title: Dose-dependent cardiotoxic effect of amiodarone in cardioplegic solutions correlates with loss of dihydropyridine binding sites: in vitro evidence for a potentially lethal interaction with procaine.
abstract: Increasing evidence suggests that amiodarone treatment may represent a potential risk in patients exposed to cardiac surgery. Conversely, amiodarone has been suggested to be beneficial as an additive to cardioplegic solutions, but its use has not been tried in vivo. We evaluated hemodynamic, ECG, and possible toxicologic effects of amiodarone when added to the cardioplegic solution. Pigs weighing (70 +/- 2 kg, n = 24) were exposed to cardiopulmonary bypass (CPB) and hypothermic cardiac arrest for 1 h with Bretschneider's (BS) or St. Thomas' Hospital (St. Th.) cardioplegic solution. Amiodarone or the solvent was added to the solutions. Only pigs receiving the lowest dose of amiodarone (0.028 mg/g tissue) could be weaned from bypass. Higher doses resulted in graded myocardial contractures without recovery of electrical activity. Electron microscopy showed severely disintegrated myocytes and swollen mitochondria in amiodarone-exposed hearts. No changes in equilibrium binding characteristics were observed for beta-adrenoceptors, whereas maximum binding capacity (MBC) and receptor affinity for voltage-operated Ca2+ channels were dose-dependently decreased (mean 73%, p < 0.0005; 105%; p < 0.05). Ca2+ paradoxlike findings similar to those in pigs were inducible in isolated, in vitro perfused rat heart exposed to normothermic or hypothermic chemical arrest with BS and amiodarone. This model was therefore used to evaluate whether the observed myocardial damage was associated with excessive tissue Ca2+ accumulation. Addition of amiodarone to BS was associated with a significant increase in 45Ca2+ content in the heart, irrespective of temperature. Only 2 of 13 hearts recovered some degree of mechanical activity during reperfusion. When procaine (an antiarrhythmic drug with membrane-stabilizing properties, an effect that is potentiated by amiodarone) was removed from BS, 45Ca2+ accumulation did not differ from that in controls and mechanical activity recovered fully in 7 of 8 hearts. In conclusion, amiodarone added to Ca(2+)-free as well as Ca(2+)-containing cardioplegic solutions led to dose-dependent myocardial damage at reperfusion, irrespective of temperature. In parallel with clinical features was a reduction in maximum binding capacity and a decrease in affinity for the Ca2+ channel antagonist. Removal of procaine from BS prevented excessive Ca2+ accumulation and mechanical deterioration in isolated heart. We hypothesize that amiodarone administered under the conditions described may change the configuration of the Ca2+ channel, rendering it more permeable to Ca2+. Pharmacologic interaction between amiodarone and procaine apparently is at least partly responsible for the increased Ca2+ uptake and the stone-heart phenomenon during reperfusion.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Institute of Experimental Clinical Research, University of Arhus, Denmark.
authors.forename: L S
authors.initials: LS
authors.lastname: Gøtzsche
authors.forename: E M
authors.initials: EM
authors.lastname: Pedersen
mesh_terms: D000638:Amiodarone / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects; D002314:Cardioplegic Solutions / Q000627:therapeutic use*; D004095:Dihydropyridines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008854:Microscopy, Electron; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011343:Procaine / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D013552:Swine
chemical_list: D015220:Calcium Channels; D002314:Cardioplegic Solutions; D004095:Dihydropyridines; D011943:Receptors, Adrenergic, beta; D011343:Procaine; C038806:1,4-dihydropyridine; D000638:Amiodarone; D002118:Calcium