Farah A E, Frangakis C J
Dept. of Molecular Pharmacology, Glaxo Research Laboratories, Research Triangle Park, North Carolina.
Basic Res Cardiol. 1989;84 Suppl 1:85-103. doi: 10.1007/BF02650349.
Milrinone is a positive inotropic and vasodilator agent when tested in experimental animals and in human heart-failure patients. It is generally believed that milrinone acts by inhibiting phosphodiesterase IV, thus increasing cyclic AMP, [Ca++]i and cardiac contractile force and relaxation. Maximal force produced by milrinone is greater when single-dose response curves are compared to cumulative dose-response curves. In vitro, milrinone produces a tachyphylaxis, the extent of which is both dose- and time-dependent. Recovery of tachyphylaxis is both dose- and time-dependent and is not influenced by inhibitors of protein or RNA synthesis. There is a specific cross-tachyphylaxis between milrinone and amrinone, theophylline, papaverine, and Bay K8644. This tachyphylaxis may explain the low maximal contractile response of the cumulative dose-response observed in isolated tissues. Milrinone increased cyclic AMP in dog and guinea pig cardiac muscle. As previously shown by Endoh et al., milrinone in low doses produced a biphasic effect on cyclic AMP. The early increase (first 60-70 s) in cyclic AMP shows a good correlation with contractile force changes. If cyclic AMP is determined at maximal contractile force this correlation was poor. Here we also present instances where the increase in cyclic AMP after milrinone (determined at maximal effect) does not correlate with the contractile response. The cross-tachyphylaxis of milrinone with Bay K8644 suggests that milrinone has an action on the sarcolemmal Ca++ channels. Bay K8644 suppresses the positive inotropic effect of catecholamines by 50%, but not the cyclic AMP response. The inotropic effect of milrinone, in contrast to norepinephrine is highly sensitive to [Ca++]0, stimulation rate, and [K+]0. In this respect milrinone behaves more like Bay K8644. We postulate that the main inotropic action of milrinone is due to a sarcolemmal effect. The early cyclic AMP production described could be in the sarcolemmal compartment and this may explain some of the similarities of milrinone's actions with those of Bay K8644. The tachyphylaxis observed with the inotropic effect of milrinone does not extend to the decreases in relaxation time. This and other findings to be discussed suggest that the positive inotropic and reduction in relaxation time by milrinone depend on different mechanisms, possibly through differential compartmentalization of cyclic AMP.
米力农在实验动物和人类心力衰竭患者中进行测试时，是一种正性肌力和血管扩张剂。一般认为，米力农通过抑制磷酸二酯酶IV起作用，从而增加环磷酸腺苷（cAMP）、细胞内钙离子浓度（[Ca++]i）以及心脏收缩力和舒张能力。当将单剂量反应曲线与累积剂量反应曲线进行比较时，米力农产生的最大力量更大。在体外，米力农会产生快速耐受性，其程度与剂量和时间有关。快速耐受性的恢复也与剂量和时间有关，且不受蛋白质或RNA合成抑制剂的影响。米力农与氨力农、茶碱、罂粟碱和Bay K8644之间存在特异性交叉快速耐受性。这种快速耐受性可能解释了在离体组织中观察到的累积剂量反应的低最大收缩反应。米力农可增加犬和豚鼠心肌中的环磷酸腺苷。如远藤等人之前所示，低剂量的米力农对环磷酸腺苷产生双相作用。环磷酸腺苷的早期增加（最初60 - 70秒）与收缩力变化具有良好的相关性。如果在最大收缩力时测定环磷酸腺苷，这种相关性则较差。在此我们还展示了一些实例，即米力农后环磷酸腺苷的增加（在最大效应时测定）与收缩反应不相关。米力农与Bay K8644的交叉快速耐受性表明米力农对肌膜钙离子通道有作用。Bay K8644可使儿茶酚胺的正性肌力作用降低50%，但不影响环磷酸腺苷反应。与去甲肾上腺素相反，米力农的正性肌力作用对细胞外钙离子浓度（[Ca++]0）、刺激频率和细胞外钾离子浓度（[K+]0）高度敏感。在这方面，米力农的行为更类似于Bay K8644。我们推测米力农的主要正性肌力作用归因于肌膜效应。所描述的早期环磷酸腺苷产生可能发生在肌膜区室，这可能解释了米力农与Bay K8644作用的一些相似之处。米力农正性肌力作用所观察到的快速耐受性并不扩展至舒张时间的缩短。这一点以及其他将讨论的发现表明，米力农的正性肌力作用和舒张时间的缩短依赖于不同机制，可能是通过环磷酸腺苷的不同区室化实现的。
