The stable pyrimidines UDPβS and UTPγS discriminate between the P2 receptors that mediate vascular contraction and relaxation of the rat mesenteric artery

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Abstract
The contractile and relaxant effects of the different P2 receptors were characterized in the rat isolated mesenteric artery by use of extracellular nucleotides, including the stable pyrimidines uridine 5′‐O‐thiodiphosphate (UDPβS) and uridine 5′‐O‐3‐thiotriphosphate (UTPγS). The selective P2X receptor agonist, αβ‐methylene‐adenosine triphosphate (αβ‐MeATP) stimulated a potent (pEC50=6.0) but relatively weak contraction (Emax=57% of 60 mM K+). The contractile concentration‐response curve of adenosine triphosphate (ATP) was biphasic when added in single concentrations. The first part of the response could be desensitized by αβ‐MeATP, indicating involvement of P2X receptors, while the second part might be mediated by P2Y receptors. The contractile P2Y receptors were further characterized after P2X receptor desensitization with 10 μM αβ‐MeATP. Uridine diphosphate (UDP), uridine triphosphate (UTP) and ATP stimulated contraction only in high concentrations (1–10 mM). The selective P2Y6 agonist, UDPβS, and the P2Y2/P2Y4‐receptor agonists UTPγS and adenosine 5′‐O‐3‐thiotriphosphate (ATPγS) were considerably more potent and efficacious (Emax∼250% of 60 mM K+). Adenosine 5′‐O‐thiodiphosphate (ADPβS) was inactive, excluding contractile P2Y1 receptors. After precontraction with 1 μM noradrenaline, UTP, ADP and ATP induced relaxations with similar potencies (pEC50∼5.0). UTPγS, ADPβS and ATPγS were approximately one log unit more potent indicating the presence of endothelial P2Y1 and P2Y2/P2Y4 receptors. The P2Y6 receptor agonist, UDPβS, had no effect. UDPβS and UTPγS are useful tools when studying P2 receptors in tissue preparations with ectonucleotidase activity. Contractile responses can be elicited by stimulation of P2Y6 and, slightly less potently, P2Y2/P2Y4 receptors. The P2X response was relatively weak, and there was no P2Y1 response. Stimulation of P2Y1 and P2Y2/P2Y4 receptors elicited relaxation, while P2Y6 did not contribute. British Journal of Pharmacology (2000) 131, 51–56; doi:10.1038/sj.bjp.0703536