Comparative Effects of the Potassium Channel Openers Chromakalim and Pinacidil and the Cromakalim Analog U-89232 on Isolated Vascular and Cardiac Tissue
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Potassium channel openers such as cromakalim and pinacidil represent a diverse group of chemical agents which selectively open ATP-sensitive K+ (KATP) channels. These compounds exhibit both potent vasodilatory and antiischemic properties. U-89232, a cyanoguanidine analog of cromakalim, has recently been found to exhibit myocardial protection during ischemia without altering in vivo hemodynamics. Due to its apparent cardiac selectivity, we examined the effects of U-89232 in comparison to cromakalim and pinacidil on isolated vascular and cardiac tissue. We also examined whether glyburide, a KATP channel blocker, could antagonize their effects. All three compounds produced concentration-dependent relaxation in isolated rabbit mesenteric artery precontracted with norepinephrine. Cromakalim was at least 100-fold more potent than either pinacidil or U-89232. Pinacidil and U-89232 were active in mesenteric artery at equimolar concentrations. Glyburide (0.5 ~) effectively antagonized the effects of pinacidil but merely blunted the effects of cromakalim and U-89232. In an isolated rabbit cardiac tissue preparation, U-89232 had little effect on maximum tension in cardiac muscle, whereas dose-response trends for cromakalim and pinacidil significantly decreased maximum tension from a slope of zero in papillary muscle, right atria, and left atria. Glyburide (1 µM) effectively antagonized the effects of cromakalim and pinacidil. U-89232 and glyburide, however, were not tested in cardiac muscle because U-89232 did not show any activity. Due to its apparent lack of cardiac selectivity in vitro, our results indicate that U-89232 may be protecting myocardium through a novel mechanism, independent of KATP channels.