AN ENDOGENOUS CANNABINOID AS AN ENDOTHELIUM-DERIVED VASORELAXANT

Since the identification of nitric oxide (NO) as an important mediator of endothelium-dependent relaxation, it has become clear that there i s an additional endothelial relaxant factor, termed the endothelium-de rived hyperpolarizing factor (EDHF). The identity of EDHF has remained elusive, but it is thought to be an arachidonic acid metabolite. We n ow report that EDHF-mediated relaxations in the rat mesenteric arteria l bed are blocked by a highly selective cannabinoid receptor antagonis t, SR141716A, consistent with EDHF being a cannabinoid-like substance. Furthermore, in conscious rats,.the NO-independent depressor and regi onal vasodilator effects of bradykinin were inhibited by SR141716A. Th e relaxations in the isolated mesentery were accompanied by the accumu lation of an arachidonic acid metabolite, which co-eluted on TLC separ ation with arachidonoylethanolamide (anandamide), an endogenous cannab inoid derived from arachidonate. We further report that anandamide is a potent vasorelaxant in the mesentery, acting via a hyperpolarizing m echanism. These findings suggest that an endogenous cannabinoid is an endothelium-derived vasorelaxant, which may be EDHF. (C) 1996 Academic Press, Inc.