Effect of halothane on in vivo and in vitro cardiotoxicity of an aminocardenolide

Paul M. Heerdt, John D. Gallagher, Robert William Caldwell

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Halothane opposes cardiotoxicity of neutralβsugar digitalis compounds in intact animals, presumably by depressing a sympathetic component of arrhythmo-genesis. However, halothane also produces a dose-related reduction in arrhythmogenicity of ouabain in isolated canine Purkinje fibers, suggesting that the anesthetic may oppose direct mechanisms of cardiotoxicity as well. The present study examined in vivo and in vitro the effect of halothane on the arrhythmogenicity of ASI-222 (3-β-O[4-amino-4-6-dideoxy-β-D-galactopyranosyl] digi-toxigen in HCl), a highly polar aminocardenolide with no sympathetic component to cardiotoxicity. For in vivo studies, ASI-222 was infused at a rate of 1 μg/kg/min until appearance of third-degree atrioventricular (AV) block or sustained ventricular arrhythmias in 5 conscious (control) and 6 halothane-anesthetized (1.4% end-tidal) dogs. For in vitro studies, standard microelectrode 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 induction of toxicity with 10-7M 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 afterdepolar-izations (DAD) were recorded. Pacing at 250 ms CL was used to trigger ectopy. In vivo studies showed no difference in the cardiotoxic dose of ASI-222 between control dogs and those anesthetized with 1.4% halothane. However, in 4 of 6 anesthetized dogs, acutely increasing the inspired halothane concentration suppressed arrhythmias once end-tidal concentration were > 2.2%. ASI-222 appliβcation to isolated Purkinje fibers induced two DADs (DADI, DAD2) after pacing at 500-ms CL; 2.0% halo thane significantly reduced DADI amplitude, whereas both 1.0 and 2.0% halothane reduced DAD2 amplitude. Pacing at 250-ms CL triggered no extra beats during control superfusion, but did after ASI-222 superfusion. Halothane reduced triggered ectopy in a dose-related fashion, with total elimination at 2.0%. We conclude that halothane opposes the direct cardiotoxicity of ASI-222 when administered at sufficient concentration. However, unlike the dose-related halothane suppression of DAD amplitude and triggered ectopy evident in isolated Purkinje fibers, an end-tidal halothane concentration >2.2% is required in intact dogs to suppress sustained ventricular ectopy. Our data thus suggest that at the low to moderate end-tidal concentrations frequently used clinically halothane opposes cardiotoxicity of conventional digitalis compounds primarily by blunting the sympathetic component of airhythmogenesis.

Original languageEnglish (US)
Pages (from-to)890-896
Number of pages7
JournalJournal of Cardiovascular Pharmacology
Volume23
Issue number6
DOIs
StatePublished - Jan 1 1994

Fingerprint

Halothane
Purkinje Fibers
Dogs
Digitalis
Cardiotoxicity
In Vitro Techniques
Action Potentials
Canidae
Cardiac Arrhythmias
Atrioventricular Block
Microelectrodes
Ouabain
ASI-222
Anesthetics

Keywords

  • Aminocardenolide
  • Cardiotoxicity
  • Halothane
  • Purkinje fiber

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Effect of halothane on in vivo and in vitro cardiotoxicity of an aminocardenolide. / Heerdt, Paul M.; Gallagher, John D.; Caldwell, Robert William.

In: Journal of Cardiovascular Pharmacology, Vol. 23, No. 6, 01.01.1994, p. 890-896.

Research output: Contribution to journalArticle

@article{9956148240704e32a8cc422e4bc5c48e,
title = "Effect of halothane on in vivo and in vitro cardiotoxicity of an aminocardenolide",
abstract = "Halothane opposes cardiotoxicity of neutralβsugar digitalis compounds in intact animals, presumably by depressing a sympathetic component of arrhythmo-genesis. However, halothane also produces a dose-related reduction in arrhythmogenicity of ouabain in isolated canine Purkinje fibers, suggesting that the anesthetic may oppose direct mechanisms of cardiotoxicity as well. The present study examined in vivo and in vitro the effect of halothane on the arrhythmogenicity of ASI-222 (3-β-O[4-amino-4-6-dideoxy-β-D-galactopyranosyl] digi-toxigen in HCl), a highly polar aminocardenolide with no sympathetic component to cardiotoxicity. For in vivo studies, ASI-222 was infused at a rate of 1 μg/kg/min until appearance of third-degree atrioventricular (AV) block or sustained ventricular arrhythmias in 5 conscious (control) and 6 halothane-anesthetized (1.4{\%} end-tidal) dogs. For in vitro studies, standard microelectrode 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 induction of toxicity with 10-7M 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 afterdepolar-izations (DAD) were recorded. Pacing at 250 ms CL was used to trigger ectopy. In vivo studies showed no difference in the cardiotoxic dose of ASI-222 between control dogs and those anesthetized with 1.4{\%} halothane. However, in 4 of 6 anesthetized dogs, acutely increasing the inspired halothane concentration suppressed arrhythmias once end-tidal concentration were > 2.2{\%}. ASI-222 appliβcation to isolated Purkinje fibers induced two DADs (DADI, DAD2) after pacing at 500-ms CL; 2.0{\%} halo thane significantly reduced DADI amplitude, whereas both 1.0 and 2.0{\%} halothane reduced DAD2 amplitude. Pacing at 250-ms CL triggered no extra beats during control superfusion, but did after ASI-222 superfusion. Halothane reduced triggered ectopy in a dose-related fashion, with total elimination at 2.0{\%}. We conclude that halothane opposes the direct cardiotoxicity of ASI-222 when administered at sufficient concentration. However, unlike the dose-related halothane suppression of DAD amplitude and triggered ectopy evident in isolated Purkinje fibers, an end-tidal halothane concentration >2.2{\%} is required in intact dogs to suppress sustained ventricular ectopy. Our data thus suggest that at the low to moderate end-tidal concentrations frequently used clinically halothane opposes cardiotoxicity of conventional digitalis compounds primarily by blunting the sympathetic component of airhythmogenesis.",
keywords = "Aminocardenolide, Cardiotoxicity, Halothane, Purkinje fiber",
author = "Heerdt, {Paul M.} and Gallagher, {John D.} and Caldwell, {Robert William}",
year = "1994",
month = "1",
day = "1",
doi = "10.1097/00005344-199406000-00006",
language = "English (US)",
volume = "23",
pages = "890--896",
journal = "Journal of Cardiovascular Pharmacology",
issn = "0160-2446",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

TY - JOUR

T1 - Effect of halothane on in vivo and in vitro cardiotoxicity of an aminocardenolide

AU - Heerdt, Paul M.

AU - Gallagher, John D.

AU - Caldwell, Robert William

PY - 1994/1/1

Y1 - 1994/1/1

N2 - Halothane opposes cardiotoxicity of neutralβsugar digitalis compounds in intact animals, presumably by depressing a sympathetic component of arrhythmo-genesis. However, halothane also produces a dose-related reduction in arrhythmogenicity of ouabain in isolated canine Purkinje fibers, suggesting that the anesthetic may oppose direct mechanisms of cardiotoxicity as well. The present study examined in vivo and in vitro the effect of halothane on the arrhythmogenicity of ASI-222 (3-β-O[4-amino-4-6-dideoxy-β-D-galactopyranosyl] digi-toxigen in HCl), a highly polar aminocardenolide with no sympathetic component to cardiotoxicity. For in vivo studies, ASI-222 was infused at a rate of 1 μg/kg/min until appearance of third-degree atrioventricular (AV) block or sustained ventricular arrhythmias in 5 conscious (control) and 6 halothane-anesthetized (1.4% end-tidal) dogs. For in vitro studies, standard microelectrode 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 induction of toxicity with 10-7M 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 afterdepolar-izations (DAD) were recorded. Pacing at 250 ms CL was used to trigger ectopy. In vivo studies showed no difference in the cardiotoxic dose of ASI-222 between control dogs and those anesthetized with 1.4% halothane. However, in 4 of 6 anesthetized dogs, acutely increasing the inspired halothane concentration suppressed arrhythmias once end-tidal concentration were > 2.2%. ASI-222 appliβcation to isolated Purkinje fibers induced two DADs (DADI, DAD2) after pacing at 500-ms CL; 2.0% halo thane significantly reduced DADI amplitude, whereas both 1.0 and 2.0% halothane reduced DAD2 amplitude. Pacing at 250-ms CL triggered no extra beats during control superfusion, but did after ASI-222 superfusion. Halothane reduced triggered ectopy in a dose-related fashion, with total elimination at 2.0%. We conclude that halothane opposes the direct cardiotoxicity of ASI-222 when administered at sufficient concentration. However, unlike the dose-related halothane suppression of DAD amplitude and triggered ectopy evident in isolated Purkinje fibers, an end-tidal halothane concentration >2.2% is required in intact dogs to suppress sustained ventricular ectopy. Our data thus suggest that at the low to moderate end-tidal concentrations frequently used clinically halothane opposes cardiotoxicity of conventional digitalis compounds primarily by blunting the sympathetic component of airhythmogenesis.

AB - Halothane opposes cardiotoxicity of neutralβsugar digitalis compounds in intact animals, presumably by depressing a sympathetic component of arrhythmo-genesis. However, halothane also produces a dose-related reduction in arrhythmogenicity of ouabain in isolated canine Purkinje fibers, suggesting that the anesthetic may oppose direct mechanisms of cardiotoxicity as well. The present study examined in vivo and in vitro the effect of halothane on the arrhythmogenicity of ASI-222 (3-β-O[4-amino-4-6-dideoxy-β-D-galactopyranosyl] digi-toxigen in HCl), a highly polar aminocardenolide with no sympathetic component to cardiotoxicity. For in vivo studies, ASI-222 was infused at a rate of 1 μg/kg/min until appearance of third-degree atrioventricular (AV) block or sustained ventricular arrhythmias in 5 conscious (control) and 6 halothane-anesthetized (1.4% end-tidal) dogs. For in vitro studies, standard microelectrode 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 induction of toxicity with 10-7M 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 afterdepolar-izations (DAD) were recorded. Pacing at 250 ms CL was used to trigger ectopy. In vivo studies showed no difference in the cardiotoxic dose of ASI-222 between control dogs and those anesthetized with 1.4% halothane. However, in 4 of 6 anesthetized dogs, acutely increasing the inspired halothane concentration suppressed arrhythmias once end-tidal concentration were > 2.2%. ASI-222 appliβcation to isolated Purkinje fibers induced two DADs (DADI, DAD2) after pacing at 500-ms CL; 2.0% halo thane significantly reduced DADI amplitude, whereas both 1.0 and 2.0% halothane reduced DAD2 amplitude. Pacing at 250-ms CL triggered no extra beats during control superfusion, but did after ASI-222 superfusion. Halothane reduced triggered ectopy in a dose-related fashion, with total elimination at 2.0%. We conclude that halothane opposes the direct cardiotoxicity of ASI-222 when administered at sufficient concentration. However, unlike the dose-related halothane suppression of DAD amplitude and triggered ectopy evident in isolated Purkinje fibers, an end-tidal halothane concentration >2.2% is required in intact dogs to suppress sustained ventricular ectopy. Our data thus suggest that at the low to moderate end-tidal concentrations frequently used clinically halothane opposes cardiotoxicity of conventional digitalis compounds primarily by blunting the sympathetic component of airhythmogenesis.

KW - Aminocardenolide

KW - Cardiotoxicity

KW - Halothane

KW - Purkinje fiber

UR - http://www.scopus.com/inward/record.url?scp=0028360623&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028360623&partnerID=8YFLogxK

U2 - 10.1097/00005344-199406000-00006

DO - 10.1097/00005344-199406000-00006

M3 - Article

VL - 23

SP - 890

EP - 896

JO - Journal of Cardiovascular Pharmacology

JF - Journal of Cardiovascular Pharmacology

SN - 0160-2446

IS - 6

ER -