Low external pH limits cell death of energy-depleted cardiomyocytes by attenuation of Ca2+ overload

We studied the effect of external pH (pH(e)) on cell injury, ATP content, and intracellular concentration of Ca2+ ([Ca2+](i)), Na+ ([Na+](i)), and H+ (pH(i)) during metabolic inhibition (NaCN + 2-deoxyglucose) in neonatal rat cardiomyocytes. Cell death during metabolic inhibition decreased at pH(e) <7.4, with almost no cell death at pH(e) 6.0. Lowering pH(e) resulted in only temporary ATP conservation. During metabolic inhibition at pH(e) 7.4, [Ca2+](i) rose from 86 +/- 44 nM to 2.5 +/- 0.4 mu M, but at pH(e) 6.0, [Ca2+](i) rose to only 510 +/- 215 nM. During metabolic inhibition at pH(e) 7.4, pH(i) decreased from 7.25 +/- 0.06 to 6.82 +/- 0.16, but at pH(e) 6.0, pH(i) decreased to 6.34 +/- 0.17. During metabolic inhibition at pH(e) 7.4, [Na+](i) increased from 9.1 +/- 0.86 to 26.1 +/- 4.1 mM. At pH(e) 6.0, [Na+](i) rose more rapidly, to 27.3 +/- 3.5 mM. At pH(e) <7.4, sarcolemmal Na+/Ca2+ exchanger activity, involved in the development of Ca2+ overload, was decreased, as assessed during Na+-free incubation. We conclude that low pH(e) protects cardiomyocytes during metabolic inhibition by limiting Ca2+ overload via Na+/Ca2+ exchanger inhibition.