Dept. of Physiology, Georgia Health Sciences Univ., 1120 15th St., Rm. CA-3147, Augusta, GA 30912, USA.
Am J Physiol Heart Circ Physiol. 2011 Aug;301(2):H409-17. doi: 10.1152/ajpheart.00084.2011. Epub 2011 May 6.
Uridine adenosine tetraphosphate (Up(4)A) was reported as a novel endothelium-derived contracting factor. Up(4)A contains both purine and pyrimidine moieties, which activate purinergic (P2)X and P2Y receptors. However, alterations in the vasoconstrictor responses to Up(4)A in hypertensive states remain unclear. The present study examined the effects of Up(4)A on contraction of isolated renal arteries (RA) and pulmonary arteries (PA) from DOCA-salt rats using isometric tension recording. RA from DOCA-salt rats exhibited increased contraction to Up(4)A versus arteries from control uninephrectomized rats in the absence and presence of N(G)-nitro-l-arginine (nitric oxide synthase inhibitor). On the other hand, the Up(4)A-induced contraction in PA was similar between the two groups. Up(4)A-induced contraction was inhibited by suramin (nonselective P2 antagonist) but not by diinosine pentaphosphate pentasodium salt hydrate (Ip(5)I; P2X(1) antagonist) in RA from both groups. Furthermore, 2-thiouridine 5'-triphosphate tetrasodium salt (2-ThioUTP; P2Y(2) agonist)-, uridine-5'-(γ-thio)-triphosphate trisodium salt (UTPγS; P2Y(2)/P2Y(4) agonist)-, and 5-iodouridine-5'-O-diphosphate trisodium salt (MRS 2693; P2Y(6) agonist)-induced contractions were all increased in RA from DOCA-salt rats. Protein expression of P2Y(2)-, P2Y(4)-, and P2Y(6) receptors in RA was similar between the two groups. In DOCA-salt RA, the enhanced Up(4)A-induced contraction was reduced by PD98059, an ERK pathway inhibitor, and Up(4)A-stimulated ERK activation was increased. These data are the first to indicate that Up(4)A-induced contraction is enhanced in RA from DOCA-salt rats. Enhanced P2Y receptor signaling and activation of the ERK pathway together represent a likely mechanism mediating the enhanced Up(4)A-induced contraction. Up(4)A might be of relevance in the pathophysiology of vascular tone regulation and renal dysfunction in arterial hypertension.
尿苷腺苷四磷酸（Up（4）A）被报道为一种新型的内皮衍生收缩因子。Up（4）A 含有嘌呤和嘧啶部分，可激活嘌呤能（P2）X 和 P2Y 受体。然而，高血压状态下对 Up（4）A 的血管收缩反应的改变尚不清楚。本研究使用等长张力记录法，检查了 Up（4）A 对 DOCA-盐大鼠分离的肾动脉（RA）和肺动脉（PA）收缩的影响。与对照组单侧肾切除大鼠的动脉相比，DOCA-盐大鼠的 RA 对 Up（4）A 的收缩反应增强，且在 N（G）-硝基-L-精氨酸（一氧化氮合酶抑制剂）存在和不存在的情况下均如此。另一方面，两组之间 PA 中 Up（4）A 诱导的收缩相似。两组 RA 中，Suramin（非选择性 P2 拮抗剂）而非二肌苷五磷酸五钠盐水合物（Ip（5）I；P2X（1）拮抗剂）抑制 Up（4）A 诱导的收缩。此外，2-硫尿苷 5'-三磷酸四钠盐（2-ThioUTP；P2Y（2）激动剂）、尿苷 5'-(γ-硫）-三磷酸三钠盐（UTPγS；P2Y（2）/P2Y（4）激动剂）和 5-碘尿苷 5'-O-二磷酸三钠盐（MRS 2693；P2Y（6）激动剂）诱导的收缩在 DOCA-盐大鼠的 RA 中均增加。两组之间 RA 中 P2Y（2）-、P2Y（4）-和 P2Y（6）受体的蛋白表达相似。在 DOCA-盐 RA 中，ERK 途径抑制剂 PD98059 可降低增强的 Up（4）A 诱导的收缩，并且 Up（4）A 刺激的 ERK 激活增加。这些数据首次表明，DOCA-盐大鼠的 RA 中 Up（4）A 诱导的收缩增强。增强的 P2Y 受体信号和 ERK 途径的激活共同代表了介导增强的 Up（4）A 诱导的收缩的可能机制。Up（4）A 可能与血管张力调节和高血压肾功能障碍的病理生理学有关。
