Receptor-Dependent Vasodilation

Receptor-dependent vasodilation may also take place in a more indirect manner through the presynaptic modulation of the release of neurotransmitters, such as norepinephrine and acetylcholine. In addition to its effects on postsynaptic receptors, norepinephrine stimulates the presynaptic a2-receptor, thereby inhibiting further transmitter release. Moreover, the activation of other presynaptic receptors such as the muscarinic cholinergic, dopaminergic, purinergic, serotoninergic, and histaminergic receptors leads to diminished norepinephrine release and subsequent vasodilation. 

Khurana S, Yamada M, Wess J, Kennedy RH, Raufman JP (2005) Deoxycholyltaurine-induced vasodilation of rodent aorta is nitric oxide- and muscarinic M3 receptor-dependent. Eur J Pharmacol 517 103-10... 

Arterioles in skin and brain lack P2 receptors. In other areas of the body, the degree of sympathomimetic-induced vasoconstriction and/or vasodilation depends on the drug s affinitv for ai (vasoconstriction) or B (vasodilation) receptors (Table 2.1 A.). 

P2Y receptors that are found on endothelial cells elicit a Ca2+-dependent release of endothelium-dependent relaxing factor (EDRF) and vasodilation. A secondary activation of a Ca2+-sensitive phospholipase A2 increases the synthesis of endothelial prostacyclin, which limits the extent of intravascular platelet aggregation following vascular damage and platelet stimulation. The P2Y-mediated vasodilation opposes a vasoconstriction evoked by P2X receptors located on vascular smooth muscle cells. The latter elicit an endothelial-independent excitation (i.e. constriction). P2Y receptors are also found on adrenal chromaffin cells and platelets, where they modulate catecholamine release and aggregation respectively. 

The anandamide precursor, phosphatidylethanol amine, is present in membranes almost always accompanied by phophatidylserine. It seemed reasonable to expect the formation of anandamide from its precursor will be paralleled by formation of N-arachidinoylserine from phosphatidyl serine. Indeed, A -arachidonoyl-L-serine (ARA-S) was found to be formed alongside anandamide (Fig. 4). This compound was isolated from bovine brain and its structure was elucidated by comparison with synthetic ARA-S. Contrary to anandamide, ARA-S binds very weakly to the known cannabinoid CBi and CB2 or vanilloid TRPVl receptors. However, it produces endothelium-dependent vasodilation of rat isolated mesenteric... 

The cardiovascular response to dopamine in humans depends on the concentration infused. Low rates of dopamine infusion can produce vasodilation in the renal, mesenteric, coronary, and intercerebral vascular beds with little effect on other blood vessels or on the heart. The vasodilation produced by dopamine is not antagonized by the p-adrenoceptor blocking agent propranolol but is antagonized by haloperidol and other dopamine receptor-blocking agents. 

The drugs discussed in this section produce a direct relaxation of vascular smooth muscle and thereby their actions result in vasodilation. This effect is called direct because it does not depend on the innervation of vascular smooth muscle and is not mediated by receptors, such as adrenoceptors, cholinoreceptors, or receptors for histamine, that are acted on by classical transmitters and mediators. 

A slow intravenous injection of histamine produces marked vasodilation of the arterioles, capillaries, and venules. This causes a fall in blood pressure whose magnitude depends on the concentration of histamine injected, the degree of baroreceptor reflex compensation, and the extent of histamine-induced release of adrenal catecholamines. Vasodilation of cutaneous blood vessels reddens the skin of the face, while a throbbing headache can result from vasodilation of brain arterioles. Vasodilation is mediated through both Hj- and Hj-receptors on vascular smooth muscle. Stimulation of Hj-receptors produces a rapid and short-lived response, whereas stimulation of H2-receptors produces a more sustained response that is slower in onset. Stimulation of Hj-receptors on sympathetic nerve terminals inhibits the release of norepinephrine and its associated vasoconstriction. 

Dopamine is an endogenous catecholamine and an immediate precursor of adrenaline and noradrenaline. At low doses it stimulates vascular DAI dopaminergic receptors, especially those in renal, mesenteric and coronary vessels. As the dose increases it progressively stimulates 31 and al adrenoceptors. Thus, depending on the dose it may act as a renal vasodilator, a myocardial inotrope, or a peripheral vasoconstrictor. Dopamine also causes release of noradrenaline from autonomic nerve endings (DA2 receptors). 

The AT2 receptor has a structure and affinity for Ang II similar to those of the A receptor. In contrast, however, stimulation of AT2 receptors causes vasodilation that may serve to counteract the vasoconstriction resulting from ATi receptor stimulation. AT2 receptor-mediated vasodilation appears to be nitric oxide (NO)-dependent and may involve the bradykinin B2 receptor-NO-cGMP pathway. 

Vascular smooth muscle tone is regulated by adrenoceptors consequently, catecholamines are important in controlling peripheral vascular resistance and venous capacitance. Alpha receptors increase arterial resistance, whereas 2 receptors promote smooth muscle relaxation. There are major differences in receptor types in the various vascular beds (Table 9-4). The skin vessels have predominantly receptors and constrict in the presence of epinephrine and norepinephrine, as do the splanchnic vessels. Vessels in skeletal muscle may constrict or dilate depending on whether ffor 13 receptors are activated. Consequently, the overall effects of a sympathomimetic drug on blood vessels depend on the relative activities of that drug at and 8receptors and the anatomic sites of the vessels affected. In addition, Di receptors promote vasodilation of renal, splanchnic, coronary, cerebral, and perhaps other resistance vessels. Activation of the Di receptors in the renal vasculature may play a major role in the natriuresis induced by pharmacologic administration of dopamine. 

Another important property of dopamine is its ability to inhibit sympathetic nerve function by interacting with presynaptic dopaminergic receptors to decrease norepinephrine release (10). These receptors are not adenylate cyclase coupled and have been classified as D-2 (8). Activation of cardiac presynaptic dopamine receptors causes bradycardia, and of vascular presynaptic dopamine receptors passive vasodilation, the magnitude of which will depend on the contribution of adrenergic activity to maintaining heart rate and vascular smooth muscle tone (11,12). 

In addition to cardiac tissue, leptin receptors have also been identified in both cerebral and coronary vessels (Bjorbaek et al. 1997 Knudson et al. 2005). With respect to the latter it was proposed that OBR-mediated leptin-induced vasodilation occurs through an NO-dependent process and which was abolished by hyperleptinemia. This finding emphasizes the potential dual role of leptin on vascular tissue, a direct NO-dependent vasodilation and vasoconstriction occurring secondarily to central stimulation of the sympathetic nervous system. These effects will be discussed below in greater detail. 

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