Assessment of the electrophysiologic, antiarrhythmic and haemodynamic profile of a new isoquinolinedione derivative.

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.