Damaging effects of the calcium paradox are reduced in isolated hearts from ethanol-dependent rats: Paradoxic effects of dihydropyridine drugs

Previous experiments showed that isolated hearts from ethanol-exposed rats show a marked increase in sensitivity to anoxic myocardial damage, and we s uggested that this may be due to excess calcium entry through L-type voltag e-operated calcium channels (L-VOCCs). To challenge this hypothesis, we inv estigated the effect of ethanol treatment ex vivo on a damaging stimulus, t he "calcium paradox," which is associated with removal of calcium from the perfusate. Adult male Sprague-Dawley rats were exposed to intoxicating conc entrations of ethanol for 6-10 days by inhalation. Isolated hearts from the se animals were perfused with Krebs-Henseleit buffer by using a modified La ngendorff technique, and the calcium paradox induced by a 10-min period of perfusion with calcium-free buffer, followed by reperfusion with calcium-co ntaining buffer. Compared with controls, hearts from ethanol-exposed rats w ere significantly protected against myocardial damage, as shown by a marked reduction in release of intracellular proteins (lactate dehydrogenase, cre atine phosphokinase, and myoglobin) during the reperfusion phase. These ind ices of myocardial damage were modified by the presence of the dihydropyrid ine (DHP) calcium channel antagonist nitrendipine (10(-6) M) and the DHP L- VOCC activator Bay K 8644 (10(-7) M) in the perfusate during the calcium pa radox. Paradoxically, both drugs appeared to increase the damaging effects of calcium-free perfusion, with this effect being generally greater in the preparations from ethanol-exposed rats. As a result, the difference between these hearts and those from control rats was reduced, although a significa nt degree of protection against the calcium paradox remained. The results s upport the hypothesis that long-term exposure to ethanol in vivo produces m arked alterations in the toxic effects of changes in :myocardial calcium co ncentration. The increased sensitivity to DHP drugs of isolated hearts from ethanol-treated rats is consistent with previous experiments showing incre ased DHP radioligand-binding sites in these tissues.