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Circulation, Vol 82, 528-535, Copyright © 1990 by American Heart Association

ARTICLES

Relative roles of Ca2(+)-dependent and Ca2(+)-independent mechanisms in hypoxic contractile dysfunction

Y Koretsune and E Marban
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.

Contractile function is known to be impaired during hypoxia or metabolic inhibition, but the relative importance of activator Ca2+ deficiency compared with the accumulation of depressant metabolites remains controversial. To distinguish between these possibilities, we used nuclear magnetic resonance (NMR) spectroscopy to measure the most likely mediators--intracellular [Ca2+] [( Ca2+]i), inorganic phosphate concentration [( Pi]), and pH--before and during hypoxia in perfused ferret hearts. Ca2+ transients were quantified by gated fluorine-19 NMR spectroscopy. Left ventricular developed pressure decreased to steady- state levels approximately 60% of control values after 20 minutes of hypoxic perfusion (induced by equilibrating the perfusate with 10% O2- 90% N2). With hypoxia, phosphorus NMR revealed an increase in [Pi] and a mild intracellular acidosis. Both [Pi] and intracellular pH correlate well with the extent of decline of developed pressure in each heart, but multiple regression analysis points to the changes in [Pi] as the dominant influence. In contrast, [Ca2+]i at end diastole was not influenced by hypoxia, whereas the peak systolic values were paradoxically increased. The ratio of Ca2+ transient amplitude in hypoxia to that in control had no correlation with percent of developed pressure. These findings indicate that contractile failure during relatively mild, steady-state hypoxia is not due to a critical failure of any of the mechanisms that regulate cytoplasmic activator Ca2+. Instead, the accumulation of Pi (and to a lesser degree, H+) mediates hypoxic contractile dysfunction.

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