Negative lusitropy and abnormal calcium handling in hypoxic cardiac myocytes exposed to the calcium-sensitizer EMD 53998.
Negative lusitropy and abnormal calcium handling in hypoxic cardiac myocytes exposed to the calcium-sensitizer EMD 53998.
复制标题
暴露于钙敏化剂 EMD 53998 的缺氧心肌细胞出现负松弛性和异常的钙处理。
DOI：
10.1006/jmcc.1993.1087
复制
发表时间：
1993
影响因子：
5
通讯作者：
Bishopric,NH
中科院分区：
文献类型：
--
作者：
Webster,KA;Bodi,I;McNamara,JP;Tracy,M;Discher,DJ;Bishopric,NH
最近已经描述了增加肌丝对钙的敏感性的正性肌力药（Kitadaet al.，1987; Gottneyet等人，1990; Ferroniet等人，1991; Lee和艾伦，1991; Beieret等人，1992年）。这些药物似乎不依赖于cAMP或钙而增强收缩力，因此可能具有与其他现有药物相比更少的不良副作用（Katz，1986; Packer 1989）。“钙增敏剂”的临床效用受到质疑，其理论依据是此类药物可能干扰舒张并损害舒张功能（Hajjar和Gwathmey，1991）。先前的研究表明，钙增敏剂EMD 53998在雪貂乳头肌中具有较小但显著的负向效应，尽管这种效应被认为是收缩力的强大增强所超过。模拟研究表明，当心肌钙异常升高时，如缺氧（艾伦和果园，1987; Lodge和Gelband，1988）和终末期心力衰竭（Hajjar和Gwathmey，1991），钙增敏剂对舒张的损害可能更为严重。我们研究了EMD 53998和米力农对心肌缺氧细胞培养模型的收缩力和钙流的影响。结果表明，增加钙敏感性的结果在缺氧条件下的松弛显着损害，可能是由于受损的钙螯合和缺氧心肌细胞表现出的钙可用性增加。这些研究表明，钙增敏剂的作用可能受到细胞内钙处理的主要状态的强烈影响，并且可能对患病或缺血心肌有害。
Positive inotropic agents that increase the sensitivity of myofilaments to calcium have recently been described (Kitadaet al., 1987; Gottneyet al., 1990; Ferroniet al., 1991; Lee and Allen, 1991; Beieret al., 1992). These drugs appear to augment contractility independently of cAMP or calcium, and thus may have fewer of the adverse side effects seen with other currently available agents (Katz, 1986; Packer 1989). The clinical utility of "calcium-sensitizers" has been questioned on the theoretical grounds that such agents may interfere with relaxation and impair diastolic function (Hajjar and Gwathmey, 1991). Previous studies have shown a small but significant negative lusitropic effect of the calcium sensitizer EMD 53998 in ferret papillary muscle, although this effect was considered to be outweighed by powerful augmentation of contractility. Modelling studies have suggested that the impairment of relaxation by calcium-sensitizers may be even more severe when myocardial calcium is abnormally elevated, such as in hypoxia (Allen and Orchard, 1987; Lodge and Gelband, 1988) and end-stage heart failure (Hajjar and Gwathmey, 1991). We have examined the effects of EMD 53998 and milrinone on contractility and calcium flux in a cell culture model of myocardial hypoxia. The results indicate that increased calcium sensitivity results in marked impairment of relaxation under hypoxic conditions, possibly due to the impaired calcium sequestration and increased calcium availability exhibited by hypoxic myocytes. These studies show that the effects of calcium sensitizers can be strongly influenced by the prevailing status of intracellular calcium handling, and may be deleterious in the diseased or ischemic myocardium.