Abnormal intracellular calcium handling, a major cause of systolic and diastolic dysfunction in ventricular myocardium from patients with heart failure.
Abnormal intracellular calcium handling, a major cause of systolic and diastolic dysfunction in ventricular myocardium from patients with heart failure.
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发表时间：
1990-02
期刊：
影响因子：
37.8
通讯作者：
J. P. Morgan;Raymond E. Erny;P. Allen;William Grossman;J. Gwathmey
中科院分区：
文献类型：
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作者：
J. P. Morgan;Raymond E. Erny;P. Allen;William Grossman;J. Gwathmey
细胞内Ca 2+的释放和再摄取是人体心脏正常收缩和舒张所必需的。用水母发光蛋白记录终末期心力衰竭患者心肌等长收缩过程中细胞内钙瞬变。与对照组相比，衰竭心脏肌肉的收缩和Ca 2+瞬变显着延长，并且Ca 2+瞬变表现出两种不同的成分。衰竭心脏的肌肉显示出恢复低静息Ca 2+水平的能力减弱。这些数据表明，在积极收缩的人心肌细胞内的Ca 2+处理是异常的，可能会导致心脏衰竭的收缩和舒张功能障碍。用于增加细胞内环磷酸腺苷（AMP）水平的药物（如β-肾上腺素能激动剂和磷酸二酯酶抑制剂）的变力作用在心力衰竭患者的肌肉中显著降低。相比之下，保留了通过环AMP非依赖性机制起作用的药物（如强心类固醇和DPI 201-106）的变力性刺激的有效性。腺苷酸环化酶激活剂毛喉素刺激细胞内环AMP的产生恢复了对磷酸二酯酶抑制剂的正性肌力反应。这些研究表明，环AMP产生的异常可能是终末期心力衰竭患者的一个根本缺陷，可能会显着降低依赖于这种核苷酸产生正性肌力作用的药物的有效性。此外，环磷酸腺苷的生产不足似乎，至少在一定程度上，占逆转的力-频率的关系，其特点是失败的心肌。感兴趣的是，直接测量总细胞环AMP含量和蛋白激酶活性没有发现控制和肌病组织之间的显着差异，这表明存在于人体心室肌的生理上不同的区室化池的环AMP。最后，收缩器官对Ca 2+的敏感性的变化似乎也在肌病与正常人心肌对药物的不同反应中起重要作用。
Intracellular Ca2+ release and reuptake are necessary for normal contraction and relaxation of the human heart. Intracellular Ca2+ transients were recorded with aequorin during isometric contraction of myocardium from patients with end-stage heart failure. In contrast to controls, contractions and Ca2+ transients of muscles from failing hearts were markedly prolonged, and the Ca2+ transients exhibited two distinct components. Muscles from the failing hearts showed a diminished capacity to restore a low resting Ca2+ level during diastole. These data obtained in actively contracting human myocardium suggest that intracellular Ca2+ handling is abnormal and might cause both systolic and diastolic dysfunction in heart failure. The inotropic effectiveness of drugs that act to increase intracellular levels of cyclic adenosine monophosphate (AMP), such as beta-adrenergic agonists and phosphodiesterase inhibitors, was markedly reduced in muscles from patients with heart failure. In contrast, the effectiveness of inotropic stimulation with drugs that act by cyclic AMP-independent mechanisms, such as the cardiotonic steroids and DPI 201-106, were preserved. Stimulation of intracellular cyclic AMP production by the adenylate cyclase activator forskolin restored the inotropic response to phosphodiesterase inhibitors. These studies indicate that an abnormality in cyclic AMP production may be a fundamental defect in patients with end-stage heart failure that may markedly diminish the effectiveness of agents that depend on generation of this nucleotide for a positive inotropic effect. Moreover, deficient production of cyclic AMP seems, at least in part, to account for the reversal of the force-frequency relation that characterizes failing myocardium. Of interest, direct measurement of total cellular cyclic AMP content and protein kinase activity did not reveal significant differences between the control and myopathic tissue, suggesting the presence in human ventricular muscle of physiologically distinct compartmentalized pools of cyclic AMP. Finally, changes in the sensitivity of the contractile apparatus to Ca2+ also seem to play an important role in the differential responsiveness to drugs of myopathic versus normal human myocardium.