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(Circulation. 2002;105:1122.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Endogenous Ligand of ₁ Sodium Pump, Marinobufagenin, Is a Novel Mediator of Sodium Chloride–Dependent Hypertension

Olga V. Fedorova, PhD; Mark I. Talan, MD, PhD; Natalia I. Agalakova, PhD; Edward G. Lakatta, MD; Alexei Y. Bagrov, MD, PhD

From the Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Md.

Correspondence to Dr Alexei Bagrov, Laboratory of Cardiovascular Science, National Institute on Aging, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail BagrovA{at}grc.nia.nih.gov

Background— Digitalis-like sodium pump ligands (SPLs) effect natriuresis via inhibition of renal tubular Na⁺,K⁺-ATPase but may induce vasoconstriction. The present study investigated the potential roles of 2 putative endogenous SPLs, an ouabain-like compound (OLC) and an ₁ Na⁺,K⁺-ATPase inhibitor, marinobufagenin (MBG), in regulating natriuresis and blood pressure (BP) responses to sustained and acute NaCl loading in Dahl salt-sensitive rats (DS).

Methods and Results— During 4 weeks of an 8% NaCl diet, DS exhibited a progressive increase in MBG renal excretion (66±13 pmol/24 hours at week 4 versus 11±1 pmol/24 hours at baseline, n=48), which paralleled an increase in systolic BP (174±10 mm Hg at week 4 versus 110±2 mm Hg at baseline). By contrast, OLC excretion peaked at week 1 and returned to baseline levels. Administration of an anti-MBG, but not anti-ouabain antibody, to DS after 3 weeks of a high NaCl diet lowered BP (139±7 versus 175±5 mm Hg, P<0.001, n=5). Acute NaCl loading (2 hours) of DS (n=5) increased MBG and OLC excretion and natriuresis. Pretreatment of acutely NaCl-loaded DS with an anti-MBG antibody (n=5) reduced the excretion of sodium and MBG but not that of OLC. An anti-ouabain antibody (n=5) reduced sodium excretion and both OLC and MBG.

Conclusions— An initial transient stimulation of OLC induced by NaCl loading of DS precedes an MBG response. A sustained increase in MBG production in DS contributes to the chronic BP elevation induced by a sustained high NaCl intake.

Key Words: hypertension • Na⁺-K⁺-exchanging ATPase • sodium • bufadienolides • ouabain

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