Effects of K(ATP) channel openers, P-1075, pinacidil, and diazoxide, on energetics and contractile function in isolated rat hearts.

Abstract

We investigated the metabolic effects of a potent opener of ATP-sensitive K(+) (K(ATP)) channels, P-1075, in perfused rat hearts with the help of(31)P NMR spectroscopy. A 20 min infusion of 5 microm 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 microm), but not by sodium 5-hydroxydecanoate (0.4 m m). A P-1075-related K(ATP) 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 microm); however, they were not abolished by glibenclamide. In addition, it was shown, using(87)Rb 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 K(ATP) 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 K(ATP) channels.

• Authors: Olga Jilkina, Bozena Kuzio, Gary J Grover, Valery V Kupriyanov
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 34 Issue 4 Pg. 427-40 (Apr 2002) ISSN: 0022-2828 [Print] England
• PMID: 11991732 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2002 Academic Press.

Chemical References

• Guanidines
• Potassium Channel Blockers
• Potassium Channels
• Pyridines
• Vasodilator Agents
• Phosphocreatine
• N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine
• Pinacidil
• Adenosine Triphosphate
• Diazoxide
• 2,4-Dinitrophenol

Topics

• 2,4-Dinitrophenol (metabolism)
• Adenosine Triphosphate (metabolism)
• Animals
• Diazoxide (pharmacology)
• Guanidines (pharmacology)
• Heart (drug effects)
• In Vitro Techniques
• Magnetic Resonance Spectroscopy
• Male
• Myocardial Contraction (drug effects)
• Myocardium (metabolism)
• Oxidative Phosphorylation
• Oxygen Consumption
• Perfusion
• Phosphocreatine (metabolism)
• Pinacidil (pharmacology)
• Potassium Channel Blockers (metabolism)
• Potassium Channels (drug effects, metabolism)
• Pyridines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Vasodilator Agents (pharmacology)