Endothelium-dependent relaxations cannot be fully explained by the release
of either NO or/and prostacyclin. Another unidentified substance(s) which h
yperpolarizes the underlying vascular smooth muscle cells map contribute to
endothelium-dependent relaxations, especially in small arteries. It has be
en termed endothelium-derived hyperpolarizing factor (EDHF). In blood vesse
ls from various species including humans, endothelium-dependent relaxations
are partially or totally resistant to inhibitors of NO synthase and cycloo
xygenase and are observed without an increase in the intracellular level of
cyclic nucleotides in the vascular smooth muscle cells. In some species (c
anine, porcine and human) nitrovasodilators do not cause hyperpolarization
while in other (rat, guinea-pig, rabbit), they evoke glibenclamide-sensitiv
e hyperpolarization, suggesting the involvement of ATP-dependent potassium
channels. In contrast, hyperpolarizations caused by EDHF are insensitive to
glibenclamide but are inhibited by apamin or the combination of charybdoto
xin plus apamin, indicating that NO and EDHF interact with two different ta
rgets. The existence of EDHF as a diffusable substance has been demonstrate
d under bioassay conditions whereby the source of EDHF was either native va
scular segments or cultured endothelial cells. The identification of EDHF m
ap allow a better understanding of its physiological and pathophysiological
role(s). (C) 1999 Academic Press.