Differential effects of uridine adenosine tetraphosphateon purinoceptors in the rat isolated perfused kidney

Abstract

BACKGROUND AND PURPOSE Purinergic signalling plays an important role in vascular tone regulation in humans. We have identified uridine adenosine tetraphosphate (Up 4A) as a novel and highly potent endothelial-derived contracting factor. Up 4A induces strong vasoconstrictive effects in the renal vascular system mainly by P2X 1 receptor activation. However, other purinoceptors are also involved and were analysed here. EXPERIMENTAL APPROACH The rat isolated perfused kidney was used to characterize vasoactive actions of Up 4A. KEY RESULTS After desensitization of the P2X 1 receptor by α,β-methylene ATP (α,β-meATP), Up 4A showed dose-dependent P2Y 2-mediated vasoconstriction. Continuous perfusion with Up 4A evoked a biphasic vasoconstrictor effect: there was a strong and rapidly desensitizing vasoconstriction, inhibited by P2X 1 receptor desensitization. In addition, there is a long-lasting P2Y 2-mediated vasoconstriction. This vasoconstriction could be blocked by suramin, but not by PPADS or reactive blue 2. In preparations of the rat isolated perfused kidney model with an elevated vascular tone, bolus application of Up 4A showed a dose-dependent vasoconstriction that was followed by a dose-dependent vasodilation. The vasoconstriction was in part sensitive to P2X 1 receptor desensitization by α,β-meATP, and the remaining P2Y 2-mediated vasoconstriction was only inhibited by suramin. The Up 4A-induced vasodilation depended on activation of nitric oxide synthases, and was mediated by P2Y 1 and P2Y 2 receptor activation. CONCLUSIONS AND IMPLICATIONS Up 4A activated P2X 1 and P2Y 2 receptors to act as a vasoconstrictor, whereas endothelium-dependent vasodilation was induced by P2Y 1/2 receptor activation. Up 4A might be of relevance in the physiology and pathophysiology of vascular tone regulation. © 2010 The British Pharmacological Society.