Dissociation of cardiodepression from cardioprotection with calcium antagonists: diltiazem protects ischemic rat myocardium with a lower functional cost as compared with verapamil or nifedipine.
This study was performed to determine if cardiodepression can be dissociated from cardioprotection with calcium antagonists and which one (diltiazem, nifedipine, or verapamil) can maximally protect ischemic myocardium at a given level of cardiodepression. Isolated rat hearts were subjected to 0.1, 0.5, or 1.0 microM diltiazem, verapamil, or nifedipine 10 min before global ischemia. Ischemia was maintained for 25 min, at which time reperfusion was instituted for 30 min. Pre- and postischemia function, flow, and lactate dehydrogenase (LDH) release were measured. All three drugs reduced preischemic function and improved postischemic function and reflow in a dose-dependent fashion. LDH release and contracture were also mitigated with all drugs. When the efficacy of these drugs was expressed as the ratio of LDH release versus preischemic, postdrug function (ability of drug to reduce LDH release at a given level of cardiodepression), diltiazem had a significantly lower ratio as compared with verapamil or nifedipine. When similar experiments were performed with various concentrations of calcium in the perfusion buffer (2.50, 1.25, 0.75, 0.50, 0.41 mM CaCl2) administered 10 min before ischemia and reperfusion with normal (1.25 mM) buffer, preischemic function was reduced in a concentration-dependent fashion. Despite severe reductions in function at the concentration of 0.50 mM CaCl2, LDH release was not reduced. The concentration of 0.41 mM CaCl2, which depressed function to the same degree as 0.50 mM CaCl2, reduced LDH release. This reduction in LDH release, however, was not as great as that which occurred with the high dose of the calcium antagonists. Reperfusion with 0.41 mM calcium buffer, however, nearly abolished LDH release. Thus, although all three calcium antagonists reduced the severity of ischemia, diltiazem reduces it with the lowest cost in cardiac function. Reduction in extracellular calcium reduces cardiac function, but reductions in severity of ischemia, as measured by LDH release, do not parallel these changes.
Grover
G J
GJ
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
Sleph
P G
PG
D000818:Animals; D002118:Calcium / Q000502:physiology; D002122:Calcium Chloride / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D003327:Coronary Disease / Q000188:drug therapy*; D004110:Diltiazem / Q000009:adverse effects / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006334:Heart Function Tests; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009543:Nifedipine / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014700:Verapamil / Q000009:adverse effects / Q000494:pharmacology*
D014700:Verapamil; D007770:L-Lactate Dehydrogenase; D004110:Diltiazem; D009543:Nifedipine; D002122:Calcium Chloride; D002118:Calcium