Endothelium-dependent hyperpolarization of vascular smooth muscle cells

In response to various neurohumoral substances endothelial cells release ni tric oxide (NO) and prostacyclin, and produce hyperpolarization of the unde rlying vascular smooth muscle cells, possibly by releasing another factor t ermed endothelium-derived hyperpolarizing factor (EDHF). NO and prostacycli n stimulate smooth muscle soluble guanylate and adenylate cyclase respectiv ely and can activate, depending on the vascular tissue studied, ATP-sensiti ve potassium (K-ATP) and large conductance calcium-activated potassium chan nels (BKCa). Furthermore, NO directly activates BKCa. In contrast to NO and prostacyclin, EDHF-mediated responses are sensitive to the combination of charybdotoxin plus apamin but do not involve KATP or BKCa. As hyperpolariza tion of the endothelial cells is required to observe endothelium-dependent hyperpolarization, an electric coupling through myoendothelial gap junction s may explain the phenomenon. An alternative explanation is that the hyperp olarization of the endothelial cells causes an efflux of potassium that in turn activates tile inwardly rectifying potassium conductance and the Na+/K + pump of the smooth muscle cells. Therefore, in some vascular tissue K+ co uld be EDHF. Endothelial cells produce metabolites of the cytochrome P450-m onooxygenase that activate BKCa, and induce hyperpolarization of coronary a rterial smooth muscle cells. Whether or not EDHF could be an epoxyeicosatri enoic acid is still a matter of debate. The elucidation of the mechanism un derlying endothelium-dependent hyperpolarizations and the discovery of spec ific inhibitors of the phenomenon are prerequisite for the understanding of the physiologic role of this alternative endothelial pathway involved in t he control of vascular tone in health and disease.