Effects of KATP channel openers, P-1075, pinacidil, and diazoxide, on energetics and contractile function in isolated rat hearts

O. JILKINA. B. KUZIO, G. J. GROVER AND V. V. KUPRIYANOV. Effects of K-ATP Channel Openers, P-1075, Pinacidil. and Diazoxide, on Energetics and Contractile Function in Isolated Rat Hearts. Journal of Molecular and Cellular Cardiology (2002) 34, 427-440. We investigated the metabolic effects of a potent opener of ATP-sensitive K+ (K,,,,) channels, P-1075. in perfused rat hearts with the help of T-31 NMR spectroscopy. A 20 min infusion of 5 mum P-1075 depleted phosphocreatine and NIT 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 pm), but not by sodium 5-hydroxydecanoate (0.4 mm). A P-1075-related K-ATP opener, pinacidil (0.3 mm), partially reversed the effects of P-1075, but a structurally unrelated opener. diazoxide (0.5 mm). 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 mum); however, they were not abolished by glibenclamide. In addition. it was shown, using (87)b NMR, that both agents, P-1075 and 14-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 K-ATP. channels. We concluded that, unlike all Uncoupling effect of 2,4-dinitrophenol, an inhibitory effect of P-1075 is produced by uncoupling of oxidative phosphorylation through the activation of mitochondrial K-ATP. channels. (C) 2002 Elsevier Science Ltd. All rights reserved.