The critical role of adenosine and guanosine in the affinity of dinucleoside polyphosphates to P2X-receptors in the isolated perfused rat kidney

The activation of P2x-receptors in the rat renal vasculature by dinucleoside polyphosphates with variable phosphate group chain length (XpnX; X=Adenin (A) /Guanin (G), n=4 – 6) was studied by measuring their effects on perfusion pressure of the isolated perfused rat kidney at constant flow in an open circuit. Like Ap4A, Ap5A and Ap6A the dinucleoside polyphosphates Ap4G, Ap5G and Ap6G exerted a vasoconstriction which could be blocked by suramin and pyridoxal-phosphate-6-azophenyl-2; 4-disulphonic acid (PPADS). Gp4G, Gp5G and Gp6G showed only very weak vasoconstriction at high doses. Ap6A and α, β-meATP could not be blocked by the selective P2x1-receptor antagonisten NF023 (30 μM), whereas Ap4A, Ap4G, Ap5A, Ap5G and Ap6G were partially blocked by NF023. Inhibition of endothelial NO-synthase by Nω-nitro-L-arginine methyl ester (L-NAME) did not affect vasoconstrictions induced by dinucleosidepolyphosphates. P2x-receptor can only be activated if at least one adenosine moiety is present in the molecule. ApnG show a weaker vasoconstrictive action than corresponding ApnA, concluding that two adenosine moieties enhance the P2x-receptor binding and activation. XpnX containing five phosphate groups show the most pronounced vasoconstrictive effect whereas four phosphate groups show the less effect, therefore the number of phosphate groups critically changes receptor affinity. Additional experiments using permanent perfusion with α, β-methylene ATP (α,β-meATP) and the selective P2x1-receptor antagonist NF023 showed that the newly discovered human dinucleoside polyphosphates activated the vascular P2x1-receptor and an recently identified new P2x-receptor subtype. The differential effects of dinucleoside polyphosphates allow a fine tuning of local perfusion via composition of XpnXs. British Journal of Pharmacology (2001) 132, 467–474; doi:10.1038/sj.bjp.0703817