Increased mortality with cardiotoxic doses of Adriamycin after verapamil pretreatment despite prevention of myocardial calcium accumulation.
The purpose of this investigation was to determine whether the calcium blocking agent, verapamil, could modify Adriamycin cardiotoxicity, and if so, whether or not such modification is mediated by a mechanism involving myocardial electrolyte distribution. The mean survival time of female New Zealand white rabbits administered Adriamycin was reduced by pretreatment with verapamil. Myocardial cellular calcium concentration, [Ca]i, in animals pretreated with verapamil before receiving Adriamycin was lower than in animals receiving Adriamycin alone (1.49 +/- 0.11 vs. 2.22 +/- 0.35 mmol/kg cell water, respectively; P = 0.05). Myocardial [Ca]i in control animals was 1.68 +/- 0.10 mmol/kg cell water. Myocardial [Mg]i in animals receiving Adriamycin alone was lower than that for animals receiving verapamil alone (15.6 +/- 1.4 vs. 19.2 +/- 0.8 mmol/kg cell water, respectively). When these drugs were combined, [Mg]i approached the control value of 17.3 +/- 0.06 mmol/kg cell water. Cellular concentrations of the monovalent electrolytes were little affected by these drugs, except for a reduction of [Cl]i by verapamil. Neither myocardial water distribution nor plasma concentrations of these electrolytes were altered by either drug. The data indicate that verapamil pretreatment increases the mortality associated with Adriamycin in rabbits despite the continued efficacy of verapamil as a Ca-blocking agent after injection of Adriamycin. Particular caution must be exercised if clinical combination of Ca-blocking agents and anthracyclines is contemplated.
D000818:Animals; D001834:Body Water / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004569:Electroencephalography; D004573:Electrolytes / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D011817:Rabbits; D014700:Verapamil / Q000494:pharmacology*
D004573:Electrolytes; D004317:Doxorubicin; D014700:Verapamil; D002118:Calcium