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OR15-2

Analysis of therapeutic utility of a multi-ion channel inhibitor acehytisine for paroxysmal supraventricular tachycardia in anesthetized guinea pigs

[Speaker] Xin Cao:1
[Co-author] Yoshinobu Nagasawa:1, Megumi Aimoto:1, Akira Takahara:1
1:Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Japan

Acehytisine is a novel diterpene alkaloid inhibiting IK, INa and ICa, which has been developed as a novel drug for the treatment of paroxysmal supraventricular tachycardia. To better understand its therapeutic utility, we assessed the pharmacological and proarrhythmic effects of acehytisine in vivo using isoflurane-anesthetized guinea pigs in comparison with those of bepridil. We administered acehytisine (4 and 10 mg/kg) and beperidil (1 and 3mg/kg) intravenously to the isoflurane-anesthetized guinea pig (n=6 for each drug) for 10 minutes and observed its effects on cardiac electrophysiology. Acehytisine at therapeutic dose (4 mg/kg) decreased the heart rate, prolonged P wave duration, QRS width, QT interval and QTc. At high dose (10 mg/kg), it prolonged the PR interval besides enhancing the changes induced by the therapeutic dose. The peak changes in P wave duration by acehytisine were 6 and 10 ms at 4 and 10 mg/kg, respectively, which were both 1.5 times longer than those of bepridil. Additionally, acehytisine at therapeutic dose increased the beat-to-beat variability, whereas a dose-related increase was not detected at high dose. In contrast, bepridil increased the beat-to-beat variability in a dose-related manner. A reverse use-dependence was observed in the repolarization delay in both drugs, but the peak changes in MAP90(sinus), MAP90(CL300) and MAP90(CL250) by acehytisine were 29, 20 and 19 ms, respectively, which is 1.9, 1.5 and 1.2 times shorter than those of bepridil. These results indicate that acehytisine in comparison with bepridil exhibits a favorable pharmacological characters, i.e. potent atrial inhibition and lower proarrhythmic toxicity, being a promising candidate for the treatment of paroxysmal supraventricular tachycardia.
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