3 years ago

Regulation of Ca2+ signaling by acute hypoxia and acidosis in rat neonatal cardiomyocytes

Ischemic heart disease is an arrhythmogenic condition, accompanied by hypoxia, acidosis, and impaired Ca2+ signaling. Here we report on effects of acute hypoxia and acidification in rat neonatal cardiomyocytes cultures. Results Two populations of neonatal cardiomyocyte were identified based on inactivation kinetics of L-type ICa: rapidly-inactivating ICa~20ms) myocytes (prevalent in 3–4-day cultures), and slow-inactivating ICa40ms) myocytes (dominant in 7-day cultures). Acute hypoxia (pO2 <5mmHg for 50–100s) suppressed ICa reversibly in both cell-types to different extent and with different kinetics. This disparity disappeared when Ba2+ was the channel charge carrier, or when the intracellular Ca2+ buffering capacity was increased by dialysis of high concentrations of EGTA and BAPTA, suggesting critical role for calcium-dependent inactivation. Suppressive effect of acute acidosis on ICa (~40%, pH6.7), on the other hand, was not cell-type dependent. Isoproterenol enhanced ICa in both cell-types, but protected only against suppressive effects of acidosis and not hypoxia. Hypoxia and acidosis suppressed global Ca2+ transients by ~20%, but suppression was larger, ~35%, at the RyR2 microdomains, using GCaMP6-FKBP targeted probe. Hypoxia and acidosis also suppressed mitochondrial Ca2+ uptake by 40% and 10%, respectively, using mitochondrial targeted Ca2+ biosensor (mito-GCaMP6). Conclusion Our studies suggest that acute hypoxia suppresses ICa in rapidly inactivating cell population by a mechanism involving Ca2+-dependent inactivation, while compromised mitochondrial Ca2+ uptake seems also to contribute to ICa suppression in slowly inactivating cell population. Proximity of cellular Ca2+ pools to sarcolemmal Ca2+ channels may contribute to the variability of inactivation kinetics of ICa in the two cell populations, while acidosis suppression of ICa appears mediated by proton-induced block of the calcium channel.

Publisher URL: www.sciencedirect.com/science

DOI: S002228281730322X

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