Positive chronotropic and inotropic effects of pimobendan (UD-CG 115 BS) in isolated, cross-circulated canine heart preparations.

The effects of pimobendan on the sinus node pacemaker activity and atrial contractility and on the left ventricular contractility were investigated in the isolated, cross-circulated right atrial and left ventricular preparations of the dog. Pimobendan, at a dose range of 1 to 1,000 nmol, injected into the sinus node artery of the isolated atrium, induced dose-dependent positive inotropic and chronotropic responses. At the same doses, it also induced dose-dependent increases in the left ventricular contractile force, similar to those in the atrial one, although the norepinephrine (NE)- and isoproterenol-induced positive inotropic effects in the ventricles were less than those in the atria. The positive cardiac effects were not inhibited by propranolol but they were depressed by intramural vagal nerve stimulation. These results suggest that pimobendan increases left ventricular contractility more effectively than atrial contractility in comparison with a beta-adrenoceptor agonist and that the positive cardiac effects of pimobendan were partially induced by a phosphodiesterase inhibition but not by a beta-adrenoceptor activation in the dog heart. When pimobendan, at a dose of 10 to 1,000 micrograms/kg, was cumulatively administered into the jugular vein of the support dog, a decrease in arterial blood pressure and an increase in heart rate were dose-dependently observed in the support dog. Half a minute after administration, the positive inotropic and chronotropic responses were induced in the isolated atrium in a dose-related manner. The pimobendan-induced positive cardiac effects were not inhibited by i.v. administration of propranolol, whereas the isosorbide dinitrate-induced positive chronotropic effects were significantly inhibited. These results indicate that pimobendan directly increases cardiac contractility and heart rate with vasodilatation in anesthetized dogs.