Effects of Milrinone on Contractility and Cyclic Adenosine Monophosphate Production Induced by β1 - and β2 -Adrenergic Receptor Activation in Human Myocardium

• Published in: Clinical therapeutics 2007-08, Vol.29 (8), p.1718-1724
• Main Authors: Carceles, Mafía D., MD, PhD, Fuentes, Teodomiro, Chem PhD, Aroca, Vicente, BPharm, Lopez, Jesús, MD, Hernández, Jesús, MD, PhD
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Internal Medicine; Medical Education; Medical sciences; Pharmacology. Drug treatments
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2007.08.009

Abstract Background: Because milrinone is a widely used phosphodiesterase-3 (PDE3) inhibitor, it would be of interest to know whether it interacts with β1 - and β2 -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 β1 -AR with norepinephrine (NE) and activation of the β2 -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 β1 -AR (NE in the presence of the β2 -blocker ICI 118, 551) and the β2 -AR (EPI in the presence of the β1 -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 β1 - and β2 -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.