EFFECT OF HALOTHANE ON IN-VIVO AND IN-VITRO CARDIOTOXICITY OF AN AMINOCARDENOLIDE

Halothane opposes cardiotoxicity of neutral-sugar digitalis compounds in intact animals, presumably by depressing a sympathetic component of arrhythmogenesis. However, halothane also produces a dose-related red uction in arrhythmogenicity of ouabain in isolated canine Purkinje fib ers, suggesting that the anesthetic may oppose direct mechanisms of ca rdiotoxicity as well. The present study examined in vivo and in vitro the effect of halothane on the arrhythmogenicity of ASI-222 eta-O[4-am ino-4-6-dideoxy-beta-D-galactopyranosyl] digitoxigen in HCl), a highly polar aminocardenolide with no sympathetic component to cardiotoxicit y. For in vivo studies, ASI-222 was infused at a rate of 1 mu g/kg/min until appearance of third-degree atrioventricular (AV) block or susta ined ventricular arrhythmias in 5 conscious (control) and 6 halothane- anesthetized (1.4% end-tidal) dogs. For in vitro studies, standard mic roelectrode techniques were used to measure action potentials (AP) in seven excised canine Purkinje fibers superfused with oxygenated Krebs- Henseleit buffer. AP were recorded during control superfusion, after i nduction of toxicity with 10(-7) M ASI-222, and during exposure to 0.5 , 1.0, and 2.0% halothane. Purkinje fibers were paced at 500-ms cycle lengths (CL) for 20 beats, and the amplitude of delayed afterdepolariz ations (DAD) were recorded. Pacing at 250 ms CL was used to trigger ec topy. In vivo studies showed no difference in the cardiotoxic dose of ASI-222 between control dogs and those anesthetized with 1.4% halothan e. However, in 4 of 6 anesthetized dogs, acutely increasing the inspir ed halothane concentration suppressed arrhythmias once end-tidal conce ntration were >2.2%. ASI-222 application to isolated Purkinje fibers i nduced two DADs (DAD1, DAD2) after pacing at 500-ms CL; 2.0% halothane significantly reduced DAD1 amplitude, whereas both 1.0 and 2.0% halot hane reduced DAD2 amplitude. Pacing at 250-ms CL triggered no extra be ats during control superfusion, but did after ASI-222 superfusion. Hal othane reduced triggered ectopy in a dose-related fashion, with total elimination at 2.0%. We conclude that halothane opposes the direct car diotoxicity of ASI-222 when administered at sufficient concentration. However, unlike the dose-related halothane suppression of DAD amplitud e and triggered ectopy evident in isolated Purkinje fibers, an end-tid al halothane concentration > 2.2% is required in intact dogs to suppre ss sustained ventricular ectopy. Our data thus suggest that at the low to moderate end-tidal concentrations frequently used clinically halot hane opposes cardiotoxicity of conventional digitalis compounds primar ily by blunting the sympathetic component of arrhythmogenesis.