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

1 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 (UDP beta S) and uridine 5'-O-3-thiotriphosphate (UTP gamma S). 2 The selective P2X receptor agonist, alpha beta-methylene-adenosine triphosphate (alpha beta-MeATP) stimulated a potent (pEC(50)=6.0) but relatively weak contraction (E-max=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 alpha beta-MeATP, indicating involvement of P2X receptors, while the second part might be mediated by P2Y receptors. 3 The contractile P2Y receptors were further characterized after P2X receptor desensitization with 10 mu M alpha beta-MeATP. Uridine diphosphate (UDP), uridine triphosphate (UTP) and ATP stimulated contraction only in high concentrations (1-10 mh I). The selective P2Y(6) agonist, UDP beta S, and the P2Y(2)/P2Y(4)-receptor agonists UTP gamma S and adenosine 5'-O-3-thiotriphosphate (ATP gamma S) were considerably more potent and efficacious (E(max)approximate to 250% of 60 mM K+). Adenosine 5'-O-thiodiphosphate (ADP beta S) was inactive, excluding contractile P2Y, receptors. 4 After precontraction with 1 mu M noradrenaline, UTP, ADP and ATP induced relaxations with similar potencies (pEC(50)approximate to 5.0). UTP gamma S, ADP beta S and ATP gamma S were approximately one log unit more potent indicating the presence of endothelial P2Y(1) and P2Y(2)/P2Y(4) receptors. The P2Y(6) receptor agonist, UDP beta S, had no effect. 5 UDP beta S and UTP gamma S are useful tools when studying P2 receptors in tissue preparations with ectonucleotidase activity. Contractile responses can be elicited by stimulation of P2Y(6) and, slightly less potently, P2Y(2)/P2Y(4) receptors. The P2X response was relatively weak, and there was no P2Y(1) response. Stimulation of P2Y(1) and P2Y(2)/P2Y(4) receptors elicited relaxation, while P2Y, did not contribute.