title: Uridine adenosine tetraphosphate-induced contraction is increased in renal but not pulmonary arteries from DOCA-salt hypertensive rats.
abstract: 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.
authors.affiliation: Dept. of Physiology, Georgia Health Sciences Univ., 1120 15th St., Rm. CA-3147, Augusta, GA 30912, USA. tmatsumoto@georgiahealth.edu
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D003900:Desoxycorticosterone; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009213:Myography; D009392:Nephrectomy; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D058914:Purinergic Antagonists / Q000494:pharmacology; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D058470:Receptors, Purinergic P2Y / Q000187:drug effects / Q000378:metabolism; D012077:Renal Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D017673:Sodium Chloride, Dietary; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D015226:Dinucleoside Phosphates; D047428:Protein Kinase Inhibitors; D058914:Purinergic Antagonists; D058912:Purinergic P2Y Receptor Agonists; D058470:Receptors, Purinergic P2Y; D017673:Sodium Chloride, Dietary; D014662:Vasoconstrictor Agents; C529314:uridine adenosine tetraphosphate; D003900:Desoxycorticosterone; D019001:Nitric Oxide Synthase; D048049:Extracellular Signal-Regulated MAP Kinases