NOVEL POSITIVE CARDIAC INOTROPIC AGENTS

所有可用于临床使用的正性肌力药物运动 它们的作用主要是通过增加细胞钙负荷。 然而，一旦心肌准备达到其收缩峰值， 响应细胞钙负荷的进一步增加与初始 随着平台期的出现， 肌肉，舒张张力增加，后收缩和心律失常。 这种被定义为“钙超载”的状况代表了 正性肌力药物临床应用的限制因素。 因此 需要开发增加心脏收缩力的药物 通过增强肌丝对钙的反应性，而不是通过 增加细胞钙负荷的程度。 我们测试了 新的噻二嗪酮衍生物（由E.默克公司、达姆施塔特、联邦德国） （1）使皮肤心肌纤维对Ca 2+敏感的效力各不相同：EMD 54622大于或等于53998 > 54650，以及（2）抑制 细胞匀浆中的磷酸二酯酶III（54650大于或等于 53998 > 54622）。 我们确定了差异性Ca 2+ -肌丝是否 在Hepes缓冲液中浸泡的完整豚鼠细胞中表达效应 (23℃），并装载荧光Ca 2+探针indo-1。 我们 结果表明，抽搐和indo-1之间的关系的陡度 在药物剂量范围内测量的荧光瞬变变化为54622 > 53998 > 54650。 因此，肌丝Ca 2+ 完整细胞中的反应可以通过以下分子修饰来实现： 噻二嗪酮增强其对肌丝对Ca 2+敏感性的效力。

All positive inotropic agents that are available for clinical use exercise their effect predominately via an increase in cell calcium loading. However, once the myocardial preparation has reached its peak contractile response a further increase in cell calcium loading is associated initially with a plateau and then with a decline in the inotropic state of the muscle, an increase in diastolic tone, aftercontractions and arrhythmias. This condition which has been defined as "calcium overload" represents the limiting factor in the clinical use of positive inotropic agents. Thus, it is desirable to develop drugs that increase the contractility of the heart via an enhancement in myofilament responsiveness to calcium rather than by increasing the extent of cell calcium loading. We tested the effect of novel thiadiazinone derivatives (designed by E. Merck, Darmstadt, FRG) that vary in potency (1) to sensitize skinned myocardial fibers to Ca 2+: EMD 54622 greater than or equal to 53998 > 54650, and (2) to inhibit phosphodiesterase III in cell homogenates (54650 greater than or equal to 53998 > 54622). We determined whether differential Ca 2+ -myofilament effects are expressed in intact guinea pig cells, bathed in Hepes buffer (23 degrees C) and loaded with the fluorescent Ca 2+ probe, indo-1. Our results show that the steepness of relationship among twitches and indo-1 fluorescence transients measured across drug dose varies as 54622 > 53998 > 54650. Thus, differential modifications of the myofilament Ca 2+ response in intact cells can be effected via molecular modifications of thiadiazinone that enhance its potency to sensitize myofilaments to Ca 2+.