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This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/L733    most recent 00403.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gui, Y. Articles by Zheng, X.-L. PubMed PubMed Citation Articles by Gui, Y. Articles by Zheng, X.-L.

Up₄A stimulates endothelium-independent contraction of isolated rat pulmonary artery

¹Smooth Muscle Research Group, Department of Biochemistry and Molecular Biology, the University of Calgary, Calgary, Alberta, Canada; and ²Charite-Universitatsmedizin Berlin, Berlin, Germany

Submitted 27 September 2007 ; accepted in final form 9 January 2008

Extracellular nucleotides, such as ATP, UDP, and UTP, regulate pulmonary vascular tone through P2X and P2Y receptors. Recently, uridine adenosine tetraphosphate (Up₄A) was reported as a novel endothelium-derived vasoconstrictive factor. Up₄A contains both purine and pyrimidine moieties, which potentially activate P2X and P2Y receptors. The present study examined the effect of Up₄A on contractility of isolated rat pulmonary artery. Up₄A at 1–100 µM stimulated contraction in a concentration-dependent manner. Up₄A 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 Up₄A was inhibited by suramin but not IP₅I or desensitization of P2X receptors with ,β-methylene-ATP (,β-Me-ATP). Up₄A-induced contraction was also inhibited by pretreatment with thapsigargin, nitrendipine, or EGTA but unaffected by H1152. Furthermore, unlike ATP and UTP, Up₄A did not induce relaxation of endothelium-intact preparations precontracted with phenylephrine. These results suggest that Up₄A is a potent vasoconstrictor, but not a vasodilator, of the rat pulmonary artery. Up₄A likely acts through a suramin-sensitive P2Y receptor. The contractile effect of Up₄A involves the entry of extracellular Ca²⁺ and release of Ca²⁺ from intracellular stores but not Ca²⁺ sensitization via the RhoA/Rho kinase pathway. Up₄A, therefore, potentially plays an important role in the regulation of pulmonary vascular tone.

extracellular nucleotides; P2 receptors; smooth muscle contraction