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


Prof Markus van der Giet, Charite – Universitätsmedizin Berlin, Medical. Klinik mit Schwerpunkt Nephrologie, Hindenburgdamm 30, 12203 Berlin. E-mail: markus.vandergiet@charite.de


BACKGROUND AND PURPOSE Purinergic signalling plays an important role in vascular tone regulation in humans. We have identified uridine adenosine tetraphosphate (Up4A) as a novel and highly potent endothelial-derived contracting factor. Up4A induces strong vasoconstrictive effects in the renal vascular system mainly by P2X1 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 Up4A.

KEY RESULTS After desensitization of the P2X1 receptor by α,β-methylene ATP (α,β-meATP), Up4A showed dose-dependent P2Y2-mediated vasoconstriction. Continuous perfusion with Up4A evoked a biphasic vasoconstrictor effect: there was a strong and rapidly desensitizing vasoconstriction, inhibited by P2X1 receptor desensitization. In addition, there is a long-lasting P2Y2-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 Up4A showed a dose-dependent vasoconstriction that was followed by a dose-dependent vasodilation. The vasoconstriction was in part sensitive to P2X1 receptor desensitization by α,β-meATP, and the remaining P2Y2-mediated vasoconstriction was only inhibited by suramin. The Up4A-induced vasodilation depended on activation of nitric oxide synthases, and was mediated by P2Y1 and P2Y2 receptor activation.

CONCLUSIONS AND IMPLICATIONS Up4A activated P2X1 and P2Y2 receptors to act as a vasoconstrictor, whereas endothelium-dependent vasodilation was induced by P2Y1/2 receptor activation. Up4A might be of relevance in the physiology and pathophysiology of vascular tone regulation.