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Cellular and molecular pharmacological studies on a role of tyrosine kinase in the signal transduction system in cardiac cells.

酪氨酸激酶在心肌细胞信号转导系统中作用的细胞和分子药理学研究。

基本信息

批准号：
07670098
负责人：
HATTORI Yuichi
金额：
$ 1.34万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

The effects of tyrosine kinase inhibitors on the positive inotropic effect of histamine via H_1-receptors in guinea-pig left atria were examined and histamine-induced changes in phosphorylation levels of the cardiac proteins on tyrosine residues were evaluated using a recombinant antiphosphotyrosine antibody. The positive inotropic effect of histamine was depressed by the tyrosine kinase inhibitors tyrphostin A25 and genistein but not by the inactive genistein analogue daidzein. At a concentration of 1 umol/l histamine produced a dual-component positive inotropic response composed of an initial increasing phase and a second and late developing, greater positive inotropic phase. Treatment with tyrphostin A25 and genistein, but not daidzein, significantly attenuated the two components of the inotropic response, although genistein suppressed the initial component more markedly than the late component. Histamine induced a rapid but transient increase in tyrosine phosphorylation in four main clusters of proteins with approximately molecular weights of 30,35,85 and 120 kDa. histamine-induced protein tyrosine phosphorylation was antagonized by the H_1-receptor antagonist chlorpheniramine. We conclude that increased protein tyrosine phosphorylation may play an important role in initiating the positive inotropic effect of H_1-receptor stimulation in guinea-pig left atria.

研究了酪氨酸激酶抑制剂通过豚鼠左心房h_1受体对组胺正性肌力作用的影响，并利用重组抗磷酸酪氨酸抗体评价了组胺诱导的心肌蛋白对酪氨酸残基磷酸化水平的变化。酪氨酸激酶抑制剂tyrphostin A25和染料木黄酮抑制组胺的正性肌力作用，而染料木黄酮类似物大豆黄酮不抑制组胺的正性肌力作用。当组胺浓度为1 μ mol/l时，产生双组分正性肌力反应，包括初始增强期和第二个和发展较晚的更大正性肌力期。用tyrphostin A25和染料木黄酮（而不是大豆黄酮）处理，显著减弱了这两种成分的肌力反应，尽管染料木黄酮对初始成分的抑制比对后期成分的抑制更明显。组胺诱导了四个主要蛋白簇（分子量分别为30,35,85和120kda）中酪氨酸磷酸化的快速但短暂的增加。h_1受体拮抗剂氯苯那敏可拮抗组胺诱导的蛋白酪氨酸磷酸化。我们认为酪氨酸蛋白磷酸化的增加可能在启动h_1受体刺激豚鼠左心房的正性肌力作用中起重要作用。