Cardiac electrophysiologic and hemodynamic activity of pimobendan (UD- CG 115 BS), a new inotropic agent

JM Kitzen, JJ Lynch, EM Driscoll and BR Lucchesi

Department of Pharmacology, University of Michigan Medical School, Ann Arbor.

The hemodynamic and cardiac electrophysiologic properties of pimobendan, a new pyridazinone-benzimidazole type inotropic agent, were studied in urethane-anesthetized dogs. The cumulative i.v. administration of 0.1, 0.3, and 1.0 mg/kg pimobendan caused a dose- dependent decrease in mean arterial pressure and an increase in sinus heart rate. When heart rate was maintained constant by overdrive atrial pacing, hemodynamic changes in response to pimobendan consisted of dose- related increases in right ventricular isometric contractile force (P less than .05 at 0.3 and 1.0 mg/kg), left ventricular +dP/dt (P less than .05 at 0.3 and 1.0 mg/kg), and left circumflex coronary artery blood flow (P less than .05 at 1.0 mg/kg). Increases in each of the aforementioned hemodynamic parameters were sustained for up to 4 hr after the i.v. administration of 1.0 mg/kg pimobendan. The cardiac electrophysiologic changes associated with pimobendan administration included decreases in the atrial (P less than .05 at 1.0 mg/kg), ventricular (P less than .05 at 0.3 and 1.0 mg/kg), and atrioventricular nodal functional (P less than .05 at 0.3 and 1.0 mg/kg) and effective (P less than .05 at 1.0 mg/kg) refractory periods. Atrioventricular conduction velocity was enhanced after pimobendan, as indicated by a shortening of the AH (P less than .05 at 0.3 mg/kg and at 1.0 mg/kg) and PR intervals (P less than 0.05 at 1.0 mg/kg). Pretreatment with propranolol (0.5 mg/kg i.v.) attenuated the pimobendan-induced decrease in the ventricular refractory period and the increase in heart rate, whereas the decrease in arterial pressure was enhanced. These results indicate that the i.v. administration of pimobendan to anesthetized dogs produces a dose-related positive inotropic effect, coronary and peripheral vasodilation, and cardiac electrophysiologic effects that include decreases in atrial, atrioventricular, and ventricular refractoriness as well as a facilitation of atrioventricular conduction. The observed electrophysiologic changes may be mediated, in part, by a baroreceptor- mediated increase in sympathetic nervous system activity.

Volume 244, Issue 3, pp. 929-939, 03/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics