Sodium pump α2 subunits control myogenic tone and blood pressure in mice

Jin Zhang, Moo Yeol Lee, Maurizio Cavalli, Ling Chen, Roberto Berra-Romani, C. William Balke, Giuseppe Bianchi, Patrizia Ferrari, John M. Hamlyn, Takahiro Iwamoto, Jerry B. Lingrel, Donald R. Matteson, W. Gil Wier, Mordecai P. Blaustein

Research output: Contribution to journalArticlepeer-review

149 Scopus citations

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+/Ca2+ 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 α1 (α1+/-) or α2 (α2+/-) catalytic subunits. Both low-dose ouabain (1-100 nM; inhibits only α2) and high-dose ouabain (≥1 μM; inhibits α1) elevate myocyte Ca2+ and constrict arteries from α1+/-, as well as α2+/- and wild-type mice. Nevertheless, only mice with reduced α2 Na+ pump activity (α2+/-), and not α1 (α1+/-), have elevated blood pressure. Also, isolated, pressurized arteries from α2+/-, but not α1+/-, 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 α2+/- 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 α2 activity (α2+/- or chronic ouabain) apparently regulates myogenic tone and long-term blood pressure whereas reduced α1 activity (α1+/-) 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 α2 Na+ pump activity and promoting Ca2+ entry via NCX in myocytes.

Original languageEnglish
Pages (from-to)243-256
Number of pages14
JournalJournal of Physiology
Volume569
Issue number1
DOIs
StatePublished - Nov 15 2005

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