Glibenclamide is a competitive antagonist of cromakalim, pinacidil and RP 49356 in guinea-pig pulmonary artery.

The relaxant effect of cromakalim (BRL 34915), pinacidil and RP 49356 (N-methyl-2-(3-pyridyl)-tetrahydro-thiopyran-2-carbothioamide-1-ox ide) on the sustained contractions induced by 20 mM KCl were compared with the effects of nicorandil. The preparation used was vascular smooth muscle of phenoxybenzamine-treated pulmonary artery rings from reserpinized guinea-pigs. Cromakalim, pinacidil, RP 49356 and nicorandil relaxed the tissues with -log EC50 values of 6.78, 6.12, 6.02 and 5.46, respectively. The inhibitory effect of cromakalim, pinacidil and RP 49356, but not of nicorandil, was competitively antagonized by glibenclamide (10(-7)-3 X 10(-6) M), yielding uniform pA2 values of 7.17-7.22 against all three relaxant drugs. The order of potency of other K+ channel blocking agents for the inhibition of vasorelaxation by cromakalim, pinacidil and RP 49356 was procaine greater than 4-aminopyridine greater than tetraethylammonium. The mainly competitive type of inhibition of the RP 49356-induced response was more comparable to that with pinacidil than with cromakalim. The relaxation caused by nicorandil was only attenuated by a high concentration of 4-aminopyridine or tetraethylammonium but was markedly antagonized by methylene blue (3 X 10(-6)-10(-5) M) and potentiated by M & B 22948 (3 X 10(-6)-10(-5) M). These results suggest that the vascular relaxation caused in guinea-pig pulmonary artery by cromakalim, pinacidil and RP 49356 is mediated through the same glibenclamide-sensitive K+ channel whereas the major mechanism for the effect of nicorandil seems to involve stimulation of guanylate cyclase.