Molecular mechanisms of endothelium-mediated vasodilation.

cGMP appears to be the intracellular messenger involved in smooth muscle relaxant effects of three major groups of vasodilators, the ANFs, the nitrovasodilators (such as nitroglycerin, sodium nitroprusside, sodium nitrite, isosorbide dinitrate), and the endothelium-dependent vasodilators (such as ACh, histamine, bradykinin, adenosine triphosphate, A23187). The endothelium-dependent vasodilators apparently act by stimulating the release of EDRF from endothelial cells, which in turn activates soluble guanylate cyclase in vascular smooth muscle cells. Because of similarities between EDRF and the nitrovasodilators, EDRF has been termed the "endogenous nitrovasodilators." Very recent evidence suggests that EDRF may be identical with nitric oxide, the intermediate substance generated by the nitrovasodilators, thus further illustrating the similarities between nitrovasodilator-induced and endothelium-dependent vasodilation. Following the elevation of cGMP levels in smooth muscle, cGMP-kinase becomes activated and phosphorylates cellular protein or proteins involved in the regulation of cytosolic free Ca2+ concentrations. This mechanism vasoconstrictor. In the absence of vasoconstrictors, cGMP, even at basal levels, seems to be important for maintaining cytosolic Ca2+ at low concentrations and for keeping the vascular smooth muscle in a relatively relaxed state. Future experiments will need to clarify further the role of cGMP and cGMP-kinase in physiologic and pathophysiologic regulation of blood vessels. Of prime interest is the identity of functional substrates for cGMP-kinase in vascular smooth muscle.