Dose-dependent cardiotoxic effect of @entity2643 in cardioplegic solutions correlates with loss of dihydropyridine binding sites: in vitro evidence for a potentially lethal interaction with XXXX .

@entity1 @entity1707 @entity2643 @entity296 @entity35 @entity8162 @entity195 @entity141 @entity1167
Increasing evidence suggests that @entity2643 treatment may represent a potential risk in @entity1 exposed to cardiac surgery. Conversely, @entity2643 has been suggested to be beneficial as an additive to cardioplegic solutions, but its use has not been tried in vivo. We evaluated hemodynamic, ECG, and possible toxicologic effects of @entity2643 when added to the cardioplegic solution. @entity1707 weighing (70 +/- 2 kg, n = 24) were exposed to cardiopulmonary bypass (CPB) and hypothermic @entity1167 for 1 h with @entity195 ( @entity195 ) or St. Thomas' Hospital (St. Th.) cardioplegic solution. @entity2643 or the solvent was added to the solutions. Only @entity1707 receiving the lowest dose of @entity2643 (0.028 mg/g tissue) could be weaned from bypass. Higher doses resulted in graded @entity296 without recovery of electrical activity. Electron microscopy showed severely disintegrated myocytes and swollen mitochondria in @entity2643 -exposed hearts. No changes in equilibrium binding characteristics were observed for beta-adrenoceptors, whereas maximum binding capacity (MBC) and receptor affinity for voltage-operated @entity141 channels were dose-dependently decreased (mean 73%, p < 0.0005; 105%; p < 0.05). @entity141 paradoxlike findings similar to those in @entity1707 were inducible in isolated, in vitro perfused @entity35 heart exposed to normothermic or hypothermic @entity1167 with @entity195 and @entity2643 . This model was therefore used to evaluate whether the observed @entity296 was associated with excessive tissue @entity141 accumulation. Addition of @entity2643 to @entity195 was associated with a significant increase in 45 @entity141 content in the heart, irrespective of temperature. Only 2 of 13 hearts recovered some degree of mechanical activity during reperfusion. When @entity8162 (an antiarrhythmic drug with membrane-stabilizing properties, an effect that is potentiated by @entity2643 ) was removed from @entity195 , 45 @entity141 accumulation did not differ from that in controls and mechanical activity recovered fully in 7 of 8 hearts. In conclusion, @entity2643 added to @entity141 -free as well as @entity141 -containing cardioplegic solutions led to dose-dependent @entity296 at reperfusion, irrespective of temperature. In parallel with clinical features was a reduction in maximum binding capacity and a decrease in affinity for the @entity141 channel antagonist. Removal of @entity8162 from @entity195 prevented excessive @entity141 accumulation and mechanical deterioration in isolated heart. We hypothesize that @entity2643 administered under the conditions described may change the configuration of the @entity141 channel, rendering it more permeable to @entity141 . Pharmacologic interaction between @entity2643 and @entity8162 apparently is at least partly responsible for the increased @entity141 uptake and the stone-heart phenomenon during reperfusion.(ABSTRACT TRUNCATED AT 400 WORDS)
