ATP activates P 2x ‐contracting and P 2y ‐relaxing purinoceptors in the smooth muscle of mouse vas deferens

1 The mechanism for the low potency of exogenous ATP in producing contraction at the P 2x ‐purinoceptors in the smooth muscle of the mouse vas deferens (VD) was examined. 2 The measure of the breakdown of ATP in contact with the VD showed that its degradation was limited and did not account for its weak contractile effect. 3 Externally applied, ATP induced a small and transient contraction but a marked and prolonged increase of the cytosolic Ca 2+ concentration ([Ca 2+ ] i ), which suggests an efficient binding to the P 2x ‐purinoceptors. Such a calcium‐force dissociation was not observed with β,γ‐methylene ATP (β,γ‐Me‐ATP), a structural ATP analogue. 4 The force response of precontracted VD to ATP was biphasic, consisting of a small initial contraction followed by a sustained marked relaxation. In contrast, β,γ‐Me‐ATP elicited a pronounced contraction without ensuing relaxation. 5 ATP was more potent than adenosine in producing relaxation, and the relaxation was not antagonized by 8‐phenyltheophylline, suggesting the activation of P 2 ‐purinoceptors. 6 For this relaxation, the rank order of potency was 2‐methyl‐thio‐ATP (2‐MeSATP) > ATP>β,γ‐Me‐ATP, which is characteristic for the P 2y ‐purinoceptors. 7 Reactive Blue 2, a P 2y ‐purinoceptor antagonist, was found to reduce the relaxation mediated by ATP. 8 These results indicate that ATP acts in VD not only on contracting but also on relaxing P 2 ‐purinoceptors, eliciting thereby overlapping opposite effects. In VD, the classical low potency of ATP for contraction is thus not explained by its low bioavailability or its low binding, but rather by its low specificity for the contracting P 2x ‐purinoceptors, leading to the activation of the relaxing P 2y ‐purinoceptors.