Adenosine mediates nitric-oxide-independent renal vasodilation by activation of A2A receptors

Objective Adenosine dilates rabbit renal arteries by an endothelium-dependent, nitric oxide (NO)- and prostaglandin-independent mechanism. The aim was to identify the responsible P1-purinoceptor subtype and to investigate the involvement of K+-channels. Methods Rabbit renal arteries were perfused with medium containing indomethacin (10 mu mol/l). After preconstriction with noradrenaline (0.4 mu mol/l), changes in vessel diameter by P1-purinoceptor agonists were measured with a photoelectric device. The P1 -receptor subtype was characterised by selective antagonists. Results Adenosine caused concentration-dependent dilation (EC50 similar to 7 mu mol/l). The mRNA for A(1), A(2A) and A(3) receptors were demonstrated by reverse transcription-polymerase chain reaction from total RNA of renal arteries. The agonists CPCA (A(2)) and CGSP1680 (A(2A)) dilated renal arteries (EC50 similar to 0.1 mu mol/l), and CPA (A(1)) was ineffective. As demonstrated by experiments using two arteries in sequence, CPCA induced release of an endothelium-derived relaxing factor. NO synthase inhibition by NG-nitro-L-arginine methyl ester (L-NAME) had no effect on CPCA-induced dilation. The concentration-response curves of adenosine, CPCA and CGS21680 were shifted to the right by the A(2A) antagonist ZM241385 (1 mu mol/l), but not by the A(1) and A(3) antagonists DPCPX (1 mu mol/l) and MRS1220 (1 mu mol/l). Iberiotoxin (0.1 mu mol/l), a blocker of Ca2+-activated K+-channels, slightly shifted the dose-response curve of CPCA, Arteries preconstricted by KCl showed dilation to CPCA, but not to acetylcholine chloride (ACh). Conclusion Adenosine induces dilation of rabbit renal arteries through activation of A(2A) receptors. This effect depends on the release of an endothelium-derived relaxing factor, which is not NO. Dilation by ACh in the presence of L-NAME is likely to be mediated by K+ as an endothelium-derived relaxing factor. However, in the A(2A)- receptor-induced dilation of rabbit renal arteries, K+ does not play this role, suggesting the involvement of a further soluble factor in the receptor-induced dilatory function of the endothelium. (C) Lippincott Williams & Wilkins.