Haeusler G, Jonas R, Minck K O, Schliep H J, Schelling P, Weygandt H, Lues I
Preclinical Research, Merck KGaA, Darmstadt, Germany.
J Cardiovasc Pharmacol. 1997 May;29(5):647-55. doi: 10.1097/00005344-199705000-00013.
The previous separation of the racemic cardiotonic thiadiazinone derivative EMD 53998 yielded two enantiomers with different pharmacologic properties: EMD 57,033, a potent Ca2+ sensitizer with some residual phosphodiesterase III (PDE III) inhibition, and EMD 57,439, a pure PDE III inhibitor. Although numerous in vitro studies demonstrated the ability of EMD 57,033 to increase the responsiveness of cardiac contractile proteins to Ca2+, in vivo evidence for such an action is lacking. Because there is no possibility of directly proving Ca2+ sensitization in vivo, we attempted to exclude PDE III inhibition as a major contributing component of the positive inotropic action of EMD 57,033. In anesthetized rats, EMD 57,033 increased left ventricular (LV) first derivative of change in systolic pressure over time (dP/dt max) without affecting blood pressure. In contrast, the PDE III-inhibitory enantiomer EMD 57,439 decreased blood pressure. The pattern of hemodynamic effects in anesthetized dogs revealed similar differences between EMD 57,033 and PDE inhibitors. Thus the increase in LV dP/dt max in response to EMD 57,033 was not accompanied by changes of heart rate and blood pressure. As expected for PDE inhibitors, pimobendan and milrinone increased cardiac contractile force in dogs, concomitant, however, with tachycardia, hypotension, and a decrease in total peripheral resistance. When regional contractility was measured separately in two different areas of the dog myocardium, the positive inotropic action of the PDE inhibitors pimobendan and milrinone was antagonized by local coronary infusion of acetylcholine. The cardiotonic effect of the Ca2+ sensitizer EMD 57,033 was entirely resistant to inhibition by acetylcholine. In conscious dogs, beta-blockade markedly attenuated the increase in LV dP/dt max produced by two different doses of the PDE III inhibitor EMD 57,439. In contrast, a dose of EMD 57,033 equieffective in positive inotropic action with the lower dose of EMD 57,439 remained unaffected by < b tau-blockade. We concluded (a) that EMD 57,033 increases cardiac contractile force in two species in vivo, (b) that this action is independent of the cardiac cyclic adenosine monophosphate (AMP) system, (c) that EMD 57,033 does not reduce blood pressure and increase heart rate, an action indicative of PDE inhibition, and (d) that, on the basis of numerous previous in vitro findings, the mechanism of action of EMD 57,033, also in vivo, is consistent with sensitization of the cardiac myofibrils to Ca2+. Of special importance is the finding that this Ca2+ sensitizer at appropriate doses may be able to improve systolic function without adverse effects on diastolic function, as indicated by a slight decrease in left ventricular end-diastolic pressure.
外消旋强心噻二嗪酮衍生物EMD 53998先前分离得到了两种具有不同药理特性的对映体：EMD 57,033，一种具有一定残余磷酸二酯酶III（PDE III）抑制作用的强效Ca2+ 增敏剂，以及EMD 57,439，一种纯PDE III抑制剂。尽管大量体外研究证明EMD 57,033能够增强心脏收缩蛋白对Ca2+ 的反应性，但缺乏这种作用的体内证据。由于无法在体内直接证明Ca2+ 增敏作用，我们试图排除PDE III抑制作用作为EMD 57,033正性肌力作用的主要促成因素。在麻醉大鼠中，EMD 57,033增加了左心室（LV）收缩压随时间变化的一阶导数（dP/dt max），而不影响血压。相比之下，PDE III抑制对映体EMD 57,439降低了血压。麻醉犬的血流动力学效应模式显示EMD 57,033与PDE抑制剂之间存在类似差异。因此，EMD 57,033引起的LV dP/dt max增加并未伴随心率和血压的变化。正如PDE抑制剂所预期的那样，匹莫苯丹和米力农增加了犬的心脏收缩力，但同时伴有心动过速、低血压和总外周阻力降低。当在犬心肌的两个不同区域分别测量局部收缩力时，PDE抑制剂匹莫苯丹和米力农的正性肌力作用被局部冠状动脉内注入乙酰胆碱所拮抗。Ca2+ 增敏剂EMD 57,033的强心作用完全不受乙酰胆碱抑制的影响。在清醒犬中，β受体阻滞剂显著减弱了两种不同剂量的PDE III抑制剂EMD 57,439所产生的LV dP/dt max增加。相比之下，与较低剂量的EMD 57,439正性肌力作用等效的EMD 57,033剂量不受β受体阻滞剂的影响。我们得出结论：（a）EMD 57,033在两种动物体内均能增加心脏收缩力；（b）这种作用独立于心脏环磷酸腺苷（AMP）系统；（c）EMD 57,033不会降低血压和增加心率，这是PDE抑制作用的表现；（d）基于先前众多体外研究结果，EMD 57,033在体内的作用机制也与心肌肌原纤维对Ca2+ 的增敏作用一致。特别重要的是，这一发现表明，这种Ca2+ 增敏剂在适当剂量下可能能够改善收缩功能，而对舒张功能无不良影响，左心室舒张末期压力略有降低即表明了这一点。
