Abstract 104: Effects of Pinacidil and Ca2+ on Sodium-loaded Rat Heart Mitochondria
Deterioration of the contractile parameters of the heart muscle caused by ischemia and followed reperfusion is known as the main postoperative complication which is related to Ca2+ and Na+ overload in cardiomyocytes and mitochondria. Pinacidil reduced the overload in ischemia/reperfusion experiments. The mechanism of this phenomenon is still not clear. We hypothesized that increased ion permeability of the inner mitochondrial membrane (IMM) followed drop of electrochemical potential (ΔΨmito) can reduce the calcium. The aim of the study was to elucidate the effect of pinacidil (100 μM) and Ca2+ (100 μM ) on swelling, oxygen consumption and ΔΨmito of isolated sodium-loaded rat heart mitochondria (RHM(Na)) energized glutamate and malate. Pinacidil significantly enchanced the permeability of IMM to protons in ammonium nitrate medium. Also increased swelling of RHM(Na) energized with substrates in potassium acetate medium revealed that pinacidil increased potassium transport into matrix. Pinacidil stimulated oxygen consumption of RHM(Na) in State 4 and detained Ca2+-induced dissipation of ΔΨmito. Under condition of Ca2+ and Na+ overload simulating ischemia/reperfusion, RHM(Na) oxygen consumption was not affected with pinacidil in State 3 and in the presence of 2,4-dinitrophenol. Cyclosporin A and ADP, the inhibitors of mitochondrial permeability transition pore (MPTP), markedly decreased Ca2+- induced swelling of RHM(Na) in nitrate ammonium or potassium acetate medium in the presence of pinacidil. Carboxyatractyloside, an inhibitor of cytosolic side-specific adenine nucleotide translocase, eliminated a pinacidil-stimulated oxygen consumption of succinate-energized RHMNa in State 4 regardless of the presence of Ca2+. Pinacidil was also concluded to accelerat potassium flux into energized RHM(Na) and promot MPTP opening in the low conduction state. Based on our data we suggested that the effect of pharmacological preconditioning induced by pinacidil could be due to it’s direct effect on mitochondria which is connected with above stimulation of the potassium permeability of the inner mitochondrial membrane and following reduce of the ΔΨmito that thus prevent calcium overload of cardiomyocytes after ischemia/reperfusion in turn.
- © 2013 by American Heart Association, Inc.