Matsumoto T, Tostes RC, Webb RC. Uridine adenosine tetraphosphate-induced contraction is increased in renal but not pulmonary arteries from DOCA-salt hypertensive rats. Am J Physiol Heart Circ Physiol 301: H409 -H417, 2011. First published May 6, 2011 doi:10.1152/ajpheart.00084.2011.-Uridine adenosine tetraphosphate (Up 4A) was reported as a novel endothelium-derived contracting factor. Up 4A contains both purine and pyrimidine moieties, which activate purinergic (P2)X and P2Y receptors. However, alterations in the vasoconstrictor responses to Up 4A in hypertensive states remain unclear. The present study examined the effects of Up 4A on contraction of isolated renal arteries (RA) and pulmonary arteries (PA) from DOCA-salt rats using isometric tension recording. RA from DOCAsalt rats exhibited increased contraction to Up 4A versus arteries from control uninephrectomized rats in the absence and presence of N Gnitro-L-arginine (nitric oxide synthase inhibitor). On the other hand, the Up 4A-induced contraction in PA was similar between the two groups. Up 4A-induced contraction was inhibited by suramin (nonselective P2 antagonist) but not by diinosine pentaphosphate pentasodium salt hydrate (Ip 5I; P2X1 antagonist) in RA from both groups. Furthermore, 2-thiouridine 5=-triphosphate tetrasodium salt (2-Thio-UTP; P2Y 2 agonist)-, uridine-5=-(␥-thio)-triphosphate trisodium salt (UTP␥S; P2Y 2/P2Y4 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-, P2Y4-, and P2Y6 receptors in RA was similar between the two groups. In DOCA-salt RA, the enhanced Up 4A-induced contraction was reduced by PD98059, an ERK pathway inhibitor, and Up 4A-stimulated ERK activation was increased. These data are the first to indicate that Up 4A-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 4A-induced contraction. Up4A might be of relevance in the pathophysiology of vascular tone regulation and renal dysfunction in arterial hypertension. extracellular nucleotide; ERK; purinoceptor EXTRACELLULAR NUCLEOTIDES contribute to the local regulation of vascular tone and play important roles in pathophysiological processes, including hypertension, diabetes, atherosclerosis, and remodeling (7,9,16). In blood vessels, nucleotides, such as ATP and UTP, can be released from platelets or from adventitial nerves and endothelial cells to induce either vasoconstriction or vasodilation through cell surface purinergic (P2) receptors (1,8,15).P2 receptors for nucleotides belong to two major families: ionotropic P2X receptors and metabotropic P2Y receptors (1,8,15). Several reports demonstrated that these purinoceptors are expressed in renal and pulmonary vascular beds (12,25,31,38,52,53), contributing to the physiology of these specialized organ systems (4,22,30). However, the involvement of these pu...