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(Hypertension. 2001;37:462.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Marinobufagenin, an Endogenous -1 Sodium Pump Ligand, in Hypertensive Dahl Salt-Sensitive Rats

Olga V. Fedorova; Nikolai I. Kolodkin; Natalia I. Agalakova; Edward G. Lakatta; Alexei Y. Bagrov

From the Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, Md (O.V.F., N.I.A., E.G.L., A.Y.B.), and Institute of Highly Pure Biopreparations, St. Petersburg, Russia (N.I.K.).

Correspondence to Alexei Y. Bagrov, Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224. E-mail bagrovA{at}grc.nia.nih.gov

Dahl salt-sensitive rats (DS), which have a mutation in the -1 subunit of Na⁺/K⁺-ATPase, exhibit impaired pressure natriuresis and on a high-salt diet, retain Na⁺ and exhibit increased blood pressure. Recently, we have shown that mammalian tissues contain a bufadienolide Na⁺/K⁺-ATPase inhibitory factor, marinobufagenin (MBG), that exhibits greater affinity for the -1 than -3 sodium pump isoform. The present study investigated the possible role of MBG in hypertension in DS on a high NaCl intake. Eight DS and 8 Dahl salt-resistant rats (DR) were placed on an 8% NaCl diet. Within 2 weeks, systolic blood pressure increased in DS (162±9 mm Hg at week 2 versus 110±2 mm Hg in baseline, P<0.01), and increased less in DR (124±3 mm Hg at week 2 versus 112±2 mm Hg in baseline). Renal excretion of MBG increased 4-fold (38.9±7.6 pmol versus 9.1±1.3 pmol in baseline, P<0.01) in DS, but by only 25% in DR (13.2±0.9 pmol versus 10.3±0.7 pmol in baseline). Excretion of endogenous ouabain did not change in either strain. MBG-immunoreactive material was purified from the urine of hypertensive DS by means of 2 steps of reverse-phase high performance liquid chromatography (HPLC) and compared with plant ouabain and amphibian MBG for its ability to inhibit the Na⁺/K⁺-ATPase from rat kidney (which expresses only -1 Na⁺/K⁺-ATPase isoform). Unlike ouabain (IC₅₀=248 µmol/L), serially diluted, HPLC-purified MBG immunoreactivity from DS and authentic MBG potently inhibited rat kidney Na⁺/K⁺-ATPase (IC₅₀=70 and 78 nmol/L, respectively). Our results suggest that an -1 Na⁺/K⁺-ATPase ligand, MBG, is elaborated to promote natriuresis in hypertensive DS. MBG acts as a selective inhibitor of the ouabain-resistant -1 Na⁺/K⁺-ATPase subunit, ie, the major sodium pump isoform of the kidneys, as would be expected of a putative natriuretic hormone.

Key Words: NaCl • Dahl rats • Na⁺/K⁺-ATPase • kidney • bufadienolides • marinobufagenin

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