title: Noradrenaline and extracellular nucleotide cotransmission involves activation of vasoconstrictive P2X(1,3)- and P2Y6-like receptors in mouse perfused kidney.
abstract: Nucleotides like ATP and UTP act as potent extracellular signalling molecules. Released from sympathetic nerve endings as cotransmitters of noradrenaline or paracrine from nonexcitatory cells, they activate specific receptors (ion-gated P2X(1-7) and G-protein-coupled P2Y(1,2,4,6,11-15)). Which of these subtypes, however, are able to modulate vasoconstriction in the kidney is unclear. Wild-type- and P2Y4-receptor-deficient mice kidneys were isolated and perfused with Krebs-Henseleit solution. Pressor responses to renal nerve stimulations (RNS) and added drugs were recorded. Release of endogenous noradrenaline was measured by HPLC. RNS (1-15 Hz) induced a frequency-dependent increase in the perfusion pressor (14.2+/-5.1-67.3+/-6.9 mmHg) and noradrenaline release (1.4+/-0.3-24.2+/-3.4 ng g(-1) kidney). Pressor responses to RNS were not (1-2 Hz) or only partially (5-15 Hz) blocked by the alpha-adrenoceptor antagonist phentolamine (1 microM). Combination of phentolamine and the P2-receptor blocker PPADS (5 microM) prevented RNS-induced pressor responses. The P2X(1,3)-receptor selective antagonist NF279 (10 microM) reduced RNS-induced pressor responses in a frequency-dependent manner. Perfusion of ATP, ADP, UTP, UDP and alpha,beta-meATP concentration dependently increased perfusion pressor with the following rank order of potency alpha,beta-meATP>ADP approximately ATP approximately UDP > or = UTP. NF279 (10 microM) reduced alpha,beta-meATP- (0.1 microM) (21.7+/-3.9% of control) but not UTP- (0.3 microM) (102.6+/-15.3% of control) induced pressor responses. No differences in nucleotide-induced effects were detected among wild-type and P2Y4-receptor knockout mice. Continuous perfusion of alpha,beta-meATP (0.01 microM) potentiated UTP-, UDP- and ATP-gamma S-induced pressor responses. Neuronally and paracrine-released nucleotides evoked renal vasoconstriction by activation of P2X(1,3)- and P2Y6-like receptors in mice. Pretreatment with the P2X(1,3)-receptor agonist alpha,beta-meATP potentiated P2Y6-like receptor-mediated vasoconstrictions.
authors.affiliation: Department of Nephrology, Marienhospital Herne, Ruhr University Bochum, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Vonend
authors.forename: Johannes
authors.initials: J
authors.lastname: Stegbauer
authors.forename: Johann
authors.initials: J
authors.lastname: Sojka
authors.forename: Sina
authors.initials: S
authors.lastname: Habbel
authors.forename: Ivo
authors.initials: I
authors.lastname: Quack
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaye
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Boeynaems
authors.forename: Lars Christian
authors.initials: LC
authors.lastname: Rump
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000098:blood supply* / Q000294:innervation; D051379:Mice; D008810:Mice, Inbred C57BL; D018377:Neurotransmitter Agents / Q000378:metabolism / Q000502:physiology*; D009638:Norepinephrine / Q000502:physiology*; D009711:Nucleotides / Q000378:metabolism / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D018377:Neurotransmitter Agents; D009711:Nucleotides; D018048:Receptors, Purinergic P2; D009638:Norepinephrine