三七皂甙Rg_1对犬心电生理特性及心室纤颤阈值的影响(英文)

目的:研究三七皂甙Rg_1对心肌电生理特性及室颤阈值(VFT)的影响.方法:17只正常犬被随机分为生理盐水对照组和Rg_1组(20 mgkg~(-1),iv).麻醉后沿正中开胸,暴露心脏.应用心脏电刺激及单相动作电位(MAP)记录技术,测量心肌电生理参数及VFT.结果:Rg_1延长窦房结恢复时间19.1％;延长房室传导文氏阻滞周长7.1％;延长心室有效不应期7.9％;延长心室MAP时程(MAPD),其中MAPD_(30)延长25.5％,MAPD_(50)延长24.2％,MAPD_(90)延长13.5％;提高VFT 19.2％.结论:Rg_1延长心室不应性及复极化时程,提高VFT,提示Rg_1的作用与胺碘酮的效应类似.     

Low-dose carvedilol reduces transmural heterogeneity of ventricular repolarization in congestive heart failure

Aim： To study the effects of carvedilol on the transmural heterogeneity of ventricular repolarization in rabbits with congestive heart failure （CHF）. Methods： Rabbits were randomly divided into 3 groups： control, CHF and carvedilol treated CHF group. Monophasic action potential duration （MAPD） in the 3 myocardial layers was simultaneously recorded. Results： All the rabbits in the CHF group had signs of severe CHF. Compared with the control group, the mean blood pressure and cardiac output were significantly decreased, while peripheral resistance was significantly increased in the CHF group. This proved that the CHF model was successful created with adriamycin in this study. Compared to the control group, the ventricular fibrillation threshold （VFT） was remarkably decreased and all MAPD of the 3 myocardial layers were extended in rabbits with CHF. However, the extension of MAPD in the midmyocardium was more obvious. The transmural dispersion of repolarization （TDR） was significantly increased in CHF. Low-dose carvedilol （0.25 mg/kg, twice daily） had no effects on ventricular remodeling. Treatment with low-dose carvedilol significantly increased VFT. Although the MAPD of the 3 myocardial layers were further prolonged in the carvedilol treated CHF group, the prolongation of MAPD in the midmyocardium was shorter than those in the epicardium and endocardium. Treatment with low-dose carvedilol significantly decreased TDR in CHF. Conclusion： In the present study, the transmural heterogeneity of ventricular repolarization increased in the rabbits with CHF. Low-dose carvedilol decreased the transmural heterogeneity of ventricular repolarization in CHF, which may be related to its direct electrophysiological property rather than its effect on ventricular remodeling.     

Antiarrhythmic and electrophysiologic effects of sublingual ibutilide fumarate

Ibutilide fumarate is a class III antiarrhythmic agent in phase III clinical trials. Due to rapid hepatic metabolism, ibutilide has a low oral bioavailability (< 10%). To assess alternate routes of administration, we performed repeated studies of the electrophysiologic effects of sublingual ibutilide (0.03, 0.1, and 0.3 mg/kg; 0.07, 0.2, and 0.7 m?mol/kg) in pentobarbital anesthetized dogs. Peak significant increases in QTc interval, ventricular effective refractory period (VERP), and right ventricular monophasic action potential duration (MAPD90) were achieved 30 min following 0.1 or 0.3 mg/kg (0.2 and 0.7 m?mol/kg) ibutilide and were coincident with peak plasma ibutilide levels. The duration of significant effects ranged from 2 to 5 h. Peak effects were: QTc + 121 msec, MAPD90 + 71 msec, and VERP + 53 msec. The 0.3 mg/kg (0.7 m?mol) dose significantly decreased heart rate 10 min post dosage through 5 h. The 0.03 mg/kg (0.07 m?mol) dose increased MAPD90 at 1 to 2 h but was otherwise ineffective. The plasma half life of ibutilide was 2.8 h, with a 72% bioavailability relative to an equivalent intravenous dose. Based on the electrophysiologic results, we chose to test the 0.1 mg/kg (0.2 m?mol) sublingual ibutilide dose for termination of sustained atrial flutter in anesthetized dogs with y-shaped right atrial incisions. The administration of 0.1 mg/kg (0.2 m?mol) sublingual ibutilide during sustained atrial flutter resulted in termination of atrial flutter in all cases (n = 4) after a mean time interval of 11.4 ± 0.8 min. Termination of atrial flutter was associated with ibutilide plasma levels of 19.6 ± 6.3 ng/ml, and 30 and 18 msec increases in atrial and ventricular effective refractory periods. Atrial flutter could be reinduced in 2 dogs, on at 3 h and one at 4 h post ibutilide administration. The ability to reinduce atrial flutter was associated with a reduction in ibutilide plasma levels to 2.3 ± 0.7 ng/ml. We conclude that sublingual ibutilide is rapidly absorbed and produces significant electrophysiologic and antiarrhythmic effects, and is a potential alternative to intravenous and oral therapy. ©1995 Wiley-Liss, Inc.     

Evaluation of the guinea pig monophasic action potential (MAP) assay in predicting drug-induced delay of ventricular repolarisation using 12 clinically documented drugs

INTRODUCTION: While the dog in vivo model is commonly employed in the later phase of discovery for assessing drug-induced QT prolongation, an early screening assay is valuable when selecting compounds for further development and when compound availability usually is low. One such screening assay is the anaesthetised guinea pig monophasic action potential (MAP) model. The aim of the present study was to evaluate the ability of this model to detect proarrhythmic properties by testing a set of reference compounds with known clinical profile. Moreover, these results were compared to data previously obtained using in vivo canine QT assays (QT PRODACT study). METHODS: Anaesthetised and ventilated male guinea pigs were vagotomised and pretreated with propranolol. After thoracotomy, a pacing electrode was clipped to the left atrial appendage and a suction MAP electrode positioned on the left ventricular epicardium. The drug or corresponding vehicle was injected intravenously in cumulative doses and MAP duration at 90% repolarisation (MAPD90) was recorded during cardiac pacing. RESULTS: The 8 drugs known to be proarrhythmic in the clinic all displayed dose-dependent prolongation of MAPD90, while the 4 drugs devoid of dysrhythmia in man had no effect. When comparing doses producing a 10% MAPD90 increase with doses reported to increase QTc by 10% in dogs a strong correlation was seen (R(2) 0.94 and 0.58 for anaesthetised and conscious dogs, respectively). DISCUSSION: The guinea pig MAP assay identified all clinically positive drugs while negative drugs were without effect on ventricular repolarisation. Furthermore, a good concurrence is shown between the guinea pig and dog models in identifying compounds with proarrhythmic properties. Overall, the study reinforces the anaesthetised guinea pig MAP model as a reliable assay predicting QT liability of new chemical entities and as a highly sensitive early screening model for cardiovascular risk.     

Blockade of IKs by HMR 1556 increases the reverse rate-dependence of refractoriness prolongation by dofetilide in isolated rabbit ventricles

1. The rate-dependent contributions of the rapid and slow components of the cardiac delayed rectifier K+ current (IKr and IKs, respectively) to repolarization are not fully understood. It is unclear whether the addition of IKs block will attenuate reverse rate-dependence seen after IKr block. 2. The individual and combined electrophysiological effects of selective IKr and IKs blockers, dofetilide and HMR 1556, respectively, were evaluated using Langendorff-perfused rabbit hearts. Monophasic action potential duration at 90% repolarization (MAPD90) and ventricular effective refractory period (VERP) were determined at cycle lengths (CLs) of 200-500 ms (at 50 ms intervals). 3. Dofetilide (1-100 nM) prolonged MAPD90 in a concentration-dependent manner (P < 0.001, n = 6) with reverse rate-dependence (P < 0.0001). In contrast, HMR 1556 (10-240 nM) alone did not prolong MAPD90. However, in the presence of 7.5 nM dofetilide, HMR 1556 (100 nM) increased the extent of reverse rate-dependence by further prolonging MAPD90 at CLs of 400, 450 and 500 ms (P < 0.05, n = 9) and, to a lesser extent, at shorter CLs (e.g. by 17 +/- 4 ms at CL 500 vs 2 +/- 3 ms at CL 200 ms). 4. Effects of dofetilide and HMR 1556 on VERP were similar to those on MAPD90. The slope of the VERP vs CL relation was steeper after the combination (0.081 +/- 0.013) than after dofetilide alone (0.028 +/- 0.018, P < 0.01, n = 9). 5. Blockade of rabbit IKs increased reverse rate-dependence of IKr block.     

快速右心室起搏对犬心脏重构的影响

目的犬快速右心室起搏3周构建心衰模型,探讨心衰模型中单个心肌细胞动作电位以及心脏结构及功能变化。方法本研究主要采用对照研究的方法,将10条杂种犬分成两组：5条起搏犬组和5条对照组犬。起搏犬组采用快频率每分钟（230±10）次起搏右心室3周,而对照犬仅放置起搏电极。观察两组犬临床表现、心功能的变化,从而构建心衰模型。并探讨心衰犬心脏大体形态及结构方面变化以及活体单个心肌细胞动作电位变化。结果杂种犬经右心室快速频率起搏3周后均发生心衰。而且心衰犬双心室壁明显薄,心腔扩大。光学显微镜和电子显微镜下可见心肌实质和间质组织发生明显重构。心衰犬单个心肌细胞动作电位测定发现：动作电位时程（Action potential duration,APD）、复极90％时间（Duration of Action Potentialat 90％,APD90）及复极50％时间（Duration of Action Potentialat 50％,APD50）均延长。结论慢性快速右心室起搏是构建可控性心衰模型的有效方法,在心衰发生发展进程中存在明显心脏电和机械重构。     

Effect of amiodarone on dispersion of ventricular repolarization in a canine congestive heart failure model

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比索洛尔对慢性充血性心力衰竭家兔中层心肌复极异质性的影响

目的研究比索洛尔对慢性充血性心力衰竭(CHF)中层心肌复极异质性的影响。方法制作CHF家兔模型,并给予比索洛尔干预,然后分别测定其室颤阈值(VFT)以及心外膜、中层心肌和心内膜心肌细胞的单相动作电位复极90时程(APD90)、跨室壁复极离散度(TDR)。结果CHF组3层心肌APD90均明显延长,但中层心肌APD90延长更为明显,跨室壁TDR增加,VFT明显降低。而与CHF组相比,比索洛尔治疗组(CHF+BIS),3层心肌APD90均进一步延长,以心内、外层心肌APD90延长更为明显,TDR减小,VFT阈值升高。结论比索洛尔能减小CHF3层心肌跨室壁复极不均一性,抑制恶性室性心律失常的发生。     

The Effect of Cocaine on Ventricular Fibrillation Threshold in the Normal Canine Heart

We determined the effect of cocaine on ventricular vulnerability to fibrillation, as measured by ventricular fibrillation threshold (VFT), and cardiac electrophysiology in 20 anesthetized dogs with normal hearts. Animals were randomized in blinded fashion to receive a continuous 3-hour infusion of cocaine 0.11 mg/kg/minute (total dose 20 mg/kg) or placebo (lactose dissolved in normal saline). The VFT, systolic and diastolic blood pressures, ventricular effective refractory period (ERP), and electrocardiographic intervals were measured at baseline and every 30 minutes during infusion. Baseline mean ± SE VFT in cocaine and placebo groups was 57.0 ± 7.8 and 51.8 ± 7.6 må, respectively (p=0.64). Cocaine did not significantly decrease VFT, but actually increased it (i.e., reduced ventricular vulnerability to fibrillation) compared with placebo (84.6 ± 10.4 vs 55.8 ± 7.2 må, respectively, at 150 minutes, p=0.04). Cocaine prolonged ERP and PR, QRS, QT, QT_c, JT, and JT_c intervals. Cocaine does not increase ventricular vulnerability to fibrillation in anesthetized dogs with normal intact hearts. Its electrophysiologic effects are similar to those of class I antiarrhythmic agents in this model.     

阿魏酸钠对家兔心室肌单相动作电位的影响

目的　探讨阿魏酸钠对心肌细胞单相动作电位的影响。方法　健康家兔 2 0只 ,随机平均分为两组 :对照组 (苄基四氢巴马汀组 )和实验组。按传统心内膜MAP记录方法经右颈外静脉插入四极接触电极导管至家兔右心室内膜记录MAP信号并同时记录Ⅱ导联心电图。对照组经耳缘静脉给予苄基四氢巴马汀 ( 5mg·kg-1) ,实验组给予阿魏酸钠( 0 6g·kg-1) ,给药前、后观察MAPA、MAPD5 0、MAPD90及ERP。结果　对照组用药前MAPA及MAPD2 0分别为( 2 7 0 1± 0 67)mV及 ( 79 0 5± 7 0 4 )ms,用药后分别为( 2 6 87± 0 73 )mV及 ( 77 5± 7 170 )mV(P >0 0 5 ) ;用药2 0 0 1 0 2 15收稿 ,2 0 0 1 0 4 13修回1 贵州省人民医院心内科 ,贵阳　 5 5 0 0 0 22 包头钢铁职工医院 ,包头　 0 14 0 0 0作者简介 :李　屏 ,女 ,36岁 ,医学硕士 ,副主任医师。Tel:0 85 1 5 934 319,E mail:lipingb @hotmail.com ;曾秋棠 ,男 ,36岁 ,医学博士 ,副教授 ,硕士生导师前MAPD5 0、MAPD90、ERP分别为 ( 97 5± 6 770 )ms、( 12 3 5± 5 80 )ms、( 111± 13 5 0 )ms,用药后分别为 ( 12 4 5± 8 96)ms、( 15 3± 7 5 3 )ms、( 14 2± 13 3 7)ms (P <0 0 1) ;实验组用药前MAPA及MAPD2 0分别为 ( 2 6 5 8±1 0 3 )mV及 ( 75± 5 77)ms,用