Endothelium-mediated and Nω-nitro- l-arginine methyl ester-sensitive responses to cromakalim and diazoxide in the rat mesenteric bed

Abstract

The effects of two `K + channel openers', (±)-6-cyano-3,4-dihydro-2,2-dimethyl- trans-4-(2-oxo-1-pyrrolidyl)-2 H-benzo[ b]-pyran-3-ol (cromakalim) and 7-chloro-3-methyl-2 H-1,2,4-benzothiadiazine 1,1-dioxide (diazoxide), were studied on the rat isolated mesenteric bed. Differences in the perfusion pressure were measured as a parameter of vascular resistance. Cromakalim (0.1–700 μM) and diazoxide (1 μM–1 mM) reduced to 60% the contractions elicited by 10 μM noradrenaline and to 30% those evoked by 100 mM KCl. The relaxant effects of cromakalim and diazoxide on the noradrenaline-induced contractions were reduced by the K +-ATP channel blocker, 5-chloro- N-[2-[4-[[[(cyclohexylamino)carbonyl]amino]-sulfonyl]phenyl]ethyl]-2-methoxybenzamide (glibenclamide, 0.01–0.3 μM), endothelium removal with 0.1% saponin and pretreatment with the nitric oxide synthesis inhibitor, S(±)- N 5-[imino(nitroamino)methyl]- l-ornithine methyl ester hydrochloride ( l-NAME, 500 μM). Reductions in the relaxant responses after endothelium removal or l-NAME pretreatment were observed with 1–100 μM cromakalim and with 30 μM diazoxide but not with 100 and 300 μM diazoxide. Pretreatment with the inactive stereoisomer d-NAME as well as with the prostanoid synthesis inhibitor, 1-[ p-chlorobenzoyl]-5-methoxy-2-methylindole-3-acetic acid (indomethacin, 10 μM), did not affect the reductions in contractile responses to noradrenaline caused by either cromakalim or diazoxide. It is concluded that the relaxant effects of cromakalim and diazoxide in the rat mesenteric bed are endothelium-mediated and l-NAME-sensitive and could at least partially involve the participation of nitric oxide.