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Structure-activity relationships of diadenosine polyphosphates , adenosine polyphospho guanosines and guanosine polyphospho guanosines at P2 receptors in the rat mesenteric arterial bed



Structure-activity relationships of diadenosine polyphosphates , adenosine polyphospho guanosines and guanosine polyphospho guanosines at P2 receptors in the rat mesenteric arterial bed



British Journal of Pharmacology 134(5): 1073-1083



1 Vascular effects of diadenosine polyphosphates (ApnAs), adenosine polyphospho guanosines (ApnGs) and guanosine polyphospho guanosines (GpnGs), novel families of naturally-occurring signalling molecules, were investigated in methoxamine preconstricted rat isolated perfused mesenteric arterial beds. 2 Three different types of response were elicited by ApnAs and ApnGs. Those with a short polyphosphate chain (n=2-3) elicited vasorelaxation. Ap3A was more potent than Ap2A, and both were more potent than the corresponding ApnG. Relaxations to Ap3A and Ap3G, but not to Ap2A and Ap2G, were blocked by endothelium removal and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), a P2 receptor antagonist. 3 Longer polyphosphate chain ApnAs and ApnGs (n=4-6) elicited dose-dependent vasoconstriction followed by prolonged vasorelaxation, with a potency order for both types of response of Ap5AgtoreqAp6A>Ap4A. A similar order and potency was observed for ApnGs. Contractions and prolonged relaxations were blocked by PPADS and P2X1 receptor desensitization with alpha,beta-methylene ATP (alpha,beta-meATP), and were largely endothelium-independent. 4 In the presence of alpha,beta-meATP rapid relaxations to contractile ApnAs and ApnGs (n=4-6) were revealed. 5 GpnGs were virtually inactive, except for Gp2G which elicited vasoconstriction via PPADS- and alpha,beta-meATP-sensitive smooth muscle P2X1-like receptors. 6 These data show that, as with ApnAs, the length of the polyphosphate chain (n) is an important determinant of the activity of ApnGs at P2 receptors in the rat mesenteric arterial bed. When the chain is short (n=2-3) the purines elicit rapid vasorelaxation, which for Ap3A and Ap3G is mediated via endothelial P2Y1-like receptors. When the chain is long (n=4-6) ApnAs and ApnGs elicit vasoconstriction via P2X1-like receptors, followed by prolonged endothelium-independent vasorelaxation. Rapid relaxation to contractile dinucleotides (n=4-6) is revealed by block of vasoconstriction. Regarding the purine moiety, one adenine is crucial and sufficient for vasoactivity as GpnGs were largely inactive, and ApnAs and ApnGs approximately equipotent.

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