Fazekas T, Carlsson L, Scherlag B J, Mabo P, Poty H, Palmer M, Patterson E, Berlin K D, Garrison G L, Lazzara R
1st Department of Medicine, Szent-Györgyi University Medical School, Hungary.
J Cardiovasc Pharmacol. 1996 Aug;28(2):182-91. doi: 10.1097/00005344-199608000-00002.
GLG-V-13, a novel 3,7-diheterabicyclo(3.3.1)nonane, was examined both in vivo and in vitro to characterize its electrophysiological, hemodynamic, and inotropic properties. In anesthetized guinea pigs, GLG-V-13 [0.5-500 micrograms/kg intravenously (i.v.), n = 6] lengthened the epicardial monophasic action potential (MAP) duration, the atrioventricular (AV) conduction time and the RR interval in a dose-dependent manner. At the highest dose, these variables were increased by 30, 13, and 23%, respectively. No significant effects were noted on QRS duration or blood pressure (BP). In rabbit atrial and papillary muscle preparations, GLG-V-13 (0.32-3.2 mg/L) did not exert a negative inotropic action and in isolated rabbit cardiomyocytes the agent blocked the rapidly activating delayed rectifier K+ current (IKr, EC50 = 48 micrograms/L). In 10 intact anesthetized mongrel dogs, the left ventricular (LV) endocardial MAP was measured during atrial pacing before and after administration of GLG-V-13 (3 and 6 mg/kg i.v.). As compared with the drug-free state, the agent induced a significant prolongation of the MAP at all pacing frequencies (2.0-4.5 Hz). In 15 anesthetized dogs studied 1-4 days after two-stage ligation of the left anterior descending coronary artery (LAD), the antiarrhythmic/proarrhythmic potential of GLG-V-13 was compared with that of lidocaine. ECG, His bundle, LV (IZepi), and composite and normal zone composite electrograms were recorded. Programmed electrical stimulation (PES) and burst pacing (4.0-7.0 Hz) were delivered to the right ventricular outflow tract. In the drug-free state, sustained monomorphic ventricular tachycardia (SMVT) was inducible in 6 dogs (6 of 15). After lidocaine, SMVT was induced in 7 other dogs (13 of 15). GLG-V-13 prevented induction of SMVT in 5 of 6 dogs; a proarrhythmic action was noted in 1 dog only. GLG-V-13 slowed the heart rate (HR), increased the AH and the HV intervals, prolonged the paced (2.5 Hz) QT interval, and increased the ventricular effective refractory period (VERP). These effects were associated with 2:1 block of late potentials in the IZepi electrograms, a phenomenon also observed during rapid atrial pacing (2.5-3.5 Hz), suggestive of a marked prolongation of refractoriness in the ischemically damaged myocardium. In light of the recent Cardiac Arrhythmia Suppression Trial (CAST) study, the antiarrhythmic efficacy, together with the low proarrhythmic potential and lack of cardiodepressant properties of GLG-V-13, may merit further investigation of this novel class III antiarrhythmic agent.
GLG-V-13是一种新型的3,7-二杂双环(3.3.1)壬烷，在体内和体外进行了研究，以表征其电生理、血流动力学和变力特性。在麻醉的豚鼠中，GLG-V-13[静脉注射(i.v.)0.5-500微克/千克，n = 6]以剂量依赖性方式延长心外膜单相动作电位(MAP)持续时间、房室(AV)传导时间和RR间期。在最高剂量时，这些变量分别增加了30%、13%和23%。未观察到对QRS持续时间或血压(BP)有显著影响。在兔心房和乳头肌制剂中，GLG-V-13(0.32-3.2毫克/升)未发挥负性变力作用，在分离的兔心肌细胞中，该药物阻断快速激活延迟整流钾电流(IKr，EC50 = 48微克/升)。在10只完整的麻醉杂种狗中，在静脉注射GLG-V-13(3和6毫克/千克)前后进行心房起搏时测量左心室(LV)心内膜MAP。与无药状态相比，该药物在所有起搏频率(2.0-4.5赫兹)下均导致MAP显著延长。在15只麻醉狗中，在左前降支冠状动脉(LAD)两阶段结扎后1-4天进行研究，将GLG-V-13的抗心律失常/促心律失常潜力与利多卡因进行比较。记录心电图、希氏束电图、LV(IZepi)电图以及复合和正常区复合电图。将程序电刺激(PES)和猝发起搏(4.0-7.0赫兹)施加到右心室流出道。在无药状态下，15只狗中有6只(6/15)可诱发持续性单形性室性心动过速(SMVT)。给予利多卡因后，另外7只狗(13/15)诱发了SMVT。GLG-V-13在6只狗中有5只预防了SMVT的诱发；仅在1只狗中观察到促心律失常作用。GLG-V-13减慢心率(HR)，增加AH和HV间期，延长起搏(2.5赫兹)QT间期，并增加心室有效不应期(VERP)。这些效应与IZepi电图中晚期电位的2:1阻滞相关，在快速心房起搏(2.5-3.5赫兹)期间也观察到这种现象，提示缺血损伤心肌的不应期明显延长。鉴于最近的心律失常抑制试验(CAST)研究，GLG-V-13的抗心律失常疗效，以及低促心律失常潜力和缺乏心脏抑制特性，可能值得对这种新型III类抗心律失常药物进行进一步研究。
