless important than NO in regulation of vascular tone, bothmediators are important in preventing activation of plateletsand their adherence to the vascular wall. The actions of pros-tacyclin are opposed by thromboxane A2, which is a majorproduct of arachidonate in activated platelets. Thus, thromboxane A2 is a potent prothrombotic substance and vasoconstrictor, important in inflammatory states and hemostasis.The release of NO by shear stress is believed to participate invascular control as follows: When blood flow to a region isincreased (for example, by vasodilation in the arterial microcirculation), the higher flow causes elevated shear stress in theendothelial cells of vessels supplying the region, which respondby increasing NO production.
Adjacent smooth muscle cellsrelax when exposed to NO, resulting in vasodilation andfurther augmentation of flow.Endothelin is a powerful vasoconstrictor protein released byendothelial cells when vessels are damaged. Its role in vascularregulation in normal tissues is controversial, although it is anThe Peripheral CirculationThe nitric oxide produced by endothelial cells is sometimes referred to as “EDRF,” or endothelium-dependentrelaxing factor. This name is based on the original discovery byRobert Furchgott that vessel segments experimentally denudedof endothelium did not display smooth muscle relaxation whenstimulated by acetylcholine and other “endothelium-dependent” vasodilators. Subsequent studies during the 1980s byseveral investigators led to the identification of EDRF as nitricoxide.
The journal Science named nitric oxide “Molecule of theYear” in 1993, and the Nobel Prize in Medicine or Physiologywent to Furchgott, Louis Ignarro, and Ferid Murad for theirwork in this area.important pathophysiologic mediator, for example in pulmonary hypertension and preeclampsia. Angiotensin-convertingenzyme (ACE) is an enzyme found on the surface of endothelial cells. This enzyme cleaves angiotensin I to angiotensin II,a potent vasoconstrictor. Like the posterior pituitary hormonevasopressin, angiotensin II is important in long-term regulation of blood pressure through its effects on renal sodium andwater retention (see Section 5), and plays a role in acuteresponses to hypotensive crises such as hemorrhage.
However,neither angiotensin II nor vasopressin is believed to be important in short-term regulation of vascular function.Until the second half of the 20th century, the endothelium was generally believed to function mainly as alining or barrier between blood and tissues. In the past fewdecades, appreciation of its role in many physiological processeshas blossomed. The endothelium is important in regulatingvascular tone, angiogenesis (formation of blood vessels), andthe hemostatic process (healthy endothelium is “antithrombogenic” due to its formation of nitric oxide and prostacyclin). Inaddition, the endothelium has a role in metabolism. An exampleis conversion of angiotensin I to angiotensin II by its angiotensinconverting enzyme. The endothelium has an important role indisease processes, for example in atherosclerosis, in whichdiminished endothelial nitric oxide production and alterationsin other endothelial functions are among the earliest changesobserved.Local Control of Blood FlowLocal regulation of blood flow occurs through mechanismsthat involve responses to local metabolic products and transmural pressure (pressure gradient across the vascular wall)(Fig.
12.5A). If blood flow to a region is occluded temporarily,when flow is reestablished, reactive hyperemia occurs. Inother words, blood flow is elevated above the original level.Reactive hyperemia occurs as a result of local metabolites thataccumulate during the occlusion. These metabolites, whichinclude CO2, H+, K+, lactic acid, and adenosine, act directly on129smooth muscle of arterioles and precapillary sphincters in theregion to produce vasodilation. Thus, flow is elevated untilthe tissue levels of O2 are restored and accumulated metabolites are removed. In contrast to reactive hyperemia, activehyperemia refers to the increase in flow that occurs in tissueswhen metabolism is elevated (Fig.
12.5B). An example of thisis the greatly increased flow to skeletal muscles during exercise. Ongoing production of local metabolites in the workingskeletal muscles causes vasodilation, thus enhancing flow tothe muscles.Autoregulation of local blood flow can occur without changesin local metabolism (Fig.
12.5C). In many tissues and organs,if blood flow is artificially increased by raising the perfusionpressure to the vascular bed, flow will be immediately elevatedas expected; however, it soon returns toward the basal rate.According to the myogenic hypothesis, smooth muscle cellsconstrict in response to elevated transmural pressure, in otherwords, in response to stretch. This is a mechanism wherebyflow to a tissue is kept fairly constant, despite changes in pressure, when metabolic needs of the tissue are not changing.Myogenic regulation does not involve the vascular endothelium, but is a direct response of smooth muscle cells.Extrinsic Regulation of Peripheral Blood FlowExtrinsic regulation of peripheral blood flow involves vasoconstriction or vasodilation in response to neural mechanismsand circulating vasoactive substances.
Smooth muscle cellshave several types of adrenergic receptors:■■α-Receptors, which mediate the constrictor responses tocatecholamines. Receptors of the subtype α1 are the predominant subtype in vascular tissue; α2-receptors alsoproduce vasoconstriction by inhibiting reuptake of norepinephrine. α1-Adrenergic vasoconstriction is mediated by the second messenger inositol trisphosphate,and α2 vasoconstriction is mediated by reduced cAMPlevels.β2-Receptors, which mediate dilator responses to catecholamines. β2-Adrenergic vasodilation is mediated bythe second messenger cAMP.When the sympathetic nerves are stimulated, the responsesof vessels will be dependent on the type of adrenergic receptors activated (a function of receptor density and agonistconcentration), with the predominant systemic responsebeing vasoconstriction. The major arterial response to sympathetic nervous system activation is α-receptor–mediatedvasoconstriction, for example in baroreceptor-mediatedresponses (see Fig.
11.2). Note that generalized arterial constriction produces elevation of arterial blood pressure, becausearterioles and small arteries are the major site of action, andconstriction of these vessels produces increased peripheralresistance. Sympathetic activation results in widespread constriction of veins, elevating venous pressure and enhancingpreload on the heart.
β2-receptors are present in some arterial130Cardiovascular PhysiologyLocal Regulation of Blood FlowA. Reactive hyperemiaBasalflowVascularocclusionReactivehyperemiaTissuebloodflowTimeC. Myogenic regulationB. Active hyperemiaBasalflowTissuebloodflowIncreasedtissuemetabolismBasalflowIncreasedperfusionpressureTissuebloodflowActive hyperemiaTimeTimeFigure 12.5 Local Regulation of Blood Flow Regional blood flow is controlled by local as well asneural and humoral factors. A, Reactive hyperemia occurs when blood flow is reestablished after occlusion.Buildup of vasodilatory metabolites such as CO2, H+, K+, lactic acid, and adenosine results in relaxation ofarterioles and precapillary sphincters directly exposed to these substances.
Hence, a period of increasedblood flow (hyperemia) occurs upon reperfusion. B, Active hyperemia refers to the increase in blood flowto a tissue when metabolism in the tissue is elevated; this hyperemia is a result of increased production ofvasodilatory metabolites. C, Myogenic regulation refers to the autoregulation of blood flow that occurs whenperfusion pressure is increased (with no change in metabolic activity in the tissue). Initially, when perfusionpressure is raised, flow to the tissue rises as expected, but returns toward the baseline. Smooth muscle ofthe arterial microcirculation constricts in response to a rise in transmural pressure, thus autoregulating bloodflow.vessels, for example, in skeletal muscle, where sympatheticoutflow in anticipation of exercise produces increased bloodflow to muscle.While the sympathetic nervous system innervates vesselsin most parts of the circulation, parasympathetic innervation of blood vessels is absent in most tissues.
Exceptions arethe genital organs, salivary glands, and lower gastrointestinaltract. In circulations innervated by the parasympathetic nervoussystem, release of acetylcholine stimulates endothelial cells torelease nitric oxide, producing nitric oxide–dependent vasodilation of underlying smooth muscle. Because acetylcholine isshort-lived in the circulation, it affects only the vessels that aredirectly innervated by parasympathetic nerves.In addition to release of catecholamines at sympatheticnerve endings in the vasculature, epinephrine may be releasedinto the bloodstream by the adrenal medulla during sympathetic nervous system activation. In this case, epinephrineacts as a circulating hormone; other circulating hormonesthat affect vascular tone include angiotensin II andvasopressin.Chemoreceptors also participate in the extrinsic regulation ofvascular tone.
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