Other endothelium-derived vasoactive factors

Abstract

A number of studies suggest the presence of endothelium-derived relaxing factors distinct from nitric oxide (NO) that contribute to local regulation of vascular smooth muscle tone. Whereas in certain arteries, endothelium- dependent relaxations to acetylcholine or vasopressin are abolished by inhibitors of NO formation, in others, mainly those of smaller diameter, this is not the case. In perfused arteries, shear stress activates a bioassayable factor distinct from NO, the action of which can be prevented by ouabain. The most likely candidate to explain this ouabain-sensitive response, which is also observed in bioassay systems using cultured porcine endothelial cells, is an endothelium-derived hyperpolarizing factor (EDHF). In several vascular preparations, acetylcholine and other endothelium-dependent agonists cause endothelium-dependent hyperpolarization. In most studies, this phenomenon cannot be prevented by inhibitors of NO formation or mimicked by NO. In contrast to NO, there appears to be no ongoing basal release of EDHF. Its release can be stimulated by acetylcholine, bradykinin, adenine nucleotides, histamine, thrombin, and substance P and is Ca2+- and calmodulin- dependent. At the level of vascular smooth muscle, EDHF opens K+ channels; the exact type of K+ channel involved is still unclear and may vary between species. Furthermore, the endothelium can mediate contractions, particularly in peripheral veins and cerebral arteries. Endothelium-dependent contractions can be mediated by withdrawal of NO production, superoxide anions, products of cyclooxygenase, and endothelin-1. Hence, in summary, although recent research has focused on NO as an endothelium-derived vasoactive substance, the cells produce a variety of other factors mediating relaxation, vascular smooth muscle cell hyperpolarization, and vasoconstriction. The relative formation of endothelium-derived relaxing and contracting factors under physiological and pathophysiological conditions importantly determines vascular tone and, in turn, flow to different organs of the body.