Hourani S M, Bailey S J, Johnson C R, Tennant J P
School of Biological Sciences, University of Surrey, Guildford, UK.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Oct;358(4):464-73. doi: 10.1007/pl00005279.
The functional effects of adenosine 5'-triphosphate (ATP), uridine 5'-triphosphate (UTP), adenosine 5'-tetraphosphate (AP4) and the diadenosine polyphosphates P1,P3-diadenosine triphosphate (Ap3A), P1,P4-diadenosine tetraphosphate (Ap4A) and P1,P5-diadenosine pentaphosphate (Ap5A) were studied in two isolated smooth muscle preparations thought to contain P2Y (P2Y1) receptors, the guinea-pig taenia caeci (which relaxes to ATP) and the rat colon muscularis mucosae (which contracts to ATP). In addition, the breakdown of these compounds by the rat colon muscularis mucosae was investigated by high pressure liquid chromatography. In the guinea-pig taenia caeci all the purine nucleotides caused relaxation with a potency order of Ap3A=Ap4A> ATP>AP4=Ap5A, and these relaxations were antagonised by suramin with apparent pA2 values in the region of 5, consistent with activation of a P2Y1 receptor. In the rat colon muscularis mucosae the nucleotides caused contraction with a potency order of Ap3A = Ap4A>ATP=AP4 =Ap5A >UTP. However, while suramin (100 microM) inhibited responses to ATP and UTP at all concentrations of agonist, it only inhibited contractions induced by the higher concentrations of AP4, Ap3A and Ap4A and had little effect on contractions induced by Ap5A. A higher concentration of suramin (1 mM) enhanced contractions induced by ATP but greatly inhibited those induced by UTP and had no effect on responses to the other agonists. The A1 adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 10 nM) had no effect on responses to ATP or UTP but inhibited responses to Ap3A, Ap4A, Ap5A and AP4. A combination of suramin (1 mM) and DPCPX (10 nM) almost abolished responses to all the agonists. ATP and UTP were rapidly degraded by the rat colon muscularis mucosae while AP4, Ap3A, Ap4A and Ap5A were degraded more slowly, and the major product detected after breakdown of the purine nucleotides was inosine rather than adenosine. The breakdown of all the nucleotides was inhibited by suramin (1 mM), although this inhibition did not achieve statistical significance in the case of ATP. These results show that while the diadenosine polyphosphates appear to act as P2 agonists in the taenia caeci, in the rat colon muscularis mucosae their major action is via adenosine A1 receptors rather than via P2 receptors. In addition, although they are more stable than ATP or UTP, their action in this tissue is clearly affected by their degradation which complicates the effects of suramin.
在两种被认为含有P2Y（P2Y1）受体的离体平滑肌制剂中，研究了5'-三磷酸腺苷（ATP）、5'-三磷酸尿苷（UTP）、5'-四磷酸腺苷（AP4）以及二腺苷多磷酸P1,P3-二腺苷三磷酸（Ap3A）、P1,P4-二腺苷四磷酸（Ap4A）和P1,P5-二腺苷五磷酸（Ap5A）的功能效应，这两种制剂分别是豚鼠盲肠带（对ATP产生舒张反应）和大鼠结肠肌黏膜（对ATP产生收缩反应）。此外，通过高压液相色谱法研究了大鼠结肠肌黏膜对这些化合物的分解情况。在豚鼠盲肠带中，所有嘌呤核苷酸均引起舒张，其效力顺序为Ap3A = Ap4A > ATP > AP4 = Ap5A，这些舒张反应可被苏拉明拮抗，其表观pA2值在5左右，这与P2Y1受体的激活一致。在大鼠结肠肌黏膜中，核苷酸引起收缩，效力顺序为Ap3A = Ap4A > ATP = AP4 = Ap5A > UTP。然而，虽然苏拉明（100 μM）在所有激动剂浓度下均抑制对ATP和UTP的反应，但它仅抑制较高浓度的AP4、Ap3A和Ap4A诱导的收缩，而对Ap5A诱导的收缩几乎没有影响。更高浓度的苏拉明（1 mM）增强了ATP诱导的收缩，但极大地抑制了UTP诱导的收缩，且对其他激动剂的反应没有影响。A1腺苷受体拮抗剂1,3-二丙基-8-环戊基黄嘌呤（DPCPX；10 nM）对ATP或UTP的反应没有影响，但抑制对Ap3A、Ap4A、Ap5A和AP4的反应。苏拉明（1 mM）和DPCPX（10 nM）的组合几乎消除了对所有激动剂的反应。ATP和UTP被大鼠结肠肌黏膜迅速降解，而AP4、Ap3A、Ap4A和Ap5A降解较慢，嘌呤核苷酸分解后检测到的主要产物是次黄嘌呤而非腺苷。所有核苷酸的分解均被苏拉明（1 mM）抑制，尽管这种抑制在ATP的情况下未达到统计学显著性。这些结果表明，虽然二腺苷多磷酸在盲肠带中似乎作为P2激动剂起作用，但在大鼠结肠肌黏膜中，它们的主要作用是通过腺苷A1受体而非P2受体。此外，尽管它们比ATP或UTP更稳定，但它们在该组织中的作用显然受到其降解的影响，这使苏拉明的作用变得复杂。
