Pm. Heerdt et al., EFFECT OF HALOTHANE ON IN-VIVO AND IN-VITRO CARDIOTOXICITY OF AN AMINOCARDENOLIDE, Journal of cardiovascular pharmacology, 23(6), 1994, pp. 890-896
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.