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.
Department of Pharmacology, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan. tsato@faculty.chiba-u.jp
Toshiaki
T
Sato
Haruaki
H
Nakaya
D019297:2,4-Dinitrophenol / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003981:Diazoxide / Q000494:pharmacology; D005420:Flavoproteins / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D006352:Heart Ventricles / Q000166:cytology*; D007700:Kinetics; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D014475:Uncoupling Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D005420:Flavoproteins; D006146:Guanidines; D015221:Potassium Channels; D011725:Pyridines; D014475:Uncoupling Agents; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; D003981:Diazoxide; D019297:2,4-Dinitrophenol