Effects of KATP Channel Openers, P-1075, Pinacidil, and Diazoxide, on Energetics and Contractile Function in Isolated Rat Hearts

We investigated the metabolic effects of a potent opener of ATP-sensitive K+ (KATP) channels, P-1075, in perfused rat hearts with the help of31P NMR spectroscopy. A 20 min infusion of 5μ m P-1075 depleted phosphocreatine and ATP by approximately 40%, concomitantly with a two-fold increase in inorganic phosphate, while oxygen consumption by the hearts increased by 50%. P-1075 induced a cardiac contracture (left ventricular end diastolic pressure increased from 6 to 60 mmHg) and a cardiac arrest after an infusion of approximately 9 min. The effects were fully reversed by glibenclamide (5 μ m), but not by sodium 5-hydroxydecanoate (0.4 m image). A P-1075-related KATP opener, pinacidil (0.3 m M), partially reversed the effects of P-1075, but a structurally unrelated opener, diazoxide (0.5 m M), had no effect. Pinacidil and diazoxide alone did not significantly affect PCr and ATP levels. Bioenergetic and functional effects similar to those of P-1075 were induced by infusion of a classic mitochondrial uncoupler, 2,4-dinitrophenol (50 μ m); however, they were not abolished by glibenclamide. In addition, it was shown, using87Rb NMR, that both agents, P-1075 and 2,4-dinitrophenol, resulted in a stimulation of Rb+ efflux from the Rb+ loaded rat hearts by approximately 130 and 65%, respectively, in a glibenclamide-sensitive manner. An inhibitory effect of P-1075 on ATP synthesis cannot be explained by its well-known action on sarcolemmal KATP channels. We concluded that, unlike an uncoupling effect of 2,4-dinitrophenol, an inhibitory effect of P-1075 is produced by uncoupling of oxidative phosphorylation through the activation of mitochondrial KATP channels.