title: Differing potencies and dose-response characteristics in the ability of slow-calcium-channel blockers to reduce enzyme leakage in the calcium paradox.
abstract: In studies of the calcium paradox, we have used an isolated rat heart preparation to investigate the relationship between myocardial creatine kinase leakage and the concentration of slow-calcium-channel blockers (nifedipine or verapamil) in the perfusion fluid during a cycle of calcium reduction and repletion. The results indicated that enzyme leakage could be further reduced to a degree greater than that seen under conditions of a full calcium paradox (complete calcium depletion). Detailed dose-response studies with verapamil and nifedipine at a calcium concentration of 1.0 mM during a 20-min period of calcium repletion following a 10-min period of calcium reduction (12 microM calcium) revealed complex dose-response characteristics for each drug. In the dose range studied (0-20 microM), nifedipine was able to reduce enzyme leakage maximally by 57 +/- 8% and verapamil by 37 +/- 4%. Optimal concentrations for verapamil and nifedipine were 4.0 and 2.0 microM, respectively. Both drugs exhibited bell-shaped dose-response curves without a loss of efficacy at higher concentrations. There was no resumption in contractile activity in the drug-treated groups. Simultaneous use of verapamil and nifedipine at their optimal concentrations failed to improve the reduction in enzyme leakage to a reduction greater than that observed with one drug alone.
authors.forename: J E
authors.initials: JE
authors.lastname: Baker
authors.forename: D J
authors.initials: DJ
authors.lastname: Hearse
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003326:Coronary Circulation / Q000187:drug effects*; D003402:Creatine Kinase / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D009543:Nifedipine / Q000494:pharmacology*; D051381:Rats; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D007473:Ion Channels; D014700:Verapamil; D003402:Creatine Kinase; D009543:Nifedipine; D002118:Calcium