Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 141, Issue 6, Pages 1059-1067Publisher
WILEY
DOI: 10.1038/sj.bjp.0705702
Keywords
ATP-sensitive potassium channels; calcium overload; membrane potential; sodium/calcium exchange; heart
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1 The opening of cardiac plasma-membrane ATP-sensitive K+ channels (pmK(ATP)) can protect the heart against ischaemia/reperfusion injury. We recently demonstrated that the resting membrane potential (E-m) of ventricular myocytes strongly modulates reoxygenation-induced Ca2+ overload. This led to the hypothesis that activation of pm(KATP) can influence the extent of chemically induced hypoxia (CIH)/reoxygenation Ca2+ overload via hyperpolarization of the diastolic membrane potential of ventricular myocytes. 2 The membrane potential (E-m) of isolated rat myocytes was determined using the perforated patch-clamp technique and DiBac(4)(3) imaging. Intracellular Ca2+ ([Ca2+](i)) was monitored using FURA-2 imaging. 3 CIH/reoxygenation caused a significant depolarization of E-m and a substantial increase in [Ca2+](i). The K-ATP opener pinacidil (100 muM) and the pm(KATP) opener P-1075 (100 muM) hyperpolarized the Em of normoxic myocytes. Pinacidil (100 muM) and P-1075 (10 and 100 muM), applied during reoxygenation, hyperpolarized E-m and prevented reoxygenation-induced increases in [Ca2+](i). 4 Myocyte hypercontracture and death increased in parallel with an E-m depolarization of 10-15 mV and increases in [Ca2+](i). Under these conditions, the selective pm(KATP) channel inhibitor HMR 1098 further depolarized myocyte membrane potential and increased hypercontracture. 5 In conclusion, activation of pm(KATP) channels can prevent CIH/reoxygenation-induced Ca2+ overload via a mechanism that is dependent on hyperpolarization of diastolic membrane potential. Hyperpolarization toward normal resting membrane potential favours the Ca2+ extrusion mode of Na+/Ca2+ exchange.
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