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

Abstract

1 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 HCI) were studied in conscious pigs, employing consecutive intravenous 10 min infusions of 10, 25, 50 and 100 pg kg-'min-' and 2, 4 and 8 pg kg-'min-' respectively. 2 Pimobendan caused dose-dependent increases in LVdPIdtmaX (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%.3 After P-adrenoceptor blockade, the pimobendan-induced increases in heart rate and cardiac output were attenuated and the increase in LVdP/dtn,,X almost abolished. The responses of left ventricular enddiastolic and mean arterial blood pressure, systemic vascular resistance and stroke volume were not modified.4 UD-CG 212 Cl caused dose-related increases in LVdP/dt,,mx (up to 100%) and heart rate (up to 25%). Cardiac output was minimally elevated (up to 8%) as stroke volume decreased dosedependently 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 dosedependently from 9.0 ± 0.8 mmHg to 3.8 ± 1.3 mmHg.5 After P-adrenoceptor blockade, the UD-CG 212 Cl-induced increases in heart rate and LVdP/dtmax 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. 6 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 P-adrenergic system is significantly involved in the positive inotropic actions. The lack of effect of P-adrenoceptor blockade on the vasodilator responses to both compounds suggest a mechanism not related to fi-adrenergic activity. IntroductionThe pyridazinone-derivative pimobendan (UD-

Cardiovascular effects of the novel Ca2+‐sensitiser EMD 57033 in pigs at rest and during treadmill exercise

“…Interestingly, the increase in cardiac output was entirely due to an increase in heart rate, with no change in stroke volume which may have resulted from the decrease in LV preload. These ®ndings with levosimendan in awake dogs are very similar to our data with pimobendan in awake normal pigs (Duncker et al, 1987a). In healthy resting humans, levosimendan also increased cardiac output, which was due to an increase in stroke volume at a lower dose, while at a higher dose it resulted entirely from an increase in heart rate (Lilleberg et al, 1994;Sundberg et al, 1995).…”

“…These ®ndings are best interpreted as a lack of an e ect of EMD 57033 per se on LV ®lling pressure. However, EMD 57033 does not decrease LV ®lling pressure,which contrasts with the decrease in LV ®lling pressure observed in pigs during infusion of pimobendan (Duncker et al, 1987a) or the pure phosphodiesterase inhibitor amrinone (Hartog et al, 1986).…”

“…Only during the highest dose did we observe an increase in heart rate which was blunted by pretreatment with propranolol suggesting that EMD 57033 produced slight phosphodiesterase inhibition at this dose (Nankervis et al, 1994). In contrast, we previously observed that the pimobendan-induced increases in cardiac output, heart rate and LVdP/dt max were markedly attenuated by pretreatment with propranolol ( Figure 7; Duncker et al, 1987a), indicating that this purported Ca 2+ sensitiser exerts a major part of its actions via phosphodiesterase inhibition in awake pigs. In awake dogs, another Ca 2+ sensitiser levosimendan also produced dose-dependent increases in LVdP/ dt max and cardiac output.…”

“…The present study describes the cardiovascular e ects of the Ca 2+ sensitizer EMD 57033 in awake pigs, free from the e ects of anaesthesia and acute surgical trauma, in which we previously studied the cardiovascular pro®le of the mixed Ca 2+ sensitizer/PDE-III inhibitor pimobendan (Duncker et al, 1987a). The main ®ndings under resting conditions were: (1) EMD 57033 produced dose-dependent increases in global LV contractility and stroke volume, with a minimal e ect on heart rate and blood pressure, and produced a decrease in systemic vascular resistance, (2) these e ects were essentially unchanged when animals were pretreated with b-adrenoceptor blockade, indicating that phosphodiesterase inhibition does not contribute signi®cantly to the positive inotropic actions of EMD 57033.…”

“…Data on the cardiovascular actions of EMD 57033 in vivo are lacking. Consequently, the present study was performed to investigate the systemic, pulmonary and coronary haemodynamic actions of EMD 57033 in chronically instrumented awake pigs and to compare these to the previously reported actions of pimobendan in the same model (Duncker et al, 1987a). To determine the contribution of PDE III inhibition to the cardiostimulatory actions of EMD 57033, we also administered the same dose regimen in animals pretreated with the non-selective b-adrenergic receptor antagonist propranolol.…”