Effects of Class III antiarrhythmic agents in an in vitro rabbit model of spontaneous torsades de pointe

DʼAlonzo, Albert J.; Zhu, Jia L.; Darbenzio, Raymond B.

doi:10.1016/s0014-2999(99)00057-6

Cited by 21 publications

(27 citation statements)

References 30 publications

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“…Hence, these LQT1 rabbits with a reduced repolarization reserve should sensitively detect APD prolonging properties of HERG/ I Kr -blocking drugs. Both HERG/ I Kr -blocking drugs, erythromycin and E-4031, significantly prolonged APD in both genotypes in all regions of the left and right ventricle, similarly as observed by other groups in wild type rabbit models [20], [30]. The percentaged erythromycin- and E-4031-induced APD prolongation related to baseline APD (%APD), however, was more pronounced in transgenic LQT1 rabbits.…”

Section: Discussionsupporting

confidence: 71%

Pronounced Effects of HERG-Blockers E-4031 and Erythromycin on APD, Spatial APD Dispersion and Triangulation in Transgenic Long-QT Type 1 Rabbits

et al. 2014

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BackgroundProlongation of action potential duration (APD), increased spatial APD dispersion, and triangulation are major factors promoting drug-induced ventricular arrhythmia. Preclinical identification of HERG/IKr-blocking drugs and their pro-arrhythmic potential, however, remains a challenge. We hypothesize that transgenic long-QT type 1 (LQT1) rabbits lacking repolarizing IKs current may help to sensitively detect HERG/IKr-blocking properties of drugs.MethodsHearts of adult female transgenic LQT1 and wild type littermate control (LMC) rabbits were Langendorff-perfused with increasing concentrations of HERG/IKr-blockers E-4031 (0.001–0.1 µM, n = 9/7) or erythromycin (1–300 µM, n = 9/7) and APD, APD dispersion, and triangulation were analyzed.ResultsAt baseline, APD was longer in LQT1 than in LMC rabbits in LV apex and RV mid. Erythromycin and E-4031 prolonged APD in LQT1 and LMC rabbits in all positions. However, erythromycin-induced percentaged APD prolongation related to baseline (%APD) was more pronounced in LQT1 at LV base-lateral and RV mid positions (100 µM, LQT1, +40.6±9.7% vs. LMC, +24.1±10.0%, p<0.05) and E-4031-induced %APD prolongation was more pronounced in LQT1 at LV base-lateral (0.01 µM, LQT1, +29.6±10.6% vs. LMC, +19.1±3.8%, p<0.05) and LV base-septal positions. Moreover, erythromycin significantly increased spatial APD dispersion only in LQT1 and increased triangulation only in LQT1 in LV base-septal and RV mid positions. Similarly, E-4031 increased triangulation only in LQT1 in LV apex and base-septal positions.ConclusionsE-4031 and erythromycin prolonged APD and increased triangulation more pronouncedly in LQT1 than in LMC rabbits. Moreover, erythromycin increased APD dispersion only in LQT1, indicating that transgenic LQT1 rabbits could serve as sensitive model to detect HERG/IKr-blocking properties of drugs.

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Section: Discussionsupporting

confidence: 71%

Pronounced Effects of HERG-Blockers E-4031 and Erythromycin on APD, Spatial APD Dispersion and Triangulation in Transgenic Long-QT Type 1 Rabbits

et al. 2014

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“…[1425] D’Alonzo et al . [14] studied the combined effect of methoxamine, ACh and nadolol on the ability of dofetilide to elicit TdP. HR was reduced by 7% following ACh and methoxamine treatment.…”

Section: Discussionmentioning

confidence: 99%

“…The ability of β-adrenoceptor antagonist to enhance the proarrhythmic action of drugs in combination of ACh and methoxamine may be explained by further reduction of HR along with elevated calcium level and decreased current of slow component of the delayed rectifier activity, which leads to further generation of TdP more easily. [14] Therefore, combinations of ACh chloride, non-selective beta blocker propranolol along with methoxamine were used to produce bradycardia and/or TdP in our experiment, which further sensitized the hearts to develop TdP in clofilium and chloroquine treated heart.…”

Section: Discussionmentioning

confidence: 99%

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Assessment of proarrhythmic activity of chloroquine in in vivo and ex vivo rabbit models

Khobragade¹,

Gupta

Gurav

et al. 2013

Journal of Pharmacology and Pharmacotherapeutics

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Objectives:To evaluate the prolongation of ventricular repolarization and proarrhythmic activity of antimalarial drug chloroquine in two rabbit proarrhythmia models viz., in vivo α1 adrenoceptor-stimulated anesthetized rabbit and ex vivo isolated Langendorff rabbit heart using clofilium as standard proarrhythmic agent.Materials and Methods:In the in vivo model, three groups of rabbits, anesthetized by pentobarbitone sodium and α-chloralose, sensitized with α1 agonist methoxamine followed by either continuous infusion of saline (control) or clofilium (3 mg/kg) or chloroquine (21 mg/kg) for 30 min. In ex vivo model, rabbit hearts were perfused with clofilium (10 μM) or chloroquine (300 μM) continuously after priming along with methoxamine, acetylcholine chloride and propranolol hydrochloride.Results:In these models, prolongation of repolarization during α1-adrenoceptor stimulation produced early after depolarization (EAD) and Torsade de pointes (TdP). Saline infusion did not induce any abnormality in the animals. Clofilium caused expected changes in the electrocardiogram in both the models including TdP (50.0% in in vivo and 66.67% in ex vivo). Chloroquine caused decrease in heart rate and increase in the corrected QT (QTc) interval in both the models. Further, apart from different stages of arrhythmia, TdP was evident in 33.33% in ex vivo model, whereas no TdP was observed in in vivo model.Conclusions:The results indicated that proarrhythmic potential of chloroquine and clofilium was well evaluated in both the models; moreover, both the models can be used to assess the proarrhythmic potential of the new drug candidates.

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“…In the present work, we studied two pharmacological models of LQT in isolated rabbit ventricular myocytes to identify differences in underlying cellular electrophysiological properties. The isolated rabbit heart is an established model for studying mechanisms of torsades de pointes ( D'Alonzo et al ., 1997 ; Zabel et al ., 1997 ; Eckhardt et al ., 1999 ). In rabbit ventricular myocytes the delayed rectifier K + channel current is thought to represent mostly I Kr ( Carmeliet, 1992 ; Clay et al ., 1995 ; Zhou et al ., 1995 ).…”

Section: Introductionmentioning

confidence: 99%

Differences in action potential and early afterdepolarization properties in LQT2 and LQT3 models of long QT syndrome

Studenik

Zhou

January

2001

British J Pharmacology

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1 Long OT syndrome has many causes from both acquired and congenital disorders. For the congenital disorders, their presentation and disease course are not identical. We studied two pharmacological models of long QT syndrome (LQT) to identify dierences in cellular electrophysiological properties that may account for this. LQT2 was simulated by suppression of the rapidly activating delayed recti®er potassium current (I Kr ) with the drug E-4031, and LQT3 was simulated by slowing of the sodium current (I Na ) decay with the toxin ATX II. 2 Single rabbit ventricular cell action potentials were studied using the amphotericin B perforated patch clamp technique. Action potential and early afterdepolarization (EAD) properties were rigorously de®ned by the frequency power spectra obtained with fast Fourier transforms.3 The E-4031 (n=43 myocytes) and ATX II (n=50 myocytes) models produced dierent eects on action potential and EAD properties. The major dierences are that ATX II, compared with E-4031, caused greater action potential prolongation, more positive plateau voltages, lower amplitude EADs with less negative take-o potentials, greater time to the EAD peak voltage, and longer duration EADs. Despite causing greater action potential prolongation, the incidence of EAD induction was much less with the ATX II model (28%) than with the E-4031 model (84%). Thus these two pharmacological models have strikingly dierent cellular electrophysiological properties. 4 Our ®ndings provide cellular mechanisms that may account for some dierences in the clinical presentation of LQT2 and LQT3.

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Effects of Class III antiarrhythmic agents in an in vitro rabbit model of spontaneous torsades de pointe

Cited by 21 publications

References 30 publications

Pronounced Effects of HERG-Blockers E-4031 and Erythromycin on APD, Spatial APD Dispersion and Triangulation in Transgenic Long-QT Type 1 Rabbits

Pronounced Effects of HERG-Blockers E-4031 and Erythromycin on APD, Spatial APD Dispersion and Triangulation in Transgenic Long-QT Type 1 Rabbits

Assessment of proarrhythmic activity of chloroquine in in vivo and ex vivo rabbit models

Differences in action potential and early afterdepolarization properties in LQT2 and LQT3 models of long QT syndrome

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