Calcium sensitization as new principle of inotropic therapy in end-stage heart failure?
Calcium sensitization as new principle of inotropic therapy in end-stage heart failure?
复制标题
钙增敏作为终末期心力衰竭正性肌力治疗的新原则？
DOI：
10.1016/s1010-7940(98)00129-8
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Hasso Scholz
中科院分区：
文献类型：
--
作者：
Norbert Zimmermann;P. Boknı́k;E. Gams;Joachim W. Herzig;Joachim Neumann;Hasso Scholz
目的：由于供体心脏的短缺和终末期心脏病患者等待名单的增加，需要新的桥接治疗的药理学原则。cAMP增加药物（例如，儿茶酚胺、磷酸二酯酶抑制剂）的正性肌力作用在衰竭心肌中减弱。因此，我们调查的有用性和机制的两个钙增敏剂，左西孟旦和CGP 48506在准备从终末期失败的人的心脏，因为正性肌力作用的确切机制尚未明确understood.Methods：失败的人的心脏，需要原位心脏移植，由于特发性扩张型心肌病进行了研究。使用心室肌条进行收缩实验。在皮肤纤维和磷酸二酯酶活性测定心室匀浆中的钙敏感性进行了研究。结果：左西孟旦（10μmol/l）使衰竭的人心肌条的收缩力仅增加到给药前的112.8±6.7%。相比之下，CGP 48506在100μmol/l时将收缩力增加至给药前值的311±59%。在100μmol/l浓度下，达到峰值张力的时间和松弛时间分别增加至对照水平的175±4%和205±15%。从衰竭的人心脏的皮肤纤维被钙敏化，EC 50为10μmol/l。其他作用机制被排除在外，因为CGP 48506既不影响失败的人心脏中磷酸二酯酶同工酶I-IV的活性，也不影响豚鼠心肌细胞中的cAMP水平。另一方面，左西孟旦（1μmol/l）使cAMP含量从6.3±0.3 pmol/mg蛋白增加到8.1± 0.3pmol/mg蛋白。结论：CGP 48506是一种具有钙增敏作用的强心药，对人心脏磷酸二酯酶同工酶无抑制作用。因此，它提供了一种新形式的正性肌力治疗，可用于移植前心力衰竭的桥接治疗。另一方面，左西孟旦是一种钙增敏剂，表现出较不有效的正性肌力作用，伴随着cAMP水平的增加。
Objective: Due to shortage of donor hearts and increasing waiting-lists of patients with end-stage heart disease, new pharmacological principles for bridging therapies are necessary. The positive inotropic effects of cAMP-increasing drugs (e.g. catecholamines, phosphodiesterase-inhibitors) are diminished in the failing myocardium. Hence, we investigated the usefulness and mechanism of the two calcium sensitizers, levosimendan and CGP 48506 in preparations from end-stage failing human hearts since the exact mechanism of the positive inotropic effects is not yet clearly understood.Methods: Failing human hearts which required orthotopic heart transplantation due to idiopathic dilated cardiomyopathy were investigated. Contraction experiments were performed using muscle strips of ventricles. Calcium sensitization was investigated in skinned fibers and phosphodiesterase activity was measured in ventricular homogenate. In addition, cAMP levels were quantified in myocytes from guinea-pig hearts.Results: In muscle stripes from failing human hearts levosimendan (10μmol/l) increased the force of contraction only to 112.8±6.7% of predrug values. In contrast, CGP 48506 increased the force of contraction to 311±59% of predrug values at 100μmol/l. The time to peak tension and time of relaxation were increased to 175±4% and 205±15% of control levels at 100μmol/l. Skinned fibers from failing human hearts were sensitized to calcium with an EC50of 10μmol/l. Other mechanisms of action were excluded since CGP 48506 affected neither the activity of phosphodiesterase isoenzymes I–IV in failing human hearts, nor cAMP levels in guinea-pig cardiomyocytes. On the other hand, levosimendan (1μmol/l) increased cAMP content from 6.3±0.3 to 8.1±0.3 pmol/mg protein.Conclusion: CGP 48506 is an inotropic agent with calcium-sensitizing properties in the human heart, that is devoid of inhibitory activity on human cardiac phosphodiesterase isoenzymes. It offers, therefore, a new form of positive inotropic therapy that can be useful for the bridging treatment of heart failure before transplantation. On the other hand, levosimendan is a calcium sensitizer showing less-effective inotropic effects accompanied by increased cAMP levels.
影响因子：
20.1
作者：
GAO, WD;ATAR, D;MARBAN, E
通讯作者：
MARBAN, E
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
发表时间：
1996
期刊：
The American journal of physiology.
影响因子：
--
作者：
Wolska,BM;Kitada,Y;Palmiter,KA;Westfall,MV;Johnson,MD;Solaro,RJ
通讯作者：
Solaro,RJ
正性肌力药物在慢性心力衰竭治疗中的潜在有害作用。
影响因子：
37.8
作者：
Katz,AM
通讯作者：
Katz,AM