Received for publication May 22, 2003.
Revised June 28, 2003.
Accepted for publication July 10, 2003.

ATP modulates noradrenaline release by activation of inhibitory P2Y-receptors and facilitatory P2X-receptors in the rat vas deferens

Abstract

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 pre-incubated 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 RB2 (reactive blue 2) and 2-MeSAMP (2-methylthioadenosine 5'-monophosphate) increased whereas the P2X-antagonist PPNDS (pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro- 4',8'-disulphonate)), 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 MRS 2179 (2'-deoxy- N⁶-methyladenosine 3',5'-bisphosphate, 10 µ M). When, besides P1-receptors, inhibitory P2Y-receptors where blocked with RB2, ,-meATP (, -methyleneadenosine 5'-triphosphate), , -imidoATP (,-imidoadenosine 5'- triphosphate), ,-meATP (,- methyleneadenosine 5'-triphosphate), 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 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.

Key words: Agonist profile, Modulation, Noradrenaline, P2X receptors, P2Y receptors, Vas deferens

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