Induction of apoptosis in cardiac myocytes by an A3 adenosine receptor agonist

被引:72
作者
Shneyvays, V
Nawrath, H
Jacobson, KA
Shainberg, A [1 ]
机构
[1] Bar Ilan Univ, Dept Life Sci, Otto Meyerhoff Drug Receptor Ctr, Ramat Gan, Israel
[2] Univ Mainz, Inst Pharmacol, D-6500 Mainz, Germany
[3] NIH, Mol Recognit Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA
关键词
adenosine receptors; apoptosis; Feulgen-staining; image analysis; cultured cardiomyocyte; Ca2+ transients; light and electron microscopy;
D O I
10.1006/excr.1998.4134
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The effects of the selective adenosine (ADO) A(3) receptor agonist IB-MECA (N-6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide) on cultured newborn rat cardiomyocytes were examined in comparison with ADO, the ADO A, receptor-selective agonist R-PIA (N-6-R-phenylisopropyladenosine), or the ADO A(3) selective antagonist MRS 1191 (3-ethyl-5-benzyl-2-methyl-6-phenyl-4-phenylethynyl-1,4-(+/-)-dihydropyride-3,5 dicarboxylate), using digital image analysis of Feulgen-stained nuclei, At high concentration, IB-MECA (greater than or equal to 10 mu M) and ADO (200 mu M) induced apoptosis; however, R-PIA or MRS 1191 did not have any detectable effects on cardiac cells. In addition, DNA breaks in cardiomyocytes undergoing apoptosis following treatment by IB-MECA were identified in situ using the nick end labeling of DNA ('TUNEL"-like) assay. In the presence of greater than or equal to 10 mu M IB-MECA, disorder in the contraction waves appeared, and a decrease in the frequency of beats was observed. Analysis with light microscopy revealed that the number of contracting cells decreased in a concentration-dependent manner. The A(3) receptor agonist IB-MECA caused an increase in intracellular free calcium concentration ([Ca2+](i)). The drug produced a rapid rise followed by a sustained increase in [Ca2+](i), which lasted for 40-60 s, Finally, cessation of beating and Ca2+ transients were observed, Full recovery of contractile activity and rhythmical Ca2+ transients were observed 15-20 min after IB-MECA treatment. The induction of apoptosis in the cardiocytes by IB-MECA led to the appearance of features of apoptotic nuclei: the onset of condensation, compacting, and margination of nuclear chromatin. These effects were accompanied by the disintegration of the structural framework of the nucleus and nuclear breakdown. The results suggest that activation of the A(3) adenosine receptor may participate in the process of apoptosis in cardiomyocytes. (C) 1998 Academic Press.
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页码:383 / 397
页数:15
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