Effects of K(ATP) 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(+) (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.
Jilkina
Olga
O
Institute for Biodiagnostics, National Research Council, Winnipeg, MB, Canada.
Kuzio
Bozena
B
Grover
Gary J
GJ
Kupriyanov
Valery V
VV
D019297:2,4-Dinitrophenol / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003981:Diazoxide / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D010477:Perfusion; D010725:Phosphocreatine / Q000378:metabolism; D020110:Pinacidil / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology
D006146:Guanidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011725:Pyridines; D014665:Vasodilator Agents; D010725:Phosphocreatine; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; D020110:Pinacidil; D000255:Adenosine Triphosphate; D003981:Diazoxide; D019297:2,4-Dinitrophenol