P-1075 Exerts Diverse Modulatory Effects on Mitochondrial ATP-Sensitive K+ Channels in Rabbit Ventricular Myocytes

P-1075 was reported to be selective for sarcolemmal ATP-sensitive K (sarcKATP) channels because of its lack of mitochondria-oxidizing effect in isolated adult rabbit myocytes. Conflicting results however have been reported on the action of P-1075 on mitochondrial KATP (mitoKATP) channels. The aim of the present study was to reevaluate the effect of P-1075 on mitoKATP channels. Endogenous flavoprotein autofluorescence in isolated rabbit ventricular myocytes was measured to assay mitoKATP channel activity. The mitoKATP channel opener diazoxide (100 microM) oxidized the flavoprotein. P-1075 at a concentration of 30 microM significantly inhibited the oxidative effect of diazoxide from 48.6 +/- 7.1% to 28.2 +/- 5.2% of the maximum value induced by 2,4-dinitrophenol (DNP, 100 microM) (n = 4, P < 0.05). Additionally, P-1075 (30 microM) significantly inhibited the pinacidil (100 microM)-induced flavoprotein oxidation by 48.4 +/- 3.9% (n = 4, P < 0.05). The inhibitory effects of P-1075 on diazoxide-induced flavoprotein oxidation were observed in the micromolar range in a concentration dependent manner. P-1075 alone oxidized flavoprotein in the range 30 nM to 5 microM, and was nearly maximal at 150 nM (11.1 +/- 1.9% of the DN P value, n = 5). These results indicate that P-1075 exerts diverse effects on mitoKATP channel in rabbit ventricular myocytes: P-1075 has a partial agonist effect and weakly activates mitoKATP channels at low concentrations, whereas P-1075 rather inhibits the opening of mitoKATP channels in the micromolar concentration range.