title: Differential effects of uridine adenosine tetraphosphate on purinoceptors in the rat isolated perfused kidney.
abstract: OBJECTIVE
  Purinergic signalling plays an important role in vascular tone regulation in humans. We have identified uridine adenosine tetraphosphate (Up(4)A) as a novel and highly potent endothelial-derived contracting factor. Up(4)A induces strong vasoconstrictive effects in the renal vascular system mainly by P2X(1) receptor activation. However, other purinoceptors are also involved and were analysed here.
  
  
  METHODS
  The rat isolated perfused kidney was used to characterize vasoactive actions of Up(4)A.
  
  
  RESULTS
  After desensitization of the P2X(1) receptor by α,β-methylene ATP (α,β-meATP), Up(4)A showed dose-dependent P2Y(2)-mediated vasoconstriction. Continuous perfusion with Up(4)A evoked a biphasic vasoconstrictor effect: there was a strong and rapidly desensitizing vasoconstriction, inhibited by P2X(1) receptor desensitization. In addition, there is a long-lasting P2Y(2)-mediated vasoconstriction. This vasoconstriction could be blocked by suramin, but not by PPADS or reactive blue 2. In preparations of the rat isolated perfused kidney model with an elevated vascular tone, bolus application of Up(4)A showed a dose-dependent vasoconstriction that was followed by a dose-dependent vasodilation. The vasoconstriction was in part sensitive to P2X(1) receptor desensitization by α,β-meATP, and the remaining P2Y(2)-mediated vasoconstriction was only inhibited by suramin. The Up(4)A-induced vasodilation depended on activation of nitric oxide synthases, and was mediated by P2Y(1) and P2Y(2) receptor activation.
  
  
  CONCLUSIONS
  Up(4)A activated P2X(1) and P2Y(2) receptors to act as a vasoconstrictor, whereas endothelium-dependent vasodilation was induced by P2Y(1/2) receptor activation. Up(4)A might be of relevance in the physiology and pathophysiology of vascular tone regulation.
authors.affiliation: Charité- Universitätsmedizin Berlin, Medical. Klinik mit Schwerpunkt Nephrologie, Hindenburgdamm 30, 12203 Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Tölle
authors.forename: Mirjam
authors.initials: M
authors.lastname: Schuchardt
authors.forename: Annette
authors.initials: A
authors.lastname: Wiedon
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.forename: Lars
authors.initials: L
authors.lastname: Klöckel
authors.forename: Joachim
authors.initials: J
authors.lastname: Jankowski
authors.forename: Vera
authors.initials: V
authors.lastname: Jankowski
authors.forename: Walter
authors.initials: W
authors.lastname: Zidek
authors.forename: Markus
authors.initials: M
authors.lastname: van der Giet
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015226:Dinucleoside Phosphates / Q000494:pharmacology / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D011983:Receptors, Purinergic / Q000502:physiology*; D013498:Suramin / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D015226:Dinucleoside Phosphates; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D058912:Purinergic P2Y Receptor Agonists; D058921:Purinergic P2Y Receptor Antagonists; D011983:Receptors, Purinergic; D014227:Triazines; C529314:uridine adenosine tetraphosphate; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; C012842:Cibacron Blue F 3GA; D011732:Pyridoxal Phosphate; D013498:Suramin; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; C002630:alpha,beta-methyleneadenosine 5'-triphosphate