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.