A NOVEL POSITIVE INOTROPIC SUBSTANCE ENHANCES CONTRACTILITY WITHOUT INCREASING THE CA-2+ TRANSIENT IN RAT MYOCARDIUM
A NOVEL POSITIVE INOTROPIC SUBSTANCE ENHANCES CONTRACTILITY WITHOUT INCREASING THE CA-2+ TRANSIENT IN RAT MYOCARDIUM
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DOI：
10.1016/0022-2828(91)90068-w
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发表时间：
1991-03-01
影响因子：
5
通讯作者：
CAPOGROSSI, MC
中科院分区：
文献类型：
--
作者：
FERRONI, C;HANO, O;CAPOGROSSI, MC
我们研究了一种新的正性肌力药物，噻二嗪酮衍生物5-（1-（3，4-二甲氧基苯甲酰基）-1，2，3，4-四氢喹啉-6-基）-6-甲基-3，6-二氢-2H-1，3，4-噻二嗪-2-酮（EMD 53998）的作用机制。这种物质抑制磷酸二酯酶III，并在皮肤心肌纤维，它增加肌丝对Ca 2+的敏感性。然而，EMD 53998对完整心肌制备物的影响仍然不确定。在离体大鼠心脏中，EMD 53998（0.5至5 μm）具有剂量依赖性的增加左心室收缩压的作用。在负载钙离子探针indo-1的酯衍生物的离体左心室肌细胞中，EMD 53998（0.5至5 μm）增强了颤搐幅度，而不增加相关的indo-1瞬变。肌丝对Ca 2+的反应性被评估为抽搐和indo-1瞬时振幅之间的关系，因为后者通过改变洗澡[Ca 2 +]或刺激模式而变化。EMD 53998可逆地将这种关系向左移动，这表明对于在不存在和存在药物的情况下相同幅度的indo-1瞬变，EMD 53998增强了抽搐幅度。在分离的肌细胞研究中，在没有电刺激，EMD 53998。(1.5至5 μm）具有浓度依赖性效应，显著且可逆地缩短细胞长度，而不增加indo-1荧光比率。因此，EMD 53998在大鼠心肌中的正性肌力作用的细胞基础与该物质增强肌丝对Ca 2+的反应性的独特作用有关，而与indo-1瞬时振幅的增加无关。
We have investigated the mechanism of action of a novel positive inotropic agent, the thiadiazinone derivative 5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydrochinolin-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-on (EMD 53998). This subsance inhibits phosphodiesterase III and, in skinned myocardial fibers, it increases myofilament sensitivity to Ca2+. However the effects of EMD 53998 on intact myocardial preparations are still undefined. In isolated rat hearts EMD 53998 (0.5 to 5 μm) had a dose-dependent effect to increase left ventricular systolic pressure. In isolated left ventricular myocytes loaded with the ester derivative of the Ca2+probe indo-1, EMD 53998 (0.5 to 5 μm) enhanced twitch amplitude without increasing the associated indo-1 transient. The myofilament responsiveness to Ca2+was assessed as the relationship between twitch and the indo-1 transient amplitudes as the latter is varied by altering the bathing [Ca2+], or stimulation pattern. EMD 53998 reversibly shifted this relationship to the left which indicates that for indo-1 transients of the same amplitude in the absence and presence of the drug, twitch amplitude was enhanched by EMD 53998. In isolated myocytes studied in the absence of electrical stimulation, EMD 53998. (1.5 to 5 μm) had a concentration-dependent effect to markedly and reversibly decrease cell length without increasing indo-1 fluorescence ratio. Thus, the cellular basis for the positive inotropic action of EMD 53998 in rat myocardium is related to the unique effect of this substance to enhance myofilament responsiveness to Ca2+and not to an increase in the indo-1 transient amplitude.