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⁺], 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.