zaprinast and aprikalim

In endothelium-denuded rat aortic rings, the sustained contractile effects produced by endothelin-1 (ET-1; 3.2 nM) were concentration-dependently overcome by nicorandil, aprikalim (RP 52891), a specific K+ channel opener, and nitroglycerin, a stimulant of guanylate cyclase (EC50: 2.55 +/- 0.06, 0.37 +/- 0.05 and 0.3 +/- 0.008 microM respectively, n = 13-16/group). The decontractant activity of aprikalim was not affected by the guanylate cyclase inhibitor methylene blue (10 microM), whereas it was markedly antagonized by glibenclamide (1 microM) (pKB: 7.19 +/- 0.15), an antagonist of ATP-gated K+ channels in pancreatic beta cells. This sulfonylurea failed to modify nitroglycerin-induced effects, but slightly reduced (10-15%) those produced by high concentrations of nicorandil. By contrast, methylene blue significantly displaced (4-fold) the control concentration-vasorelaxant response curves obtained with nitroglycerin and nicorandil. Zaprinast (20 microM), an inhibitor of soluble low Km cyclic GMP phosphodiesterase, enhanced the effects of nitroglycerin and nicorandil but did not alter those of aprikalim. Nicorandil relaxed ET-1-contracted rings from micropig left circumflex coronary artery with an EC50 of 24 +/- 2.8 microM (n = 7); this effect was antagonized by methylene blue (10 microM) and glibenclamide (3 microM) (2- and 4-fold dextral shift of the control concentration-response curve, respectively). In rat Langendorff-perfused heart with base-line coronary flow reduced by the addition of ET-1 to the perfusion medium, nicorandil and aprikalim increased coronary flow, while nitroglycerin did not. The vasodilator effects of the two compounds were also inhibited by glibenclamide (pKB congruent to 7).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Coronary Vessels; Endothelins; Endothelium, Vascular; Glyburide; Guanylate Cyclase; Heart; Hemodynamics; In Vitro Techniques; Male; Methylene Blue; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Niacinamide; Nicorandil; Nitroglycerin; Picolines; Potassium Channels; Purinones; Pyrans; Rats; Rats, Inbred Strains; Stimulation, Chemical; Swine; Swine, Miniature; Vasodilator Agents

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.

Topics: Animals; Benzopyrans; Cromakalim; Glyburide; Guanidines; Guinea Pigs; In Vitro Techniques; Male; Methylene Blue; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Niacinamide; Nicorandil; Picolines; Pinacidil; Potassium Channels; Potassium Chloride; Pulmonary Artery; Purinones; Pyrans; Pyrroles; Tetraethylammonium Compounds