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2 subunits control myogenic tone and blood pressure in mice
Departments of
1 Physiology
2 Medicine
3 Center for Heart, Hypertension and Kidney Disease, University of Maryland School of Medicine, Baltimore, MD, USA
4 Departments of Medicine and Physiology and the Institute for Molecular Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
5 Division of Nephrology, Dialysis and Hypertension, Hospital San Raffaele, Milan, Italy
6 Prassis Instituto Ricerche Sigma-Tau, Milan, Italy
7 Department of Pharmacology, Fukuoka University School of Medicine, Fukuoka, Japan
8 Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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 
1 (1+/–) or 2 (2+/–) catalytic subunits. Both low-dose ouabain (1–100 nM; inhibits only 2) and high-dose ouabain (
1 µM; inhibits 1) elevate myocyte Ca2+ and constrict arteries from 1+/–, as well as 2+/– and wild-type mice. Nevertheless, only mice with reduced 2 Na+ pump activity (2+/–), and not 1 (1+/–), have elevated blood pressure. Also, isolated, pressurized arteries from 2+/–, but not 1+/–, 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 2+/– 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 2 activity (2+/– or chronic ouabain) apparently regulates myogenic tone and long-term blood pressure whereas reduced 1 activity (1+/–) 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 2 Na+ pump activity and promoting Ca2+ entry via NCX in myocytes.
(Received 31 May 2005;
accepted after revision 8 September 2005;
first published online 15 September 2005)
Corresponding author M. P. Blaustein: Department of Physiology, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201, USA. Email: mblauste{at}umaryland.edu
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