Gui Yu, Walsh Michael P, Jankowski Vera, Jankowski Joachim, Zheng Xi-Long
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Am J Physiol Lung Cell Mol Physiol. 2008 Apr;294(4):L733-8. doi: 10.1152/ajplung.00403.2007. Epub 2008 Jan 11.
Extracellular nucleotides, such as ATP, UDP, and UTP, regulate pulmonary vascular tone through P2X and P2Y receptors. Recently, uridine adenosine tetraphosphate (Up(4)A) was reported as a novel endothelium-derived vasoconstrictive factor. Up(4)A contains both purine and pyrimidine moieties, which potentially activate P2X and P2Y receptors. The present study examined the effect of Up(4)A on contractility of isolated rat pulmonary artery. Up(4)A at 1-100 microM stimulated contraction in a concentration-dependent manner. Up(4)A was equipotent as UTP and UDP in the endothelium-denuded artery while much more effective than UTP and UDP in endothelium-intact preparations. The vasoconstrictor effect of Up(4)A was inhibited by suramin but not IP(5)I or desensitization of P2X receptors with alpha,beta-methylene-ATP (alpha,beta-Me-ATP). Up(4)A-induced contraction was also inhibited by pretreatment with thapsigargin, nitrendipine, or EGTA but unaffected by H1152. Furthermore, unlike ATP and UTP, Up(4)A did not induce relaxation of endothelium-intact preparations precontracted with phenylephrine. These results suggest that Up(4)A is a potent vasoconstrictor, but not a vasodilator, of the rat pulmonary artery. Up(4)A likely acts through a suramin-sensitive P2Y receptor. The contractile effect of Up(4)A involves the entry of extracellular Ca(2+) and release of Ca(2+) from intracellular stores but not Ca(2+) sensitization via the RhoA/Rho kinase pathway. Up(4)A, therefore, potentially plays an important role in the regulation of pulmonary vascular tone.
细胞外核苷酸，如ATP、UDP和UTP，通过P2X和P2Y受体调节肺血管张力。最近，四磷酸尿苷腺苷（Up(4)A）被报道为一种新型的内皮源性血管收缩因子。Up(4)A同时含有嘌呤和嘧啶部分，这可能激活P2X和P2Y受体。本研究检测了Up(4)A对离体大鼠肺动脉收缩性的影响。1-100微摩尔的Up(4)A以浓度依赖的方式刺激收缩。在去内皮的动脉中，Up(4)A与UTP和UDP的效力相当，而在内皮完整的制剂中，其效力比UTP和UDP强得多。苏拉明可抑制Up(4)A的血管收缩作用，但IP(5)I或用α,β-亚甲基ATP（α,β-Me-ATP）使P2X受体脱敏则不能。用毒胡萝卜素、尼群地平或EGTA预处理也可抑制Up(4)A诱导的收缩，但不受H1152影响。此外，与ATP和UTP不同，Up(4)A不会诱导用去氧肾上腺素预收缩的内皮完整制剂舒张。这些结果表明，Up(4)A是大鼠肺动脉的一种强效血管收缩剂，而非血管舒张剂。Up(4)A可能通过一种对苏拉明敏感的P2Y受体发挥作用。Up(4)A的收缩作用涉及细胞外Ca(2+)的内流和细胞内钙库中Ca(2+)的释放，但不涉及通过RhoA/Rho激酶途径的Ca(2+)致敏。因此，Up(4)A可能在肺血管张力的调节中起重要作用。
