Novel Mediator of Sodium Chloride–Dependent Hypertension

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. (Circulation. 2002;105:1122-1127.)