Investigation of the actions of PPADS, a novel P2X‐purinoceptor antagonist, in the guinea‐pig isolated vas deferens

Abstract

Pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS) was investigated for its ability to act as an antagonist at P2X‐purinoceptors which mediate neurogenic excitatory junction potentials (e.j.ps) and contractions in the guinea‐pig isolated vas deferens. PPADS (10−7 m) caused a small potentiation of the phasic, predominantly purinergic component of contractions evoked by symapthetic nerve stimulation, but higher concentrations of PPADS (3 × 10−6–3 × 10−5 m) elicited a substantial and significant concentration‐dependent inhibition. In contrast, over the same concentration‐range, PPADS had no effect on the tonic, predominantly noradrenergic phase. PPADS (3 × 10−;5 m) also inhibited contractile responses to exogenous α,β‐methyleneATP (10−8–10−3 m), a P2X‐purinoceptor agonist, without affecting the responses to exogenous noradrenaline (10−8−10−3 m), carbachol (10−5 m) or histamine (10−4 m). PPADS (10−7–3 × 10−5 m) produced a concentration‐dependent reduction in e.j.p. magnitude and resting membrane potential. The maximum effect was seen at 10−5 m PPADS, which reduced e.j.p. magnitude from 13.7 ± 0.6 mV (n = 12) to 1.8 ± 0.7 mV (n = 12) and membrane potential from − 64.8 ± 0.6 mV (n = 51) to − 55.0 ± 1.8 mV (n = 12). The PPADS‐induced depolarization was not inhibited by the P2X‐purinoceptor antagonist, suramin (10−4 m). This indicates that the depolarization was not due to an agonist action of PPADS at P2X‐purinoceptors. The results support the proposal that PPADS is a selective antagonist at P2X purinoceptors as opposed to non‐P2‐purinoceptors in the guinea‐pig vas deferens, but its ability to cause membrane depolarization independently of P2X‐purinoceptors and also, at a low concentration, to potentiate the phasic component of the neurogenic contraction indicates that it has other actions. 1994 British Pharmacological Society