Endogenous ligand of alpha(1) sodium pump, marinobufagenin, is a 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 alpha(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).


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.
Fedorova
Olga V
OV
Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Talan
Mark I
MI
Agalakova
Natalia I
NI
Lakatta
Edward G
EG
Bagrov
Alexei Y
AY
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002018:Bufanolides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002298:Cardenolides; D004077:Digoxin; D004791:Enzyme Inhibitors / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D008024:Ligands; D008297:Male; D023421:Models, Animal; D009318:Natriuresis / Q000187:drug effects; D010902:Pituitary Gland / Q000378:metabolism; D011188:Potassium / Q000097:blood; D051381:Rats; D020303:Rats, Inbred Dahl; D012503:Saponins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012964:Sodium / Q000097:blood; D012965:Sodium Chloride / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000378:metabolism
D000906:Antibodies; D002018:Bufanolides; D002298:Cardenolides; D004791:Enzyme Inhibitors; D008024:Ligands; D012503:Saponins; D017673:Sodium Chloride, Dietary; D014662:Vasoconstrictor Agents; C034504:digoxin-like factors; C093896:marinobufagenin; D012965:Sodium Chloride; D004077:Digoxin; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium