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.
Eltze
M
M
Department of Pharmacology, Byk Gulden Pharmaceuticals, Konstanz, F.R.G.
D000818:Animals; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019806:Cromakalim; D005905:Glyburide / Q000494:pharmacology*; D006146:Guanidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D020108:Nicorandil; D010847:Picolines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects*; D011688:Purinones / Q000494:pharmacology; D011714:Pyrans / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
D001578:Benzopyrans; D006146:Guanidines; D010847:Picolines; D015221:Potassium Channels; D011688:Purinones; D011714:Pyrans; D011758:Pyrroles; D013757:Tetraethylammonium Compounds; D019806:Cromakalim; D009536:Niacinamide; D020108:Nicorandil; C061043:aprikalim; D011189:Potassium Chloride; D020110:Pinacidil; C011145:zaprinast; D005905:Glyburide; D008751:Methylene Blue