The third pathway: Endothelium-dependent hyperpolarization

In response to various neurohumoral substances endothelial cells-release ni tric oxide (NO), prostacyclin and produce hyperpolarization of the underlyi ng vascular smooth muscle cells, possibly by releasing another factor terme d endothelium-derived hyperpolarizing factor (EDHF). EDHF-mediated response s are sensitive to the combination of two toxins, charybdotoxin plus apamin , but do not involve ATP-sensitive or large conductance calcium-activated p otassium channels. As hyperpolarization of the endothelial cells is require d in order to observe endothelium-dependent hyperpolarization, and electric al coupling through myo-endothelial gap junctions may explain the phenomeno n. An alternative explanation is that the hyperpolarization of the endothel ial cells causes an efflux of potassium that in turn activates the inwardly rectifying potassium conductance and the Na+/K+ pump of the smooth muscle cells. Endothelial cells produce metabolites of the cytochrome P450-monooxy genase that activate BKCa, and induce hyperpolarization of coronary arteria l smooth muscle cells; The elucidation of the mechanism underlying endothel ium-dependent hyperpolarization and the discovery of specific inhibitors of the phenomenon are prerequisite for,the understanding of the physiological role of this alternative endothelial pathway involved in the control of va scular tone in health and disease.