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Insights into adenosine A 1 and A 3 receptors function: Cardiotoxicity and cardioprotection
Author(s) -
Shneyvays Vladimir,
Safran Noam,
HaliliRutman Irit,
Shainberg Asher
Publication year - 2000
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/1098-2299(200007/08)50:3/4<324::aid-ddr16>3.0.co;2-b
Subject(s) - ccpa , adenosine , adenosine a3 receptor , cardioprotection , adenosine receptor , adenosine a1 receptor , agonist , pharmacology , chemistry , endocrinology , medicine , receptor , biology , biochemistry , ischemia
Adenosine (ADO) is a well‐known regulator of a variety of physiological functions in the heart. It exerts protective effects in the heart by activation of the adenosine receptors (AR). In stress conditions like hypoxia or ischemia, the concentration of ADO in the extracellular space rises dramatically. This elevated amount of adenosine might protect the heart from the hypoxic damage. It has been also shown that adenosine can significantly decrease doxorubicin (DOX)‐induced heart toxicity. An highly selective A 1 receptor (A 1 R) agonist CCPA (2‐chloro‐N 6 ‐ cyclopentyladenosine) and A 3 R agonists IB‐MECA or Cl‐IB‐MECA (2‐chloro‐N 6 ‐(3‐iodobenzyl)adenosine‐5′‐N‐ methyluronamide) have been shown to protect against hypoxia or DOX. Blocking adenosine receptors with selective A 1 and A 3 receptor antagonists DPCPX (8‐cyclopentyl‐1‐3‐dipropylxanthine) for A 1 R and MRS1523 [5‐propyl‐2‐ethyl‐4‐propyl‐3‐ (ethylsulfanylcarbonyl)‐6‐phenylpyridine‐5‐ carboxylate] for A 3 R abolished the protective effects of adenosine. In addition the mean survival time of cardiomyocytes cultures treated with ADO together with DOX was significantly increased. However, at high concentrations A 3 R agonists IB‐MECA, Cl‐IB‐MECA (≥10 μM), or ADO (200 μM) induced apoptosis. Under these conditions, A 1 R, A 2A R, and A 2B R agonists did not have any detectable effect on cardiac cells. The selective antagonist MRS1523 protected the cardiocytes if briefly exposed to Cl‐IB‐MECA and only partially protected from prolonged (48 h) agonist exposure. Apoptosis induced by Cl‐IB‐MECA was not redox‐dependent, since the mitochondrial membrane potential remained constant until the terminal stages of cell death. Drug Dev. Res. 50:324–337, 2000. © 2000 Wiley‐Liss, Inc.