The Effects of Olprinone, a Phosphodiesterase 3 Inhibitor, on Systemic and Cerebral Circulation

Abstract

Olprinone, a phosphodiesterase (PDE) 3 inhibitor, is used to treat heart failure due to its positive inotropic and vasodilative effects. Selective inhibition of the PDE 3 isozyme increases intracellular adenosine 3;5;-cyclic monophosphate and enhances Ca(2+) influx into cardiac muscle cells. The most significant advantage of PDE 3 inhibitors is their ability not only to enhance myocardial contraction, but to reduce, through vasodilatory action, the stress to which the heart is subjected. In peripheral vessels, the decrease of cytosolic free Ca(2+) induces the vasorelaxation of vascular smooth muscle cells. In this way, olprinone reduces mean aortic and pulmonary artery pressures. Additionally, olprinone exerts differential vasodilatory effects on peripheral vessels in each organ, based on the differences in the distribution of PDE 3 among the organs. With respect to the cerebral circulation, olprinone augments blood flow in the cerebral cortex through direct vasodilatory effects on small cerebral arteries or arterioles. Olprinone increases hepatosplanchnic blood flow and improves oxygen supply. While long-term therapy with PDE 3 inhibitors in patients with chronic heart failure may accelerate the progress of the underlying disease and provoke serious ventricular arrhythmia, olprinone shows good potential for short-term treatment in patients who have experienced severe heart failure or patients who have undergone cardiac surgery.

Chemical–Genetic Profiling of Imidazo[1,2-a]pyridines and -Pyrimidines Reveals Target Pathways Conserved between Yeast and Human Cells

“…Members of this family of compounds have been widely used in medicinal chemistry and include pharmacological agents such as the phosphodiesterase 3 inhibitor olprinone [15], the hypnotic zolpidem [16], and the anxiolytic divaplon [17]. Members also exhibit analgesic, anti-inflammatory [18], anti-viral [19],[20], and anti-microbial activities [21]–[24], and have been optimized as cyclin-dependent kinase inhibitors [25] and as GABA receptor ligands [26],[27].…”

Differential vasodilation response to olprinone in rabbit renal and common carotid arteries

“…This would cause less intracellular accumulation of cAMP in carotid vascular smooth muscle, thereby resulting in a reduced level of vasodilation. Heterogeneous distribution and regulation of PDE3 isozymes has been reported in previous studies and different effects of PDE3 inhibitors on each artery can be explained, at least in part, by the varying distribution of the PDE3 isozyme [14,16,17].…”

“…Olprinone is now one of the PDE3 inhibitors most frequently used to treat acute heart failure [14]. It inhibits the degradation of cAMP.…”

“…Although this finding suggests that the direct vasodilation may play an important role in the olprinone-induced change in cerebral blood flow, the direct effect of olprinone on the cerebral artery is poorly understood. The carotid artery plays a role in the regulation of cerebral blood flow, and recent studies have also revealed that the distensibility of the wall of the common carotid artery is improved by olprinone [3,14]. PDE3 inhibitors are known to have a potent vasodilation effect on renal and splanchnic arteries [4][5][6]15].…”

Development of rapid and high‐throughput LC–MS/MS method for quantification of olprinone in rabbit plasma

“…Olprinone {OLP; 1,2‐dihydro‐5‐(imidazo[1,2‐α]pyridin‐6‐yl)‐6‐methyl‐2‐oxo‐3‐pyridinecarbonitrile} is a representative of highly selective PDE 3 inhibitors with a half maximal inhibitory concentration for PDE 3 of 0.35 ± 0.03 mmol/L (Mizushige, Ueda, Yukiiri, & Suzuki, ). OLP was developed in Japan and has been approved for treatment of acute heart failure and myocardial depression after cardiac surgery (Iwade, Nomura, Uezono, Ashikari, & Ozaki, ; Ueda & Mizushige, ). Besides cardiac disorders, olprinone exhibited positive effects in the therapy of bronchial asthma, as well as in models of meconium‐ and lipopolysaccharide‐induced acute lung injury (Koike et al, ; Mokra et al, ; Myou et al, ).…”