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.