Carceles Mafía D, Fuentes Teodomiro, Aroca Vicente, Lopez Jesús, Hernández Jesús
Department of Anesthesia, University Hospital C.S.V. Arrixaca, Murcia, Spain.
Clin Ther. 2007 Aug;29(8):1718-24. doi: 10.1016/j.clinthera.2007.08.009.
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.
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.
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.
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).
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.
由于米力农是一种广泛使用的磷酸二酯酶-3（PDE3）抑制剂，了解其是否与人心肌中的β1和β2肾上腺素能受体（AR）激动剂相互作用将很有意义。
进行这项体外研究以测试米力农是否差异调节环磷酸腺苷（cAMP）的产生，并研究米力农对去甲肾上腺素（NE）激活β1-AR和肾上腺素（EPI）激活β2-AR所诱导的人心房肌正性肌力反应和cAMP产生的影响。
从接受瓣膜修复心脏手术的患者获取右心房小梁。在不存在和存在1 μmol/L米力农的情况下，获得通过β1-AR（在β2阻滞剂ICI 118,551存在下的NE）和β2-AR（在β1阻滞剂CGP 20712A存在下的EPI）介导的正性肌力反应的浓度-反应曲线。选择该米力农浓度是因为它相当于其作为PDE3抑制剂的50%抑制浓度及其治疗血浆浓度。在不存在和存在米力农的情况下，还测量了暴露于选择性β1和β2-AR刺激所诱导的cAMP产生。
从12例接受瓣膜修复心脏手术的白人患者（7名女性，5名男性；平均[标准误]年龄，64.6[6.3]岁）（8例二尖瓣，4例主动脉瓣）获取右心房组织样本。米力农的存在与NE和EPI的浓度-反应曲线向左移位相关。仅在NE诱导下，存在米力农时心肌组织样本中的cAMP产生增加（平均[标准误]，不存在米力农时为745.0[136.7]pmol/g，存在米力农时为1620.5[372.3]pmol/g；P<0.05）。
在这项针对人心房肌的初步研究中，米力农增强了对NE和EPI的收缩反应。然而，仅在存在米力农时NE对组织cAMP水平的影响增加。
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