Mediation of adenosine effects in ventricular myocardium by receptor subtype.

摘要

Adenosine has multiple effects upon the heart including bradycardia, decreased action potential duration, decreased conduction velocity, and vasodilation. These effects are mediated by various adenosine receptors on distinct cell types. However, the two known effects of adenosine on entricular myocardium, namely, the negative modulation of beta-adrenergic-stimulated increases in inotropy (anti-adrenergic) and reduction of post-ischemic injury, are indirect and have been associated with adenosine A1 receptor activation.; Recent studies with a purportedly selective A3 receptor agonist have suggested that A3 receptor activation is also cardioprotective. Additionally, mixed reports exist regarding A2a agonist-stimulated increases in inotropy. The aim of this study was to characterize the effects of A3 and A2a receptor activation on the ventricular myocardium.; The A3 agonist 2-chloro-N6-(3-iodobenzyl)-adenosine-5 '-N-methyluronamide (CI-IB-MECA, 50 nM) produced a level of cardioprotection equal to that of adenosine (100 muM) and the A1 agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 200 nM) in the isolated rat heart. However, protection by both adenosine and CI-IB-MECA was completely abolished by treatment with the A1 antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 100 nM). Further, in isolated rabbit hearts, cardioprotection by another A3 agonist N6-(3-iodobenzyl)-adenosine-5 '-N-methyluronamide (IB-MECA, 50 nM) was blocked by both DPCPX (100 nM) and the non-specific methylxanthine adenosine antagonist 8- p-sulfophenyltheophylline (8-SPT, 5 muM). Finally, CI-IB-MECA (50 nM) was ineffective at reducing the positive inotropic effects of the beta-adrenergic agonist isoproterenol (ISO, 10 nM) in the rat. That A3 agonist-induced cardioprotection could be blocked with A1 antagonists and A 3 agonist application provided no anti-adrenergic effect suggests a minimal role of A3 receptor participation in these effects.; The application of the A2a agonist 2-[4-[(2-carboxyethyl)phenyl]ethylamino]-5 '-N-ethylcarboxamidoadenosine (CGS 21680, 100 nM) produced no changes in developed pressure in Langendorff-perf used rat hearts. Neither did that dose of CGS 21680 alter myocyte twitch amplitude or cAMP accumulation. Despite lack of functional effects, western blot analysis revealed the presence of the A2a receptor protein in isolated rat ventricular myocytes.; In conclusion, A3 agonist effects appear to be mediated via A1 receptor activation and A2a agonists are without contractile effects. Therefore, the results of this study suggest that the effects of adenosine in ventricular myocardium are mediated only by activation of the A1 receptor.