CGP-48506 increases contractility of ventricular myocytes and myofilaments by effects on actin-myosin reaction.
CGP-48506 increases contractility of ventricular myocytes and myofilaments by effects on actin-myosin reaction.
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CGP-48506 通过影响肌动蛋白-肌球蛋白反应来增加心室肌细胞和肌丝的收缩力。
DOI：
10.1152/ajpheart.1996.270.1.h24
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Solaro,RJ
中科院分区：
文献类型：
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作者：
Wolska,BM;Kitada,Y;Palmiter,KA;Westfall,MV;Johnson,MD;Solaro,RJ
我们测定了苯二氮杂环辛衍生物CGP-48506（5-甲基-6-苯基-1，3，5，6-四氢-3，6-亚甲基-1，5-苯二氮杂环辛-2，4-二酮）对完整心肌细胞和大鼠心室肌透化纤维收缩的影响。CGP-48506的独特之处在于它能够使心肌肌丝对Ca 2+敏感，但与该类中的所有其他药物不同，它不是III型磷酸二酯酶的抑制剂。当加入到分离的完整的肌细胞，CGP-48506显着增加细胞缩短的幅度，很少或没有变化的Ca 2+瞬变，确定的荧光比率的呋喃2。CGP-48506存在时，fura 2比例与细胞长度关系的晚期向左移动。CGP-48506还诱导舒张期长度相对较小的减少。然而，与噻二嗪酮EMD-57033相比，CGP-48506在具有较大变力作用的浓度下对舒张长度的影响要小得多。当加入到洗涤剂提取的（剥皮的）纤维束的溶液中时，CGP-48506增加了最大力。CGP-48506还增加了次最大力，并使pGa-力关系向左偏移。然而，与EMD-57033相比，CGP-48506在相对高的pCa值下对力的影响较小。CGP-48506不改变Ca 2+与肌丝肌钙蛋白C的结合。CGP-48506能够逆转丁二酮单肟诱导的完整细胞和剥皮纤维束的收缩抑制。我们的研究结果表明，CGP-48506与EMD-57033一样，是一种正性肌力药物，通过肌钙蛋白C下游的直接作用发挥作用。然而，CGP-48506似乎具有独特的机制，导致对舒张功能的影响较小。
We measured the effects of the benzodiazocine derivative, CGP-48506 (5-methyl-6-phenyl-1,3,5,6-tetrahydro-3,6-methano-1, 5-benzodiazocine-2,4-dione), on contraction of intact myocytes and permeabilized fibers of rat ventricular muscle. CGP-48506 is unique in that it is able to sensitize cardiac myofilaments to Ca2+, but unlike all other agents in this class, it is not an inhibitor of type III phosphodiesterase. When added to isolated intact myocytes, CGP-48506 significantly increased the amplitude of cell shortening with little or no change in the Ca2+ transient, as determined by the fluorescence ratio of fura 2. The late phase of the relation between fura 2 ratio and cell length was shifted to the left in the presence of CGP-48506. CGP-48506 also induced a relatively small decrease in diastolic length. However, compared with the thiadiazinone EMD-57033, CGP-48506 had a much smaller effect on diastolic length at concentrations in which there was a bigger inotropic effect. When added to solutions bathing detergent-extracted (skinned) fiber bundles, CGP-48506 increased maximum force. CGP-48506 also increased submaximal force and shifted the pGa-force relation to the left. However, compared with EMD-57033, there was less of an effect of CGP-48506 on force at relatively high pCa values. CGP-48506 did not alter Ca2+ binding to myofilament troponin C. CGP-48506 was able to reverse inhibition of contraction induced by butanedione monoxime both in intact cells and in skinned fiber bundles. Our results indicate that CGP-48506, like EMD-57033, is a positive inotropic agent working through a direct effect downstream from troponin C. CGP-48506, however, appears to have a unique mechanism resulting in less effect on diastolic function.