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Effects of HNS-32, a novel antiarrhythmic drug, on ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats

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Abstract

HNS-32 (N1,N1-dimethyl-N2-(2-pyridylmethyl)-5-isopropyl-3, 8-dimethylazulene-1-carboxamidine: CAS 186086-10-2) is a newly synthesized compound, and possesses antiarrhythmic properties with vasodilator action in dog hearts. The aim of this study was to investigate the dose-dependent effects of HNS-32 on ischemia- and/or reperfusion-induced ventricular arrhythmias in anesthetized rats in vivo and compared with those of mexiletine. Saline or drugs were administered intravenously 5 min prior to coronary artery occlusion. On the ischemia-induced ventricular arrhythmias, HNS-32 showed dose-dependent reduction of total number of premature ventricular complexes (PVC) from 2091 ± 225 to 656 ± 116 and 286 ± 69 beats/30 min (p < 0.05), the ventricular tachycardia (VT) duration from 183 ± 33 to 28 ± 9 and 4 ± 2 sec (p < 0.05), the incidence of VT from 100 to 90 (n.s.) and 40% (p < 0.05), and the incidence of ventricular fibrillation (VF) from 50 to 0 and 0% (p < 0.05) with 3 and 5 mg/kg, respectively. Mexiletine also reduced these parameters to 936 ± 159 beats/30 min (p < 0.05), 39 ± 22 sec (p < 0.05), 90% (n.s.) and 10% (n.s.), respectively. HNS-32 completely suppressed the late reperfusion-induced arrhythmias, however mexiletine did not affect them. On the early reperfusion-induced ventricular arrhythmias, HNS-32 showed dose-dependent reduction of VT duration from 126 ± 34 to 37 ± 12 and 3 ± 2 sec (p < 0.05), incidence of VT from 100 to 90 (n.s.) and 40% (p < 0.05), incidence of VF from 100 to 10 and 0% (p < 0.05), and mortality rate from 90 to 0 and 0% (p < 0.05), with 3 and 5 mg/kg, respectively. Mexiletine also reduced these parameters to 16 ± 9 sec (p < 0.05), 80 (n.s.), 50 (p < 0.05), and 10% (p < 0.05), respectively. HNS-32 significantly reduced the heart rate in a dose-dependent manner, from 399 ± 14 to 350 ± 8 and 299 ± 10 beats/min (p < 0.05) with 3 and 5 mg/kg, respectively. The antiarrhythmic effects of HNS-32 were more potent than that of the similar dose of mexiletine against occlusion-induced and reperfusion-induced arrhythmias in in vivo rats.

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Authors and Affiliations

  1. Department of Pharmacology, Yamanashi Medical University, Tamaho-cho, Nakakoma-gun, Yamanashi, 409 3898, Japan

    Masaki Saitoh, Nu Nu Aye & Keitaro Hashimoto

  2. Department of Human Science, Yamanashi Medical University, Tamaho-cho, Nakakoma-gun, Yamanashi, 409 3898, Japan

    Sadayoshi Komori

  3. Department of Chemistry, Yamanashi Medical University, Tamaho-cho, Nakakoma-gun, Yamanashi, 409 3898, Japan

    Tomoo Nakazawa

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  1. Masaki Saitoh
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  4. Tomoo Nakazawa
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  5. Keitaro Hashimoto
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Saitoh, M., Aye, N.N., Komori, S. et al. Effects of HNS-32, a novel antiarrhythmic drug, on ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats. Mol Cell Biochem 205, 133–140 (2000). https://doi.org/10.1023/A:1007074115503

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