Gülker H, Spyra W, Thale J, Krimphove F, Hübner A, Bender F
University Hospital, Department of Cardiology-Angiology, Münster/Westf., Fed. Rep. of Germany.
Arzneimittelforschung. 1987 Aug;37(8):917-9.
The electrophysiological, antiarrhythmic and haemodynamic profile of a new isoquinolinedione derivative, 2,2'-[iminobis(trimethylene)]-di(4,4-dimethyl-1,3-(2H,4H)-isoqu inolinedione) hydrochloride (AR-03 Cl) was evaluated using dog models relevant to conditions in humans. In 16 animals dose-related effects on intercardiac conduction, ventricular refractoriness and on haemodynamic parameters were determined. In another 7 dogs antiarrhythmic actions of AR-03 Cl on delayed reperfusion arrhythmias following release of coronary artery occlusion after 2 h of obstruction were investigated. The results show: AR-03 Cl causes a significant prolongation in conduction through all parts of the conducting system. The AH-interval, HV-interval and QRS-duration are significantly lengthened. Ventricular repolarization is only slightly changed. There are no significant changes in heart rate, systolic and diastolic aortic pressure up to doses of 2 mg/kg b.w. However, left ventricular (dp/dtmax) and cardiac output are significantly reduced, and left ventricular enddiastolic pressure is increased. In acute myocardial necrosis delayed reperfusion arrhythmias are almost completely abolished, the effective dose is lower than that required with any other antiarrhythmic drug investigated so far in this particular experimental set-up. Further experimental and clinical testing of the new compound seems to be promising because of its strong dose-related antiarrhythmic potency. However, there is a need for further analysis of potential haemodynamic side effects of the new compound to establish the clinical significance of negative inotropic actions at therapeutic doses.
使用与人类情况相关的犬模型，对一种新的异喹啉二酮衍生物2,2'-[亚氨基双(三亚甲基)]-二(4,4-二甲基-1,3-(2H,4H)-异喹啉二酮)盐酸盐（AR-03 Cl）的电生理、抗心律失常和血流动力学特征进行了评估。在16只动物中，测定了其对心脏内传导、心室不应期和血流动力学参数的剂量相关效应。在另外7只犬中，研究了AR-03 Cl对冠状动脉阻塞2小时后解除阻塞所致延迟再灌注心律失常的抗心律失常作用。结果显示：AR-03 Cl可使整个传导系统各部位的传导显著延长。AH间期、HV间期和QRS时限显著延长。心室复极仅有轻微改变。在剂量达2mg/kg体重时，心率、主动脉收缩压和舒张压无显著变化。然而，左心室（dp/dtmax）和心输出量显著降低，左心室舒张末期压力升高。在急性心肌坏死时，延迟再灌注心律失常几乎完全消除，有效剂量低于目前在该特定实验设置中研究的任何其他抗心律失常药物所需的剂量。由于其强大的剂量相关抗心律失常效力，对该新化合物进行进一步的实验和临床测试似乎很有前景。然而，需要进一步分析该新化合物潜在的血流动力学副作用，以确定治疗剂量下负性肌力作用的临床意义。
