Mechanism of ischemic contracture in ferret hearts: relative roles of Ca2+i elevation and ATP depletion

When coronary perfusion is interrupted, the diastolic force generated by the myocardium first falls but eventually increases. The delayed rise in force, ischemic contracture, has been attributed either to ATP depletion or to elevation of the intracellular free calcium concentration (Ca2+i). To distinguish between these possibilities, we measured Ca2+i and ATP concentration ( ATP) in ferret hearts using nuclear magnetic resonance (NMR) spectroscopy. Mean time-average Ca2+i and ATP equaled 0.25 microM and 2.7 mumol/g wet wt, respectively, under control perfusion conditions. Ca2+i increased and ATP fell during total global ischemia. Although Ca2+i exceeded the usual systolic levels of 1.7 microM within 20-25 min of ischemia and reached a steady level between 2 and 3 microM by 30-35 min, force only began to rise after 40 min. In contrast, the time required for ATP to fall to less than 10% of control levels coincided closely with the onset of contracture. Ischemia in the presence of iodoacetate, an inhibitor of glycolysis, led to a precipitous fall in ATP and a concomitant rise in force, both of which preceded any elevation of Ca2+i. Thus changes in Ca2+i are neither sufficient nor necessary for the initiation of ischemic contracture. We conclude that ATP depletion is primary and that the rise in resting force reflects the formation of rigor cross bridges.