Relative roles of Ca2(+)-dependent and Ca2(+)-independent mechanisms in hypoxic contractile dysfunction.
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.
Koretsune
Y
Y
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Marban
E
E
D000818:Animals; D002118:Calcium / Q000502:physiology*; D005289:Ferrets; D006706:Homeostasis; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000503:physiopathology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009200:Myocardial Contraction; D009994:Osmolar Concentration; D010758:Phosphorus / Q000502:physiology
D010758:Phosphorus; D002118:Calcium