The effect of calmodulin antagonists trifluoperazine (2.5 X 10(-7) M and 2.5 X 10(-6) M) and R 24571 (10(-8) M and 10(-7) M) on Langendorff-perfused rabbit hearts subjected to 180 min hypoxia and 30 min reoxygenation was studied. Coronary flow, force of contraction, oxygen consumption and release of lactate, noradrenaline and LDH were measured. Both drugs were found to reduce some of the deleterious consequences of hypoxia, i.e., they caused: marked reduction in the hypoxic LDH release; reduction in hypoxic contracture; increased recovery of active tension, oxygen consumption and coronary flow upon reoxygenation as compared to those in the untreated controls. The drugs prevented reoxygenation-induced LDH release in the drug-pretreated hearts and had no effect when given only during reoxygenation. This suggests that the drugs do not prevent reoxygenation damage as such, but only some changes developing during hypoxia, which make myocardium vulnerable to the reoxygenation damage. Although other interpretations are possible (e.g., the effects are related to the membrane stabilizing action of the drugs), our data are consistent with the hypothesis that a calmodulin-sensitive process is involved in the hypoxia damage of the myocardium.