Chemical Pathways Proposed for the In Vitro Metabolism of Nitrovasodilators and Their Conversion into Vasoactive Species
Despite the extensive therapeutic use of nitrovasodilators and a fairly good knowledge of the hemodynamic alterations which lead to an improvement in myocardial performance, until recently surprisingly poor data were available concerning their mode of action at the molecular level. It now seems well documented that the pharmacodynamic action of these compounds is mediated by an activation of the soluble isoenzyme of guanylate cyclase (sGC, EC, 220.127.116.11). Relaxation studies with isolated vessel preparations revealed that there are at least two independent ways of sGC stimulation: an indirect endothelium-related process and a second one which results in sGC stimulation on bypassing the endothelium-dependent process. Substances like acetylcholine, ATP, or bradykinin on the one hand only behave in a vasodilatory manner in the presence of an intact endothelial layer while nitrovasodilators like nitrite (NO2 −), glyceryl trinitrate (GTN), and sodium nitroprusside (SNP) on the other hand are relaxant agents in either case. That is why the existence of a humoral “endothelium-derived relaxing factor” (EDRF) was postulated, which after penetration into the smooth muscle cell is responsible for sGC activation by endothelium-dependent vasodilators. The consecutive raise in cytosolic cyclic guanosine monophosphate (cGMP) concentration induces a complex cascade of protein phosphorylations, finally resulting in smooth muscle relaxation [12, 34].
KeywordsNitric Oxide Guanylate Cyclase Thiol Compound Organic Nitrate Thiosalicylic Acid
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