title: Sodium pump alpha2 subunits control myogenic tone and blood pressure in mice.
abstract: A key question in hypertension is: How is long-term blood pressure controlled? A clue is that chronic salt retention elevates an endogenous ouabain-like compound (EOLC) and induces salt-dependent hypertension mediated by Na(+)/Ca(2)(+) exchange (NCX). The precise mechanism, however, is unresolved. Here we study blood pressure and isolated small arteries of mice with reduced expression of Na(+) pump alpha1 (alpha1(+/-)) or alpha2 (alpha2(+/-)) catalytic subunits. Both low-dose ouabain (1-100 nm; inhibits only alpha2) and high-dose ouabain (> or =1 microm; inhibits alpha1) elevate myocyte Ca(2)(+) and constrict arteries from alpha1(+/-), as well as alpha2(+/-) and wild-type mice. Nevertheless, only mice with reduced alpha2 Na(+) pump activity (alpha2(+/-)), and not alpha1 (alpha1(+/-)), have elevated blood pressure. Also, isolated, pressurized arteries from alpha2(+/-), but not alpha1(+/-), have increased myogenic tone. Ouabain antagonists (PST 2238 and canrenone) and NCX blockers (SEA0400 and KB-R7943) normalize myogenic tone in ouabain-treated arteries. Only the NCX blockers normalize the elevated myogenic tone in alpha2(+/-) arteries because this tone is ouabain independent. All four agents are known to lower blood pressure in salt-dependent and ouabain-induced hypertension. Thus, chronically reduced alpha2 activity (alpha2(+/-) or chronic ouabain) apparently regulates myogenic tone and long-term blood pressure whereas reduced alpha1 activity (alpha1(+/-)) plays no persistent role: the in vivo changes in blood pressure reflect the in vitro changes in myogenic tone. Accordingly, in salt-dependent hypertension, EOLC probably increases vascular resistance and blood pressure by reducing alpha2 Na(+) pump activity and promoting Ca(2)(+) entry via NCX in myocytes.
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Moo Yeol
authors.initials: MY
authors.lastname: Lee
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cavalli
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Roberto
authors.initials: R
authors.lastname: Berra-Romani
authors.forename: C William
authors.initials: CW
authors.lastname: Balke
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bianchi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ferrari
authors.forename: John M
authors.initials: JM
authors.lastname: Hamlyn
authors.forename: Takahiro
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Jerry B
authors.initials: JB
authors.lastname: Lingrel
authors.forename: Donald R
authors.initials: DR
authors.lastname: Matteson
authors.forename: W Gil
authors.initials: WG
authors.lastname: Wier
authors.forename: Mordecai P
authors.initials: MP
authors.lastname: Blaustein
mesh_terms: D000818:Animals; D001158:Arteries / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009129:Muscle Tonus / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D021122:Protein Subunits; D000254:Sodium-Potassium-Exchanging ATPase / Q000172:deficiency / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D021122:Protein Subunits; C401838:Atp1a2 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase