The critical role of adenosine and guanosine in the affinity of dinucleoside polyphosphates to P-2X-receptors in the isolated perfused rat kidney

1 The activation of P-2x-receptors in the rat renal vasculature by dinucleo side polyphosphates with variable phosphate group chain length (Xp(n)X: 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 Row in an open circuit. 2 Like Ap(4)A, Ap(5)A and Ap(6)A the dinucleoside polyphosphates Ap(4)G, Ap (5)G and Ap(6)G exerted a vasoconstriction which could be blocked by surami n and pyridoxal-phosphate-6-azophenyl-2; 4-disulphonic acid (PPADS). 3 Gp(4)G, Gp(5)G acid Gp(6)G showed only very weak vasoconstriction at high doses. 4 Ap(6)A and alpha, beta -meATP could not be blocked by the selective P-2x1 -receptor antagonisten NF023 (30 muM), whereas Ap(4)A, Ap(4)G. Ap(5)A, Ap(5 )G and Ap(6)G were partially blocked by NF023. 5 Inhibition of endothelial NO-synthase by N-w-nitro-L-arginine methyl este r (L-NAME) did not affect vasoconstrictions induced by dinucleosidepolyphos phates. 6 P-2x-receptor can only be activated if at least one adenosine moiety is p resent in the molecule. 7 Ap(n)G show a weaker vasoconstrictive action than corresponding Ap(n)A, c oncluding that two adenosine moieties enhance the P-2x-receptor binding and activation. 8 Xp(n)X containing five phosphate groups show the most pronounced vasocons trictive effect whereas four phosphate groups show the less effect, therefo re the number of phosphate groups critically changes receptor affinity. 9 Additional experiments using permanent perfusion with alpha, beta -methyl ene ATP (alpha,beta -meATP) and the selective beta (2x1)-receptor antagonis t NF023 showed that the newly discovered human dinucleoside polyphosphates activated the vascular P-2x1-receptor and an recently identified new P-2x-r eceptor subtype. 10 The differential effects of dinucleoside polyphosphates allow a fine tun ing of local perfusion via composition of Xp(n)Xs.