Queiroz Gloria, Talaia Carlos, Gonçalves Jorge
Laboratório de Farmacologia, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha 164, 4050-047 Porto, Portugal.
J Pharmacol Exp Ther. 2003 Nov;307(2):809-15. doi: 10.1124/jpet.103.054809. Epub 2003 Sep 9.
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 > or = 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 microM) and by 2-MeSAMP (10 microM) but not by the selective P2Y1 receptor antagonist 2'-deoxy-N6-methyladenosine 3',5'-bisphosphate (MRS 2179; 10 microM). When, besides P1 receptors, inhibitory P2Y receptors were blocked with RB2, alpha,beta-methyleneadenosine 5'-triphosphate (alpha,beta-meATP), beta,gamma-imidoadenosine 5'-triphosphate (beta,gamma-imidoATP), beta,gamma-methyleneadenosine 5'-triphosphate (beta,gamma-meATP), 2-MeSATP, and ATP enhanced tritium overflow up to 140%, with the following order of potency: alpha,beta-meATP > 2-MeSATP = ATP = beta,gamma-meATP > or = beta,gamma-imidoATP. The facilitatory effects of alpha,beta-MeATP and beta,gamma-imidoATP were prevented by PPNDS. Under the same conditions, apyrase attenuated, whereas the ectonucleotidase inhibitor 6-N,N-diethyl-D-beta,gamma-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.
在预先用[³H]去甲肾上腺素孵育的大鼠输精管前列腺部，研究了三磷酸腺苷（ATP）对电刺激（100个脉冲/8赫兹）诱发的去甲肾上腺素释放的调节作用。在存在P1拮抗剂的情况下，核苷酸2-甲硫腺苷-5'-三磷酸（2-MeSATP）、2-甲硫腺苷5'-二磷酸（2-MeSADP）、二磷酸腺苷（ADP）和ATP使电诱发的氚溢出减少高达44%，其效力顺序如下：2-MeSATP > 2-MeSADP > ADP ≥ ATP。P2Y拮抗剂活性蓝2（RB2）和2-甲硫腺苷5'-单磷酸（2-MeSAMP）可增加氚溢出，而P2X拮抗剂吡哆醛-5'-磷酸-6-（2'-萘基偶氮-6'-硝基-4'，8'-二磺酸盐）（PPNDS）则减少诱发的氚溢出。2-MeSATP的抑制作用可被RB2（10微摩尔）和2-MeSAMP（10微摩尔）拮抗，但不能被选择性P2Y1受体拮抗剂2'-脱氧-N6-甲基腺苷3'，5'-双磷酸（MRS 2179；10微摩尔）拮抗。当除P1受体外，抑制性P2Y受体被RB2阻断时，α，β-亚甲基腺苷5'-三磷酸（α，β-meATP）、β，γ-亚氨基腺苷5'-三磷酸（β，γ-imidoATP）、β，γ-亚甲基腺苷5'-三磷酸（β，γ-meATP）、2-MeSATP和ATP可使氚溢出增加高达140%，其效力顺序如下：α，β-meATP > 2-MeSATP = ATP = β，γ-meATP ≥ β，γ-imidoATP。α，β-MeATP和β，γ-imidoATP的促进作用可被PPNDS阻断。在相同条件下，腺苷三磷酸双磷酸酶可减弱氚溢出，而异核苷酸酶抑制剂6-N，N-二乙基-D-β，γ-二溴亚甲基5'-三磷酸则增强氚溢出，这一作用可被PPNDS阻断。在大鼠输精管前列腺部，内源性ATP对去甲肾上腺素释放发挥双重且相反的调节作用：通过激活药理学特性类似于P2Y12和P2Y13受体的P2Y受体产生抑制作用，以及通过激活药理学特性类似于P2X1和P2X3或P2X2/P2X3受体的P2X受体产生促进作用。
