Modulation of relaxation to levcromakalim by s ‐nitroso‐ n ‐acetylpenicillamine (SNAP) and 8‐bromo cyclic GMP in the rat isolated mesenteric artery

1 Levcromakalim caused concentration‐dependent relaxations of methoxamine‐induced tone in both endothelium‐denuded and intact vessels. Its potency was reduced by the nitric oxide donor, S‐nitroso‐N‐acetylpenicillamine (SNAP; 0.1 μ m or 1 μ m ) in both denuded and intact vessels. The maximal relaxation (R max ) was reduced only in denuded vessels. 2 SNAP was more potent in endothelium‐denuded than intact vessels but there were no differences in R max . Glibenclamide (10 μ m ) did not affect relaxation to SNAP in endothelium‐denuded or intact vessels. 3 The soluble guanylyl cyclase inhibitor, 1 H ‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ, 10 μ m ) increased the potency and R max of levcromakalim in endothelium‐intact vessels. ODQ had no effect in denuded vessels. 4 ODQ (10 μ m ) reduced the vasorelaxant potency of SNAP in both intact and endothelium‐denuded vessels by 190‐fold and 620‐fold, respectively. 5 8‐bromo cyclic GMP (10 or 30 μ m ) reduced both the potency and R max of levcromakalim in de‐endothelialized vessels, but had no effect in intact vessels although it reduced both the potency and R max of levcromakalim in intact vessels incubated with ODQ (10 μ m ). 6 In the presence of ODQ (10 μ m ), SNAP (0.1 μ m or 1 μ m ) reduced the potency of levcromakalim in intact vessels, without altering R max , but had no effect in denuded vessels. SNAP (50 μ m ) reduced both the potency and R max of levcromakalim in intact and endothelium‐denuded vessels. 7 Therefore, although SNAP causes relaxation principally through generation of cyclic GMP, it can modulate the actions of levcromakalim through mechanisms both dependent on, and independent of, cyclic GMP; the former predominate in endothelium‐denuded vessels and the latter in intact vessels.British Journal of Pharmacology (1998) 124 , 1219–1226; doi: 10.1038/sj.bjp.0701973