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NEUROPHARMACOLOGY

ATP Modulates Noradrenaline Release by Activation of Inhibitory P2Y Receptors and Facilitatory P2X Receptors in the Rat Vas Deferens

Laboratório de Farmacologia, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal

The role of ATP on the modulation of noradrenaline release elicited by electrical stimulation (100 pulses/8 Hz) was studied in the prostatic portion of rat vas deferens preincubated with [³H]noradrenaline. In the presence of P1 antagonists, the nucleotides 2-methylthioadenosine-5'-triphosphate (2-MeSATP), 2-methylthioadenosine 5'-diphosphate (2-MeSADP), ADP, and ATP decreased electrically evoked tritium overflow up to 44%, with the following order of potency: 2-MeSATP > 2-MeSADP > ADP ATP. The P2Y antagonists reactive blue 2 (RB2) and 2-methylthioadenosine 5'-monophosphate (2-MeSAMP) increased, whereas the P2X antagonist pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) (PPNDS) decreased evoked tritium overflow. The inhibitory effect of 2-MeSATP was antagonized by RB2 (10 µM) and by 2-MeSAMP (10 µM) but not by the selective P2Y1 receptor antagonist 2'-deoxy-N⁶-methyladenosine 3',5'-bisphosphate (MRS 2179; 10 µM). When, besides P1 receptors, inhibitory P2Y receptors were blocked with RB2, ,-methyleneadenosine 5'-triphosphate (,-meATP), ,-imidoadenosine 5'-triphosphate (,-imidoATP), ,-methyleneadenosine 5'-triphosphate (,-meATP), 2-MeSATP, and ATP enhanced tritium overflow up to 140%, with the following order of potency: ,-meATP > 2-MeSATP = ATP = ,-meATP ,-imidoATP. The facilitatory effects of ,-MeATP and ,-imidoATP were prevented by PPNDS. Under the same conditions, apyrase attenuated, whereas the ectonucleotidase inhibitor 6-N,N-diethyl-D-,-dibromomethylene 5'-triphosphate enhanced tritium overflow, an effect that was prevented by PPNDS. In the prostatic portion of the rat vas deferens, endogenous ATP exerts a dual and opposite modulation of noradrenaline release: an inhibition through activation of P2Y receptors with a pharmacological profile similar to that of the P2Y12 and P2Y13 receptors and a facilitation through activation of P2X receptors with a pharmacological profile similar to that of P2X1 and P2X3, or PX2/P2X3 receptors.

Address correspondence to: Dr. Jorge Gonçalves, Laboratório de Farmacologia, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha, 164, 4050-047 Porto, Portugal. E-mail: jorge.goncalves{at}ff.up.pt

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