Comparison of Electropharmacological Effects of Bepridil and Sotalol in Halothane-Anesthetized Dogs

Ishizaka, Tomomichi; Takahara, Akira; Iwasaki, Hiroshi; Mitsumori, Yoshitaka; Kise, Hiroaki; Nakamura, Yuji; Sugiyama, Atsushi

doi:10.1253/circj.72.1003

Cited by 36 publications

(34 citation statements)

References 42 publications

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“…Next, we examined the cardiovascular effects of dl-sotalol on the halothane-anesthetized microminipigs. We compared these results with those obtained by the halothane-anesthetized canine model (Ishizaka et al, 2008), since the canine model has been demonstrated to be useful for predicting the drug-induced cardiohemodynamic and electrophysiological responses in humans (Sugiyama, 2008). We found that each cardiovascular response was directionally the same as that reported in dogs, although the extent of the changes was greater in microminipigs than in dogs under the same anesthetic condition (Ishizaka et al, 2008).…”

Section: Discussionmentioning

confidence: 77%

“…In a previous experiment using the halothane-anesthetized canine model with the same experimental protocol, the peak plasma concentrations of dl-sotalol after the administration of 0.3 and 3 mg/kg were 1.2 and 12 μg/mL, respectively (Ishizaka et al, 2008). Since the peak plasma concentrations of pilsicainide, verapamil and E-4031 have been shown to be 1.7-4.8 times greater in microminipigs than those in dogs in spite of the same i.v.…”

Section: Rationale Of Drug Doses Administeredmentioning

confidence: 89%

“…We compared these results with those obtained by the halothane-anesthetized canine model (Ishizaka et al, 2008), since the canine model has been demonstrated to be useful for predicting the drug-induced cardiohemodynamic and electrophysiological responses in humans (Sugiyama, 2008). We found that each cardiovascular response was directionally the same as that reported in dogs, although the extent of the changes was greater in microminipigs than in dogs under the same anesthetic condition (Ishizaka et al, 2008). A vehicle saline did not alter the heart rate, mean blood pressure, PR interval, QRS width, QT interval or QTcF, indicating that each cardiovascular variable assessed in the halothane-anesthetized microminipigs can be kept stable for > 90 min.…”

Section: Discussionmentioning

confidence: 99%

“…Then, we examined the cardiovascular effects of dl-sotalol on the halothane-anesthetized microminipigs by using the same experimental protocol as that used in the halothane-anesthetized dogs. We have assessed cardiovascular effects of dl-sotalol in the halothane-anesthetized dogs (Ishizaka et al, 2008), which can make it possible for us to directly compare the cardiovascular profile of the drug between the halothane-anesthetized microminipigs and dogs.…”

Section: Introductionmentioning

confidence: 99%

“…dl-Sotalol is a potent I Kr -inhibitor with β-adrenoceptor blocking activity (Hohnloser and Woosley, 1994;Ishizaka et al, 2008), which has been used as a positive control for confirming the sensitivity and reliability of various animal models (Lynch et al, 2008;Sakaguchi et al, 2009;Sugiyama, 2008). In order to better analyze proarrhythmic potential of dl-sotalol with microminipigs, we adopted the corrected J-T peak interval (J-T peak c) and T peak -T end interval, which reflect the early and late repolarization phases, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological characterization of <i>microminipig</i> as a model to assess the drug-induced cardiovascular responses for non-clinical toxicity and/or safety pharmacology studies

et al. 2017

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-We tried to establish the halothane-anesthetized microminipigs as an alternative animal model for non-clinical toxicity and/or safety pharmacology studies. In order to characterize the halothane-anesthetized microminipigs, we firstly clarified the effects of halothane anesthesia on their cardiovascular system (n = 5). Then, we examined the cardiovascular effects of dl-sotalol in doses of 0.1, 0.3 and 1 mg/kg, i.v. on the halothane-anesthetized microminipigs (n = 6). Induction of the halothane anesthesia by itself prolonged the QT interval as well as QTcF, suggesting that the halothane anesthesia can reduce the cardiac repolarization reserve in microminipigs like in dogs. dl-Sotalol showed more potent negative chronotropic, dromotropic and hypotensive effects together with repolarization delay in microminipigs than in dogs, although each cardiovascular response to dl-sotalol was directionally similar between them, suggesting greater basal sympathetic tone and/or smaller volume of distribution of the drug in microminipigs than in dogs. Analyses of proarrhythmic surrogate markers indicate that T peak -T end and short-term variability of QT interval may be more sensitive to detect the dl-sotalol-induced direct electrophysiological changes in microminipigs than in dogs, but its reverse will be true for J-T peak c. Thus, these results may help better understand the drug-induced cardiovascular responses in microminipigs.

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Section: Discussionmentioning

confidence: 77%

Section: Rationale Of Drug Doses Administeredmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Pharmacological characterization of <i>microminipig</i> as a model to assess the drug-induced cardiovascular responses for non-clinical toxicity and/or safety pharmacology studies

et al. 2017

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In vivo characterization of anti-atrial fibrillatory potential and pharmacological safety profile of INa,L plus IKr inhibitor ranolazine using the halothane-anesthetized dogs

et al. 2021

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Cardiohemodynamic and Electrophysiological Effects of Anti-influenza Drug Oseltamivir In Vivo and In Vitro

et al. 2013

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Electropharmacological effects of oseltamivir were studied in comparison with pilsicainide using halothane-anesthetized dogs (n = 4) and isolated left atrium of guinea pigs (n = 5). Oseltamivir (0.3, 3 and 30 mg/kg, i.v.) or pilsicainide (1 and 3 mg/kg, i.v.) was additionally administered to the dogs. The low dose of oseltamivir provided clinically relevant plasma concentrations with C max of 4 μM. The low and middle doses of oseltamivir increased cardiac output, whereas the middle dose increased blood pressure and delayed intra-atrial conduction and ventricular repolarization. The high dose of oseltamivir exerted negative chronotropic, inotropic and hypotensive effects, while it delayed intra-atrial, atrioventricular nodal and intra-ventricular conduction and ventricular repolarization. Use-dependent delay of ventricular repolarization was observed after oseltamivir, whereas reverse use-dependent prolongation was induced by pilsicainide. Moreover, oseltamivir more selectively suppressed intra-atrial conduction than intra-ventricular conduction, which was less selective for pilsicainide. Action potential assay using isolated atrium indicated that oseltamivir (10 μM) decreased V max more than pilsicainide (10 μM) and that oseltamivir (10-100 μM) prolonged action potential duration, which was not induced by pilsicainide (1-10 μM). Thus, oseltamivir in clinically relevant to its 10 times higher doses is relatively safe, whereas 10-100 times higher doses possess unique electrophysiological profile.

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Comparison of Electropharmacological Effects of Bepridil and Sotalol in Halothane-Anesthetized Dogs

Cited by 36 publications

References 42 publications

Pharmacological characterization of <i>microminipig</i> as a model to assess the drug-induced cardiovascular responses for non-clinical toxicity and/or safety pharmacology studies

Pharmacological characterization of <i>microminipig</i> as a model to assess the drug-induced cardiovascular responses for non-clinical toxicity and/or safety pharmacology studies

In vivo characterization of anti-atrial fibrillatory potential and pharmacological safety profile of INa,L plus IKr inhibitor ranolazine using the halothane-anesthetized dogs

Cardiohemodynamic and Electrophysiological Effects of Anti-influenza Drug Oseltamivir In Vivo and In Vitro

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