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Cardiovascular Research 2001 50(1):56-64; doi:10.1016/S0008-6363(00)00318-7
© 2001 by European Society of Cardiology
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Copyright © 2001, European Society of Cardiology

A3 adenosine receptor stimulation modulates sarcoplasmic reticulum Ca2+ release in rat heart

Riccardo Zucchi*, Gongyuan Yu, Sandra Ghelardoni, Francesca Ronca and Simonetta Ronca-Testoni

Dipartimento di Scienze dell'Uomo e dell'Ambiente, Sezione di Biochimica, University of Pisa, via Roma 55, I-56126 Pisa, Italy

* Corresponding author. Tel.: +39-050-561-912; fax: +39-050-550-241 r.zucchi{at}med.unipi.it

Objective: Stimulation of A3 adenosine receptors has been shown to protect cardiac myocytes from ischemic injury, but the mechanism of this action is unknown. We evaluated the effect of adenosine agonists and antagonists on the sarcoplasmic reticulum (SR) Ca2+ channels. Methods: Isolated rat hearts were perfused with control buffer or different adenosine agonists and antagonists. Hearts were then homogenized and used to determine SR Ca2+-induced Ca2+ release, assayed by quick filtration technique after loading with 45Ca2+, and the binding of [3H]ryanodine, a specific ligand of the SR Ca2+ release channel. In parallel experiments, hearts were challenged with 30 min of global ischemia and 120 min of reperfusion, and the extent of tissue necrosis was evaluated by triphenyltetrazolium chloride staining. Results: Perfusion with the A1<A3 agonist R-PIA and the A3<A1 agonist IB-MECA was associated with reduced [3H]ryanodine binding, due to reduced Bmax (by about 20%), whereas Kd and Ca2+-dependence of the binding reaction were unaffected. These actions were abolished by the A3 antagonist MRS 1191, while they were not affected by A1 and A2 antagonists. The rate constant of SR Ca2+ release decreased by 25–30% in hearts perfused with R-PIA or IB-MECA. Tissue necrosis was significantly reduced in the presence of R-PIA or IB-MECA. Protection was removed by MRS 1191, and it was not affected by A1 and A2 antagonists. Hearts were also protected by administration of dantrolene, a ryanodine receptor antagonist. In the presence of dantrolene, no further protection was provided by IB-MECA. Conclusion: A3 adenosine receptor stimulation modulates the SR Ca2+ channel. This action might account for the protective effect of adenosine.

KEYWORDS Adenosine; Calcium (cellular); Ion channels; Receptors; SR (function)


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