Purinoceptors mediate renal vasodilation by nitric oxide dependent and independent mechanisms.

Abstract

Adenosine triphosphate (ATP) and its metabolites including adenosine modulate renal vascular tone under physiological and pathophysiological conditions. Their effects are brought about by activation of membrane bound P1- and P2-purinoceptors located on smooth muscle and endothelial cells. In this study we analyzed the purinoceptor mediated dilation of rabbit and human renal arteries, and evaluated the possible involvement of endothelium-derived relaxing factors. Segments of rabbit and human renal arteries were incubated and perfused with medium containing indomethacin. After preconstriction, drug induced changes in the vessel diameters were measured by a photoelectric device. ATP (EC50 = 1 mumol/liter), added intraluminally, caused maximal vasodilation of 80 to 100% of the preconstriction response in both species. This effect was inhibited by the P1-purinoceptor antagonist 8-p-(sulphophenyl)theophylline (100 mumol/liter), suggesting that it was in part due to breakdown of ATP to adenosine. The nature of purinoceptor mediated renal vasodilation was studied further in rabbit renal arteries. Adenosine (EC50 = 1 mumol/liter) as well as the P2Y-receptor agonists ADP beta S (EC50 = 0.4 mumol/liter) and 2-MeSATP (EC50 = 0.2 mumol/liter) dilated the arteries by 80 to 100%. The effects of 2-MeSATP, which were to a much lesser extent that of ADP beta S but not that of adenosine, were attenuated by the P2Y-antagonist reactive blue 2 (3 mumol/liter). Removal of the endothelium almost abolished the vasodilation induced by adenosine and ATP. In contrast, these dilator response were only slightly attenuated by the nitric oxide synthase blockers NG-nitro-L-arginine methyl ester and NG-nitro-L-arginine (300 mumol/liter each), whereas acetylcholine and 2-MeSATP induced dilation was markedly reduced by NG-nitro-L-arginine methyl ester. P1-purinoceptors activated by adenosine dilate rabbit renal arteries by an endothelium-derived relaxing factor that appears to be distinct from nitric oxide. In contrast, P2Y-purinoceptor induced renal dilation is mediated by nitric oxide. ATP, the physiological activator of P2Y-purinoceptors, is rapidly broken down to adenosine in rabbit and human renal arteries. Therefore, in rabbit and human renal arteries the vasodilatory effect of exogenous ATP mainly results from P1-purinoceptor activation probably through its breakdown product, adenosine.