The temperature-sensitivity of slow channel calcium blockers in relation to their effect upon the calcium paradox

The isolated perfused rat heart preparation was used to investigate the interrelationship between temperature and the ability of calcium antagonists to reduce protein leakage in the calcium paradox. Exploiting the fact that although the calcium depletion phase of calcium paradox-injury is highly temperature sensitive, the calcium repletion phase, during which time the injury is manifested, is temperature independent. Verapamil (4 μmol l−1) included in a 10 min period of calcium depletion (37ΰC) and a 20 min period of calcium repletion (37δC) was known to reduce cumulative protein leakage by 22±3%. With calcium depletion again at 37δC but repletion at 21δC verapamil failed to achieve any reduction in protein leakage despite the fact that leakage in the 21δC control group did not differ signficantly from that in the 37δC control group. Temperature-response studies (repletion temperature of 4, 10, 21. 23, 25, 28. 31. 34 and 37δC) revealed an abrupt loss of drug effect below 25δC. Studies with D600 (10 μmol l−1 nifedipine (4 μmol l−1) terodiline (4 μmol l−1) fendiline (20 μmol l−1) and diltiazem (2 μmol l−1) revealed that while all of these drugs reduced protein leakage at 37δC(24±3%, 31±2%, 31±3%, 23±3% and 29±3%. respectively), like verapamil they had no effect at 21δC. Additional studies showed that the loss of efficacy could not be attributed to either a temperature-induced change in protein leakage kinetics or drug dose-response characteristics. The similarity of results between this highly diverse group of drugs would suggest that the temperature effect is more likely to be operative upon the target rather than the drug and might possibly be attributable to some nonspecific membrane-lipoprotein phase transition or to some temperature-induced change in the conformation of the slow calcium channel.