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

2001; Lippincott Williams & Wilkins; Volume: 37; Issue: 2 Linguagem: Inglês

10.1161/01.hyp.37.2.462

1524-4563

О. В. Федорова, Nikolai I. Kolodkin, Natalia I. Agalakova, Edward G. Lakatta, Alexei Y. Bagrov,

Renin-Angiotensin System Studies

Dahl salt-sensitive rats (DS), which have a mutation in the α-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 α-1 than α-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 α-1 Na + /K + -ATPase isoform). Unlike ouabain (IC 50 =248 μmol/L), serially diluted, HPLC-purified MBG immunoreactivity from DS and authentic MBG potently inhibited rat kidney Na + /K + -ATPase (IC 50 =70 and 78 nmol/L, respectively). Our results suggest that an α-1 Na + /K + -ATPase ligand, MBG, is elaborated to promote natriuresis in hypertensive DS. MBG acts as a selective inhibitor of the ouabain-resistant α-1 Na + /K + -ATPase subunit, ie, the major sodium pump isoform of the kidneys, as would be expected of a putative natriuretic hormone.