Low external pH limits cell death of energy-depleted cardiomyocytes by attenuation of Ca2+ overload.
We studied the effect of external pH (pHe) on cell injury, ATP content, and intracellular concentration of Ca2+ ([Ca2+]i), Na+ ([Na+]i), and H+ (pHi) during metabolic inhibition (NaCN + 2-deoxyglucose) in neonatal rat cardiomyocytes. Cell death during metabolic inhibition decreased at pHe < 7.4, with almost no cell death at pHe 6.0. Lowering pHe resulted in only temporary ATP conservation. During metabolic inhibition at pHe 7.4, [Ca2+]i rose from 86 +/- 44 nM to 2.5 +/- 0.4 microM, but at pHe 6.0, [Ca2+]i rose to only 510 +/- 215 nM. During metabolic inhibition at pHe 7.4, pHi decreased from 7.25 +/- 0.06 to 6.82 +/- 0.16, but at pHe 6.0, pHi decreased to 6.34 +/- 0.17. During metabolic inhibition at pHe 7.4, [Na+]i increased from 9.1 +/- 0.86 to 26.1 +/- 4.1 mM. At pHe 6.0, [Na+]i rose more rapidly, to 27.3 +/- 3.5 mM. At pHe < 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 pHe protects cardiomyocytes during metabolic inhibition by limiting Ca2+ overload via Na+/Ca2+ exchanger inhibition.
Atsma
D E
DE
Department of Cardiology, University Hospital, Leiden, The Netherlands.
Bastiaanse
E M
EM
Van der Valk
L
L
Van der Laarse
A
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004734:Energy Metabolism; D006859:Hydrogen / Q000378:metabolism / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012508:Sarcolemma / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger
D002352:Carrier Proteins; D019831:Sodium-Calcium Exchanger; D006859:Hydrogen; D000255:Adenosine Triphosphate; D012964:Sodium; D007770:L-Lactate Dehydrogenase; D002118:Calcium