Systemic haemodynamic actions of pimobendan (UD-CG 115 BS) and its O-demethylmetabolite UD-CG 212 Cl in the conscious pig

The cardiovascular effects of the pyridazinone-derivatives pimobendan and its O-demethylmetabolite UD-CG 212 Cl (2-(4-hydroxy-phenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole HCl) were studied in conscious pigs, employing consecutive intravenous 10 min infusions of 10, 25, 50 and 100 μgrams kg^-1 min^-1 and 2, 4 and 8 μgrams kg^-1 min^-1 respectively.

Pimobendan caused dose-dependent increases in LV dP/dt_max (up to 115%) and heart rate (up to 30%), while cardiac output was slightly elevated (up to 15%) and stroke volume decreased by 12%. Left ventricular end-diastolic pressure decreased in a dose-related manner from 8.7 +/- 1.0 mmHg to 2.7 +/- 1.7 mmHg. Mean arterial blood pressure was not significantly affected because systemic vascular resistance decreased dose-dependently up to 15%.

After β-adrenoceptor blockade, the pimobendan-induced increases in heart rate and cardiac output were attenuated and the increase in LV dP/dt_max almost abolished. The responses of left ventricular end-diastolic and mean arterial blood pressure, systemic vascular resistance and stroke volume were not modified.

UD-CG 212 Cl caused dose-related increases in LV dP/dt_max (up to 100%) and heart rate (up to 25%). Cardiac output was minimally elevated (up to 8%) as stroke volume decreased dose-dependently up to 15%. As systemic vascular resistance decreased up to 12%, mean arterial blood pressure was slightly reduced (5%). Left ventricular end-diastolic blood pressure decreased dose-dependently from 9.0 +/- 0.8 mmHg to 3.8 +/- 1.3 mmHg.

After β-adrenoceptor blockade, the UD-CG 212 Cl-induced increases in heart rate and LV dP/dt_max were attenuated and almost abolished and amounted up to 15% and 20%, respectively. The responses of the other systemic haemodynamic parameters were not significantly modified.

We conclude that pimobendan and UD-CG 212 Cl are compounds with marked positive inotropic and venodilator properties in the conscious pig. The attenuation of the inotropic effects by pretreatment with propranolol strongly suggests that, in the conscious pig, the β-adrenergic system is significantly involved in the positive inotropic actions. The lack of effect of β-adrenoceptor blockade on the vasodilator responses to both compounds suggest a mechanism not related to β-adrenergic activity.