The interaction of diadenosine polyphosphates with P2X‐receptors in the guinea‐pig isolated vas deferens

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Abstract
The site(s) at which diadenosine 5′,5′′′‐P1, P4‐tetraphosphate (AP4A) and diadenosine 5′, 5′′′‐P1, P5‐pentaphosphate (AP5A) act to evoke contraction of the guinea‐pig isolated vas deferens was studied by use of a series of P2‐receptor antagonists and the ecto‐ATPase inhibitor 6‐N, N‐diethyl‐D‐β,γ‐dibromomethyleneATP (ARL 67156). Pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS) (300 nM–30 μM), suramin (3–100 μM) and pyridoxal‐5′‐phosphate (P‐5‐P) (3–1000 μM) inhibited contractions evoked by equi‐effective concentrations of AP5A (3 μM), AP4A (30 μM) and α,β‐methyleneATP (α,β‐meATP) (1 μM), in a concentration‐dependent manner and abolished them at the highest concentrations used. PPADS was more potent than suramin, which in turn was more potent than P‐5‐P. PPADS inhibited AP5A, AP4A and α,β‐meATP with similar IC50 values. No significant difference was found between IC50 values for suramin against α,β‐meATP and AP5A or α,β‐meATP and AP4A, but suramin was more than 2.5 times more potent against AP4A than AP5A. P‐5‐P showed the same pattern of antagonism. Desensitization of the P2X1‐receptor by α,β‐meATP abolished contractions evoked by AP5A (3 μM) and AP4A (30 μM), but had no effect on those elicited by noradrenaline (100 μM). ARL 67156 (100 μM) reversibly potentiated contractions evoked by AP4A (30 μM) by 61%, but caused a small, significant decrease in the mean response to AP5A (3 μM). It is concluded that AP4A and AP5A act at the P2X1‐receptor, or a site similar to the P2X1‐receptor, to evoke contraction of the guinea‐pig isolated vas deferens. Furthermore, the potency of AP4A, but not AP5A, appears to be inhibited by an ecto‐enzyme which is sensitive to ARL 67156. British Journal of Pharmacology (1997) 121, 57–62; doi:10.1038/sj.bjp.0701099