Cardiovascular Effects of a Phosphodiesterase III inhibitor in the Presence of Carvedilol in Dogs

Abstract

ABSTRACT. The aim of this study was to determine whether dobutamine, dopamine, or milrinone (a phosphodiesterase [PDE] III inhibitor) would support cardiac function that had been attenuated by administration of the β-blocker, carvedilol (0.2, 0.4, or 0.8 mg/kg). Hemodynamic and cardiac parameters including the heart rate (HR), left-ventricular fractional shortening (FS), and arterial pressure were measured in six healthy dogs without cardiac disease. Carvedilol did not affect FS or arterial pressure, but decreased the HR significantly. The positive inotropic and chronotropic responses to dobutamine and dopamine were attenuated by carvedilol, whereas arterial pressure was unaffected. Milrinone did not affect the HR and decreased arterial pressure, whereas FS was significantly greater both in the control and carvedilol-treated groups. Although milrinone affect the negative chronotropic effects of carvedilol, milrinone increased FS and prevented the decrease in arterial pressure. These results suggest that inhibition of PDE III preserves cardiac contractility and hemodynamic function in the presence of carvedilol.KEY WORDS: β-blocker, cardiac function, heart failure, inotropic agent.J. Vet. Med. Sci. 68(6): 549-553, 2006 Clinical studies on humans have shown that treatment of congestive heart failure with β-blockers can reduce mortality [4,5,10,16] by improving myocardial energy metabolism, reducing arrhythmia, reducing damage to cardiac myocytes, up-regulating β 1 receptor expression, and improving diastolic function [5]. However, cardiac function must be monitored carefully in heart failure patients who are undergoing treatment with β-blockers because such treatment is associated with side effects that include bradycardia, hypotension, and A-V node blocking [2,21].It has been established that sympathomimetic drugs such as dobutamine and dopamine may prevent acute heart failure and circulatory collapse. However, the down-regulation of myocardial β-receptors that occurs during heart failure leads to an attenuation of the chronotropic and inotropic effects of β-receptor agonists such as adrenaline, noradrenaline, dobutamine, and dopamine [3,7,9]. Milrinone, an inhibitor of phosphodiesterase (PDE) III, increases the concentration of intracellular cyclic adenosine monophosphate (cAMP) by retarding the degradation of this molecule [1,22]. The modulation of intracellular cAMP by milrinone produces inotropic and chronotropic effects on the heart and relaxation of vessels in the absence of β-receptor stimulation [1,12,23]. Therefore, milrinone may produce beneficial effects even though myocardial β-receptors are downregulated during heart failure. Presumably, the beneficial effects of milrinone also apply in situations in which β-receptors have been blocked by the administration of a β-The objective of this study was to determine whether dobutamine, dopamine, or milrinone could support cardiac function that had been attenuated by the administration of a β-blocker. To achieve the objective, the hemodynamic and cardia...

Milrinone and theophylline act as lower oesophageal sphincter relaxing agents: a comparative pharmacodynamic study in the rabbit

“…On the other hand, milrinone, a potent cardiac bipyridine with positive inotropic and vasodilator properties, referred also as selective cardiac or PDE III inhibitor, exhibits pronounced effects on both heart contractility and vasorelaxation, and it is recommended in the treatment of congestive heart failure in both human and animals (Muir, 1995; Uechi et al. , 2006).…”