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During myocardial ischemia, electrical uncoupling and contracture herald irreversible damage. In the present study, we tested the hypothesis that an increase of intracellular Ca 2+ is an important factor initiating these events. Therefore, we simultaneously determined tissue resistance, mechanical activity, pH o , and intracellular Ca 2+ (with the fluorescent indicator indo 1, Molecular Probes, Inc) in arterially perfused rabbit papillary muscles. Sustained ischemia was induced in three experimental groups: (1) control, (2) preparations preconditioned with two 5-minute periods of ischemia followed by reperfusion, and (3) preparations pretreated with 1 mmol/L iodoacetate to block anaerobic metabolism and minimize acidification during ischemia. In a fourth experimental group, intracellular Ca 2+ was increased under nonischemic conditions by perfusing with 0.1 mmol/L ionomycin and 0.1 μmol/L gramicidin. Ca 2+ transients and contractions rapidly disappeared after the induction of ischemia. In the control group, diastolic Ca 2+ began to rise after 12.6±1.3 minutes of ischemia; uncoupling, after 14.5±1.2 minutes of ischemia; and contracture, after 12.6±1.5 minutes of ischemia (mean±SEM). Preconditioning significantly postponed Ca 2+ rise, uncoupling, and contracture (21.5±4.0, 24.0±4.1, and 23.0±5.3 minutes of ischemia, respectively). Pretreatment with iodoacetate significantly advanced these events (1.9±0.7, 3.6±0.9, and 1.9±0.2 minutes of ischemia, respectively). In all groups, the onset of uncoupling always followed the start of Ca 2+ rise, whereas the start of contracture was not different from the rise in Ca 2+ . Perfusion with ionomycin and gramicidin permitted estimation of a threshold Ca 2+ for electrical uncoupling of 685±85 nmol/L. In conclusion, the rise in intracellular Ca 2+ is the main trigger for cellular uncoupling during ischemia. Contracture is closely associated with the increase of intracellular Ca 2+ during ischemia.
Dekker et al. (Thu,) studied this question.