Subcellular mechanisms of endothelin action in vascular system.

To elucidate the role of endothelin in the regulation of vascular function, the cellular and subcellular mechanisms for the synthesis of endothelin and the function of endothelin-receptors have been studied extensively. In this article, recent results regarding these problems are reviewed. (1) Oxidatively modified low-density-lipoprotein (LDL) reduces nitric oxide (NO) release via inhibition of the high-affinity arginine transporter of endothelial cells. (2) Endothelin-1-induced vasoconstriction is mediated by Ca2+ influx through a non-selective cation channel sensitive to 1-[beta-[3-(4-methoxyphenyl) propoxyl]-4-methoxyphenethyl]-1H-imidazole HCl (SK & F96365). (3) A distinct domain of the endothelin-receptor is required for the coupling of different G(alpha)-proteins. (4) Endothelin ET(A) receptor-mediated mitogenic activity is mediated by two pathways, one classical protein kinase C(PKC)-dependent, and the other phosphoinositide 3-kinase dependent. Both stimulate mitogen-activated protein kinase (MAPK). Endothelin ET(B) receptor-mediated mitogenic activity is also mediated by the PKC-dependent pathway. In contrast, endothelin ET(B) receptor-mediates differentiation and apoptosis via G(alpha)i coupling.