Effects of Milrinone on Contractility and Cyclic Adenosine Monophosphate Production Induced by β 1- and β 2-Adrenergic Receptor Activation in Human Myocardium

Abstract

Background: Because milrinone is a widely used phosphodiesterase-3 (PDE3) inhibitor, it would be of interest to know whether it interacts with β 1- and β 2-adrenergic receptor (AR) agonists in human myocardium. Objectives: This in vitro study was conducted to test whether milrinone differentially regulates cyclic adenosine-3',5'-monophosphate (cAMP) production and to examine the effect of milrinone on the positive inotropic responses and cAMP production induced by activation of the β 1-AR with norepinephrine (NE) and activation of the β 2-AR with epinephrine (EPI) in human atrial myocardium. Methods: Right atrial trabeculae were obtained from patients undergoing cardiac surgery for valve repair. Concentration-response curves for inotropic responses mediated through the β 1-AR (NE in the presence of the β 2-blocker ICI 118, 551) and the β 2-AR (EPI in the presence of the β 1-blocker CGP 20712A) were obtained in the absence and presence of milrinone 1 μmol/L. This concentration of milrinone was chosen because it corresponded to its 50% inhibitory concentration as a PDE3 inhibitor and its therapeutic plasma concentration. The production of cAMP induced by exposure to selective β 1- and β 2-AR stimulation was also measured in the absence and presence of milrinone. Results: Right atrial tissue samples were obtained from 12 white patients (7 women, 5 men; mean [SE] age, 64.6 [6.3] years) undergoing cardiac surgery for valve repair (8 mitral, 4 aortic). The presence of milrinone was associated with leftward shifts in the concentration-response curves for both NE and EPI. cAMP production in myocardial tissue samples in the presence of milrinone was increased only with NE induction (mean [SEM], 745.0 [136.7] pmol/g in the absence of milrinone vs 1620.5 [372.3] pmol/g in the presence of milrinone; P < 0.05). Conclusions: In this preliminary study in human atrial myocardium, milrinone potentiated the contractile responses to both NE and EPI. However, only the effect of NE on tissue levels of cAMP was increased in the presence of milrinone.