Clinically Relevant Concentrations of Olprinone Reverse Attenuating Effect of Propofol on Isoproterenol-induced Cyclic Adenosine Monophosphate Accumulation in Cardiomyocytes

Propofol has been shown to attenuate β-adrenoreceptor-mediated signal transduction in cardiomyocytes. Cyclic adenosine monophosphate (cAMP) is an essential second messenger of β-signal transduction, while olprinone, a phosphodiesterase-III inhibitor, improves poor cardiac performance by increasing cAMP levels. In the present study, we investigated the effects of olprinone toward the reducing effect of propofol on β-adrenoreceptor-mediated increases in cAMP production. First, suspensions of rat ventricular myocytes were incubated with isoproterenol or olprinone and the effects on cAMP concentrations were assessed. Next, propofol was added prior to the addition of isoproterenol or olprinone. Finally, following preincubation with propofol, isoproterenol with or without olprinone was added. Both isoproterenol and olprinone increased cAMP production in a dose-dependent manner. However, clinically relevant concentrations of olprinone (up to 10-7 M) did not cause a significant increase. Propofol (l0-7-10-4 M) attenuated isoproterenol-stimulated increases in cAMP production (decrease of 2 ± 4% - 43 ± 1%, as compared to the isoproterenol-stimulated state). However, the agent did not alter olprinone (10- 7 M)-stimulated cAMP production. Olprinone (10- 8 -10-6 M) reversed the attenuating effect of propofol (l0-5 M) toward isoproterenol (l0-7 M)-stimulated cAMP production dose-dependently (increase of 10 ± 5% - 79 ± 4% as compared to the propofolattenuated state). Our results suggest that an improvement in cardiac function is provided by olprinone when the β-adrenoreceptor-mediated signaling pathway is inhibited by propofol.