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

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 t he sarcoplasmic reticulum (SR) Ca2+ channels. Methods: Isolated rat hearts were perfused with control buffer or different adenosine agonists and antag onists. Hearts were then homogenized and used to determine SR Ca2+-induced Ca2+ release, assayed by quick filtration technique after loading with Ca-4 5(2+), and the binding of [H-3]ryanodine, a specific ligand of the SR Ca2release channel. In parallel experiments, hearts were challenged with 30 mi n of global ischemia and 120 min of reperfusion, and the extent of tissue n ecrosis was evaluated by triphenyltetrazolium chloride staining. Results: P erfusion with the A1>A3 agonist R-PIA and the A3>A1 agonist IB-MECA was ass ociated with reduced [H-3]ryanodine binding, due to reduced B-max (by about 20%), whereas K-d and Ca2+-dependence of the binding reaction were unaffec ted. 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+ r elease 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. Pr otection was removed by MRS 1191, and it was not affected by A1 and A2 anta gonists. Hearts were also protected by administration of dantrolene, a ryan odine receptor antagonist. In the presence of dantrolene, no further protec tion was provided by IB-MECA. Conclusion: A3 adenosine receptor stimulation modulates the SR Ca2+ channel. This action might account for the protectiv e effect of adenosine. (C) 2001 Elsevier Science B.V. All rights reserved.