Effects of milrinone on contractility and cyclic adenosine monophosphate production induced by beta1- and beta2-adrenergic receptor activation in human myocardium.
BACKGROUND
Because milrinone is a widely used phosphodiesterase-3 (PDE3) inhibitor, it would be of interest to know whether it interacts with beta1- and beta2-adrenergic receptor (AR) agonists in human myocardium.


OBJECTIVE
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 beta1-AR with norepinephrine (NE) and activation of the beta2-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 beta1-AR (NE in the presence of the beta2-blocker ICI 118, 551) and the beta2-AR (EPI in the presence of the beta1-blocker CGP 20712A) were obtained in the absence and presence of milrinone 1 micromol/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 beta1- and beta2-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.
Carceles
Mafía D
MD
Department of Anesthesia, University Hospital C.S.V. Arrixaca, Murcia, Spain.
Fuentes
Teodomiro
T
Aroca
Vicente
V
Lopez
Jesús
J
Hernández
Jesús
J
D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000368:Aged; D000242:Cyclic AMP / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D020105:Milrinone / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism
D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D007093:Imidazoles; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C026777:ICI 118551; C049763:CGP 20712A; D000242:Cyclic AMP; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D020105:Milrinone; D009638:Norepinephrine; D004837:Epinephrine