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 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, α,β-methyleneadenosine 5′-triphosphate (α,β-meATP), β,γ-imidoadenosine 5′-triphosphate (β,γ-imidoATP), β,γ-methyleneadenosine 5′-triphosphate (β,γ-meATP), 2-MeSATP, and ATP enhanced tritium overflow up to 140%, with the following order of potency: α,β-meATP > 2-MeSATP = ATP = β,γ-meATP ≥ β,γ-imidoATP. The facilitatory effects of α,β-MeATP and β,γ-imidoATP were prevented by PPNDS. Under the same conditions, apyrase attenuated, whereas the ectonucleotidase inhibitor 6-N,N-diethyl-d-β,γ-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.
Footnotes
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This work was supported by FCT (I&D no. 226/94, POCTI-QCAIII, and FEDER) and POCTI/36545/FCB/2000.
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DOI: 10.1124/jpet.103.054809.
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ABBREVIATIONS: 2-MeSATP, 2-methylthioadenosine-5′-triphosphate; 2-MeSADP, 2-methylthioadenosine-5′-diphosphate; RB2, reactive blue 2; 2-MeSAMP, 2-methylthioadenosine 5′-monophosphate; MRS 2179, 2′-deoxy-N6-methyladenosine 3′,5′-bisphosphate; α,β-meATP, α,β-methyleneadenosine 5′-triphosphate; β,γ-imidoATP, β,γ-imidoadenosine 5′-triphosphate; β,γ-meATP, β,γ-methyleneadenosine 5′-triphosphate; PPNDS, pyridoxal-5′-phosphate-6-(2′-naphthylazo-6′-nitro-4′,8′-disulphonate); DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; ZM 241385, 4-(2[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)-phenol; NF 279, 8,8′-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid; ARL 67156, 6-N,N-diethyl-d-β,γ-dibromomethylene 5′-triphosphate; PPADS, pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid.
- Received May 21, 2003.
- Accepted July 10, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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