Comparison of the proarrhythmic effect of GLG-V-13, a novel class III antiarrhythmic compound, in two rabbit models of torsades de pointes ventricular tachycardia

Tamás Fazekas, Z. Szilvássy, Leif Carlsson, K. Darrell Berlin, Benjamin J. Scherlag, Eugene Patterson, Ralph Lazzara

Research output: Contribution to journalArticle

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Abstract

Objective: The proarrhythmic potential of a new [(kr)-blocking Class III antiarrhythmic agent, GLGV-13 was studied and compared in two rabbit models of torsades de pointes (TdP) ventricular tachycardia (TdP). Methods: Chloralose-anesthetized rabbits (n = 8) were given a concomitant infusion of GLG-V13 (84 nmol/kg per min) and the α-agonist methoxamine (70 nmol/kg per min); in another set of experiments, GLG-V-13 was administered solely into the ear vein of electrode catheter instrumented conscious rabbits (n = 6). The doses of GLG-V-13, to produce maximum prolongation of the QTU, interval or the right ventricular effective refractory period (VERP), and that inducing ventricular ectopic beats (EBs) and TdP, respectively, were determined. Results: In anesthetized rabbits, GLG-V-13 increased QTU, from 125 ± 3 to 161 ± 6 ms after a cumulative dose of 0.84 μmol/kg (P <0.001) and caused EBs at a mean cumulative dose of 3.9 ± 1.1 μmol/kg. In five of the rabbits, the EBs turned into TdP at a dose of 5.2 ± 3.2 μmol/kg. In conscious rabbits, maximum prolongation of the VERP (27% ± 4.3% P <0.01) by GLG-V-13 was seen at a dose of 1.2 ± 0.54 μmol/kg, whereas EBs and TdP were induced after 6.3 ± 1.4 (6/6) and 8.1 ± 1.4 μmol/kg (6/6), respectively. Conclusion: (1) The dose-dependent 'torsadogenic' potential of l(kr)-blockers can be evaluated in conscious rabbits without concomitant methoxamine administration; (2) in the conscious state, the EB- and TdP-inducing dose of GLG-V-13 is about 50% higher than in the chloralose-anesthetized animal; and (3) irrespective of the chemical nature of the compound applied, blockade of the cardiac l(kr), potassium channel is associated with proarrhythmic effect.

Original languageEnglish
Pages (from-to)33-39
Number of pages7
JournalAnnals of Noninvasive Electrocardiology
Volume2
Issue number1
DOIs
Publication statusPublished - 1997

Fingerprint

GLG-V 13
Torsades de Pointes
Ventricular Tachycardia
Rabbits
Methoxamine
Chloralose
Ventricular Premature Complexes
Potassium Channels
Ear
Veins

Keywords

  • early afterdepolarization
  • GLG-V-13
  • rabbit
  • torsades de pointes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Comparison of the proarrhythmic effect of GLG-V-13, a novel class III antiarrhythmic compound, in two rabbit models of torsades de pointes ventricular tachycardia. / Fazekas, Tamás; Szilvássy, Z.; Carlsson, Leif; Berlin, K. Darrell; Scherlag, Benjamin J.; Patterson, Eugene; Lazzara, Ralph.

In: Annals of Noninvasive Electrocardiology, Vol. 2, No. 1, 1997, p. 33-39.

Research output: Contribution to journalArticle

Fazekas, Tamás ; Szilvássy, Z. ; Carlsson, Leif ; Berlin, K. Darrell ; Scherlag, Benjamin J. ; Patterson, Eugene ; Lazzara, Ralph. / Comparison of the proarrhythmic effect of GLG-V-13, a novel class III antiarrhythmic compound, in two rabbit models of torsades de pointes ventricular tachycardia. In: Annals of Noninvasive Electrocardiology. 1997 ; Vol. 2, No. 1. pp. 33-39.
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abstract = "Objective: The proarrhythmic potential of a new [(kr)-blocking Class III antiarrhythmic agent, GLGV-13 was studied and compared in two rabbit models of torsades de pointes (TdP) ventricular tachycardia (TdP). Methods: Chloralose-anesthetized rabbits (n = 8) were given a concomitant infusion of GLG-V13 (84 nmol/kg per min) and the α-agonist methoxamine (70 nmol/kg per min); in another set of experiments, GLG-V-13 was administered solely into the ear vein of electrode catheter instrumented conscious rabbits (n = 6). The doses of GLG-V-13, to produce maximum prolongation of the QTU, interval or the right ventricular effective refractory period (VERP), and that inducing ventricular ectopic beats (EBs) and TdP, respectively, were determined. Results: In anesthetized rabbits, GLG-V-13 increased QTU, from 125 ± 3 to 161 ± 6 ms after a cumulative dose of 0.84 μmol/kg (P <0.001) and caused EBs at a mean cumulative dose of 3.9 ± 1.1 μmol/kg. In five of the rabbits, the EBs turned into TdP at a dose of 5.2 ± 3.2 μmol/kg. In conscious rabbits, maximum prolongation of the VERP (27{\%} ± 4.3{\%} P <0.01) by GLG-V-13 was seen at a dose of 1.2 ± 0.54 μmol/kg, whereas EBs and TdP were induced after 6.3 ± 1.4 (6/6) and 8.1 ± 1.4 μmol/kg (6/6), respectively. Conclusion: (1) The dose-dependent 'torsadogenic' potential of l(kr)-blockers can be evaluated in conscious rabbits without concomitant methoxamine administration; (2) in the conscious state, the EB- and TdP-inducing dose of GLG-V-13 is about 50{\%} higher than in the chloralose-anesthetized animal; and (3) irrespective of the chemical nature of the compound applied, blockade of the cardiac l(kr), potassium channel is associated with proarrhythmic effect.",
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AU - Fazekas, Tamás

AU - Szilvássy, Z.

AU - Carlsson, Leif

AU - Berlin, K. Darrell

AU - Scherlag, Benjamin J.

AU - Patterson, Eugene

AU - Lazzara, Ralph

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N2 - Objective: The proarrhythmic potential of a new [(kr)-blocking Class III antiarrhythmic agent, GLGV-13 was studied and compared in two rabbit models of torsades de pointes (TdP) ventricular tachycardia (TdP). Methods: Chloralose-anesthetized rabbits (n = 8) were given a concomitant infusion of GLG-V13 (84 nmol/kg per min) and the α-agonist methoxamine (70 nmol/kg per min); in another set of experiments, GLG-V-13 was administered solely into the ear vein of electrode catheter instrumented conscious rabbits (n = 6). The doses of GLG-V-13, to produce maximum prolongation of the QTU, interval or the right ventricular effective refractory period (VERP), and that inducing ventricular ectopic beats (EBs) and TdP, respectively, were determined. Results: In anesthetized rabbits, GLG-V-13 increased QTU, from 125 ± 3 to 161 ± 6 ms after a cumulative dose of 0.84 μmol/kg (P <0.001) and caused EBs at a mean cumulative dose of 3.9 ± 1.1 μmol/kg. In five of the rabbits, the EBs turned into TdP at a dose of 5.2 ± 3.2 μmol/kg. In conscious rabbits, maximum prolongation of the VERP (27% ± 4.3% P <0.01) by GLG-V-13 was seen at a dose of 1.2 ± 0.54 μmol/kg, whereas EBs and TdP were induced after 6.3 ± 1.4 (6/6) and 8.1 ± 1.4 μmol/kg (6/6), respectively. Conclusion: (1) The dose-dependent 'torsadogenic' potential of l(kr)-blockers can be evaluated in conscious rabbits without concomitant methoxamine administration; (2) in the conscious state, the EB- and TdP-inducing dose of GLG-V-13 is about 50% higher than in the chloralose-anesthetized animal; and (3) irrespective of the chemical nature of the compound applied, blockade of the cardiac l(kr), potassium channel is associated with proarrhythmic effect.

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