Vascular smooth muscle relaxation factor

The precise mechanism of nitrate action is not cleady understood and may be a combination of many factors. The basic pharmacologic action of nitrates is a relaxation of most vascular smooth muscle, eg, vascular, bronchial, gastrointestinal, uretal, uterine, etc. Vascular smooth muscle relaxation is a... 

Proposed mechanism by which nitroglycerin and the organic nitrates produce relaxation in vascular smooth muscle. Nitrates induce endothelial cells to release NO or a nitrosothiol (endothelium-derived releasing factor, or EDRF). EDRF activates the enzyme guanylate cyclase, which causes the generation of cyclic guanosine monophosphate (GMP), producing a decrease in cytosolic free calcium. The end result is vascular smooth muscle relaxation. SH, sulfhydryl. 

Ignarro, L. J., Byms, R. E., Buga, G. M., Wood, K. S., and Chaudhuri, G. (1988b). Pharmacological evidence that endothelium-derived relaxing factor is nitric oxide Use of pyrogallol and superoxide dismutase to study endothelium-dependent and nitric oxide-elicited vascular smooth muscle relaxation, j. Pharmacol. Exp. Ther. 244, 181-189. 

The antioxidant actions of flavonoids appear to be involved in their observed antithrombotic action [50-52]. The antithrombotic and vasoprotective actions of quercetin, rutin, and other flavonoids have been attributed to their ability to bind to platelet membranes and scavenge free radicals [50]. In this manner, flavonoids restore the biosynthesis and action of endothelial prostacyclin and endothelialderived relaxing factor (EDRF), both of which are known to be inhibited by free radicals [50, 53, 54]. However, some flavonoids may inhibit arachidonic acid metabolism and platelet function by flavonoid-enzyme interactions rather than by antioxidant effects [55]. In addition to their antiaggregatory effects, flavonoids appear to increase vasodilation by inducing vascular smooth muscle relaxation, which may be mediated by inhibition of protein kinase C, PDFs, or by decreased cellular uptake of calcium [56]. 

Furchgott and Zawadzki [1] first discovered that endothelial cells release a substance(s) responsible for the relaxation of vascular smooth muscle by acetylcholine this substance was named endothelium-derived relaxing factor (EDRF). This epoch-making discovery answers the question raised for nearly one hundred years by pharmacologists about why vascular smooth muscle is relaxed by acetylcholine, which however elicits contraction of the other smooth muscles. Because of its instability, the true chemical nature of EDRF was not easily identified. Several years later, several research groups independently found that the biological activities and biochemical properties of EDRF were identical... 

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. 

Atrial natriuretic factor (ANF), produced by cells in the atrium of the heart in response to distension, binds the ANF receptor in vascular smooth muscle and in the kidney. The ANF receptor spans the membrane and has guanylate cyclase activity associated wMi the cytoplasmic domain. It causes relaxation of vascular smooth muscle, resulting in vasodilation, and in the kidney it promotes sodium and water excretion. 

An early consequence of overexposure to PGDN is vasodilation of the cerebral vessels, which is the major factor in the development of headache. With more severe exposure, relaxation of the vascular smooth muscle can result in a fall in blood pressure followed by a compensatory vasoconstriction. 

Furchgott, R. F. (1988). Studies on relaxation of rabbit aorta by sodium nitrite The basis for the proposal that the acid-activatable factor from bovine retractor penis is inorganic nitrite and the endothelium-derived relaxing factor is nitric oxide. In Vasodilatation Vascular Smooth Muscle, Peptides, Autonomic Nerves, and Endothelium (P. M. Vanhoutte, ed.), pp. 401-414. Raven, New York. 

Muscarinic agonists release endothelium-derived relaxing factor, identified as nitric oxide (NO), from the endothelial cells. The NO diffuses to adjacent vascular smooth muscle, where it activates guanylyl cyclase and increases cGMP, resulting in relaxation (see Figure 12-2). Isolated vessels prepared with the endothelium preserved consistently reproduce the... 

Activation of endothelial cell muscarinic receptors by acetylcholine (Ach) releases endothelium-derived relaxing factor (nitric oxide), which causes relaxation of vascular smooth muscle precontracted with norepinephrine, 10-8M. Removal of the endothelium by rubbing eliminates the relaxant effect and reveals contraction caused by direct action of Ach on vascular smooth muscle. (NA, noradrenaline [norepinephrine]. Numbers indicate the log concentration applied at the time indicated.)... 

Ignarro, L., Byms, RE, and Wood, KS. 1988. Biochemical and pharmacological properties of endothelium-derived relaxing factor and its similarity to nitric oxide radicals. Pages 427-436 In P. Vanhoutte, (ed.) Vasodilation Vascular smooth muscle, peptides, autonomic nerves, and endothelium. Raven Press, New York. 

The nitrates act by releasing nitric oxide, which relaxes vascular smooth muscle. The discovery that endothelium-derived relaxing factor (EDRF) is nitric oxide (1) stimulated new interest in these drugs, as nitric oxide not only controls local vessel wall tension in response to shear stress, but also plays a role in regulating the interaction of platelets with blood vessel walls. The release of nitric oxide from the walls of atheromatous arteries is reduced, because of malfunctioning or absent endothelium. Atheromatous arteries behave differently from healthy arteries, in that these vessels vasoconstrict rather than vasodilate when stimulated by acetylcholine. This impairment of the acetylcholine vasomotor response appears to be related to serum cholesterol concentration (2). 

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