Postcardioplegic myocardial recovery: effects of halothane, nifedipine, HOE 694, and quinacrine.
Halothane has been shown to be a powerful myocardial protectant during normothermic cardioplegic arrest and subsequent reperfusion. In view of its multiple effects on cellular Ca2+ movements and the role of this ion in ischemia-reperfusion injury, the questions of whether halothane is capable of maximally protecting the heart or whether combination therapy of halothane with other Ca2+ blocking agents may be more effective arose. Therefore, the effects of combination therapy with halothane and a calcium antagonist (nifedipine), or a Na+/H+ inhibitor (HOE 694), or a Na+/Ca2+ inhibitor (quinacrine) on postcardioplegic functional recovery were evaluated. The isolated perfused rat heart subjected to 45 minutes normothermic cardiac arrest was used as an experimental model. Dose-response curves were performed for each drug. Using the optimal dosage for each drug, the following results were obtained: (1) Nifedipine (10(-7) M; administered retrogradely 10 minutes before and after cardioplegia) and halothane (1.5% administered during cardioplegia), when administered separately, improved functional recovery. Combination therapy did not further improve protection. (2) HOE 694 (10(-7) M) or quinacrine (10(-9) M) improved post-cardioplegic functional recovery when added for 2 minutes at the onset of reperfusion. Simultaneous administration of HOE 694 and 1.5% halothane was the only combination that yielded additive protection. (3) Quinacrine, a phospholipase and Na+/Ca2+ exchanger inhibitor, appeared to be the most powerful drug used. In summary, the results obtained indicate that interventions aimed at preventing intracellular Ca2+ overload improve recovery after cardioplegic arrest. The beneficial effects of halothane could be further improved by HOE 694.
Department of Medical Physiology and Biochemistry, Faculty of Medicine, University of Stellenbosch, Tygerberg, Republic of South Africa. alo@gerge.sun.ac.za
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Lochner
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Genade
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Tromp
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Theron
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Trollip
D000704:Analysis of Variance; D018685:Anesthetics, Inhalation / Q000627:therapeutic use*; D000818:Animals; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006146:Guanidines / Q000627:therapeutic use*; D006221:Halothane / Q000627:therapeutic use; D006324:Heart Arrest, Induced; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D009543:Nifedipine / Q000627:therapeutic use; D011796:Quinacrine / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013450:Sulfones / Q000627:therapeutic use*
D018685:Anesthetics, Inhalation; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D006146:Guanidines; D013450:Sulfones; C074107:3-methylsulfonyl-4-piperidinobenzoyl guanidine; D011796:Quinacrine; D009543:Nifedipine; D006221:Halothane