Xue Y, Yamada C, Aye N N, Hashimoto K
Department of Pharmacology, Yamanashi Medical University, Japan.
Br J Pharmacol. 1998 Aug;124(8):1712-8. doi: 10.1038/sj.bjp.0701987.
We investigated the proarrhythmic effects of MS-551 and KCB-328, class III antiarrhythmic drugs using adrenaline-induced arrhythmia models in halothane anaesthetized, closed-chest dogs. In the control period, adrenaline, starting from a low dose of 0.25 to up to 1.0 microg/kg/50 s i.v., was injected to determine the arrhythmia inducing dose and the non-inducing dose. After MS-551 or KCB-328 administration, the adrenaline injection was repeated and the interval between the injection and the occurrence of arrhythmia (latent interval), the changes in arrhythmic ratio (as calculated by dividing the number of ventricular premature contraction by the number of the total heart rate) and the severity of arrhythmia were observed. MS-551 infusion, 1 mg/kg/30 min, decreased the heart rate (HR) by 16% (P<0.01) and prolonged the QTc interval by 20% (P<0.01). During the 30 min of MS-551 infusion, arrhythmias occurred in three out of seven dogs (torsades de pointes (TdP) type VT in one dog). After these arrhythmias disappeared, MS-551 decreased the latent interval of the adrenaline arrhythmias produced by the inducing dose (30+/-2 s compared with 43+/-3 s of the control interval, P < 0.05), increased the arrhythmic ratio (P<0.05) and induced arrhythmias by non-inducing adrenaline doses (P<0.05). Effect of a new class III drug KCB-328 infusion, 0.3 mg/kg/30 min, was compared witih MS-551 using the same model. KCB-328 decreased the HR by 21% (P<0.01) and prolonged the QTc interval by 25% (P<0.01). During the 30 min of infusion, arrhythmias occurred in five out of seven dogs (TdP in two dogs). KCB-328 also decreased the latent interval of the adrenaline arrhythmias produced by the inducing doses (31+/-3 s compared with 49+/-7 s of the control period, P<0.05), but did not significantly alter the arrhythmic ratio. Adrenaline induced TdP only after MS-551 or KCB-328 was administered, i.e. after MS-551, 1 mg/kg/30 min, 3/7 versus 0/7 in the control; KCB, 0.3 mg/kg/30 min, 3/7 versus 0/7 in the control. To examine the direct arrhythmogenic effect of MS-551 and whether an adrenergic mechanism plays some role on this arrhythmogenesis, a bolus injection of MS-551, 3 mg/kg, was injected either without pre-treatment or after pre-treatment with propranolol 0.3 mg/kg. MS-551 induced arrhythmias in five out of seven dogs (TdP in one dog). Also in the propranolol pre-treated dogs, MS-551 induced arrhythmias in five out of seven dogs (TdP in 1 dog). In conclusion, these observations indicate that MS-551 and KCB-328 induced arrhythmias and intensified proarrhythmic effects of adrenaline, MS-551 being stronger than KCB-328 at the same QTc prolonging doses. The direct arrhythmogenic effect of MS-551 was not influenced by beta-blocker treatment.
我们使用氟烷麻醉的闭胸犬肾上腺素诱发心律失常模型，研究了Ⅲ类抗心律失常药物MS - 551和KCB - 328的促心律失常作用。在对照期，静脉注射肾上腺素，起始剂量为0.25μg/kg/50s，逐渐增加至1.0μg/kg/50s，以确定诱发心律失常的剂量和非诱发剂量。给予MS - 551或KCB - 328后，重复注射肾上腺素，并观察注射与心律失常发生之间的间隔（潜伏间隔）、心律失常发生率的变化（通过室性早搏数除以总心率数计算）以及心律失常的严重程度。以1mg/kg/30min的剂量输注MS - 551，可使心率（HR）降低16%（P<0.01），QTc间期延长20%（P<0.01）。在输注MS - 551的30min内，7只犬中有3只发生心律失常（1只犬为尖端扭转型室性心动过速（TdP））。这些心律失常消失后，MS - 551缩短了诱发剂量产生的肾上腺素性心律失常的潜伏间隔（与对照间隔43±3s相比为30±2s，P<0.05），增加了心律失常发生率（P<0.05），并使非诱发剂量的肾上腺素诱发了心律失常（P<0.05）。使用相同模型，比较了以0.3mg/kg/30min的剂量输注新型Ⅲ类药物KCB - 328与MS - 551的效果。KCB - 328使心率降低21%（P<0.01），QTc间期延长25%（P<0.01）。在输注的30min内，7只犬中有5只发生心律失常（2只犬为TdP）。KCB - 328也缩短了诱发剂量产生的肾上腺素性心律失常的潜伏间隔（与对照期49±7s相比为31±3s，P<0.05），但未显著改变心律失常发生率。仅在给予MS - 551或KCB - 328后，肾上腺素才诱发TdP，即给予1mg/kg/30min的MS - 551后，TdP发生率为3/7，对照为0/7；给予0.3mg/kg/30min的KCB - 328后，TdP发生率为3/7，对照为0/7。为了研究MS - 551的直接致心律失常作用以及肾上腺素能机制是否在这种心律失常发生中起作用，在未预处理或用0.3mg/kg普萘洛尔预处理后，静脉推注3mg/kg的MS - 551。MS - 551使7只犬中有5只发生心律失常（1只犬为TdP）。在普萘洛尔预处理的犬中，MS - 551也使7只犬中有5只发生心律失常（1只犬为TdP）。总之，这些观察结果表明，MS - 551和KCB - 328诱发心律失常并增强了肾上腺素的促心律失常作用，在相同QTc延长剂量下，MS - 551比KCB - 328更强。MS - 551的直接致心律失常作用不受β受体阻滞剂治疗的影响。
