新型抗心律失常药物HNS-32对麻醉大鼠冠状动脉闭塞和再灌注诱发的室性心律失常的影响。

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

作者信息

Saitoh M, Aye N N, Komori S, Nakazawa T, Hashimoto K

机构信息

Department of Pharmacology, Yamanashi Medical University, Japan.

出版信息

Mol Cell Biochem. 2000 Feb;205(1-2):133-40. doi: 10.1023/a:1007074115503.

DOI:10.1023/a:1007074115503

PMID:10821431

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.

摘要

HNS - 32（N1，N1 - 二甲基 - N2 -（2 - 吡啶甲基）- 5 - 异丙基 - 3,8 - 二甲基薁 - 1 - 甲脒：CAS 186086 - 10 - 2）是一种新合成的化合物，在犬心脏中具有抗心律失常特性及血管舒张作用。本研究旨在探讨HNS - 32对麻醉大鼠体内缺血和/或再灌注诱导的室性心律失常的剂量依赖性影响，并与美西律进行比较。在冠状动脉闭塞前5分钟静脉注射生理盐水或药物。对于缺血诱导的室性心律失常，HNS - 32使室性早搏总数（PVC）呈剂量依赖性减少，从2091±225降至656±116和286±69次/30分钟（p < 0.05），室性心动过速（VT）持续时间从183±33降至28±9和4±2秒（p < 0.05），VT发生率从100%降至90%（无统计学意义）和40%（p < 0.05），室颤（VF）发生率从50%降至0和0%（p < 0.05），分别对应3毫克/千克和5毫克/千克剂量。美西律也使这些参数分别降至936±159次/30分钟（p < 0.05）、39±22秒（p < 0.05）、90%（无统计学意义）和10%（无统计学意义）。HNS - 32完全抑制了再灌注后期诱导的心律失常，然而美西律对其无影响。对于再灌注早期诱导的室性心律失常，HNS - 32使VT持续时间呈剂量依赖性减少，从126±34降至37±12和3±2秒（p < 0.05），VT发生率从100%降至90%（无统计学意义）和40%（p < 0.05），VF发生率从100%降至10%和0%（p < 0.05），死亡率从90%降至0和0%（p < 0.05），分别对应3毫克/千克和5毫克/千克剂量。美西律也使这些参数分别降至16±9秒（p < 0.05）、80%（无统计学意义）、50%（p < 0.05）和10%（p < 0.05）。HNS - 32以剂量依赖性方式显著降低心率，分别对应3毫克/千克和5毫克/千克剂量时，从399±14降至350±8和299±10次/分钟（p < 0.05）。在体内大鼠中，HNS - 32对闭塞诱导和再灌注诱导的心律失常的抗心律失常作用比相同剂量的美西律更强。