Coordinated shifts in Na/K-ATPase isoforms and their endogenous ligands during cardiac hypertrophy and failure in NaCl-sensitive hypertension.
OBJECTIVE
NaCl loading of Dahl salt-sensitive rats (DS) stimulates marinobufagenin (MBG), an alpha1 Na/K-ATPase (NKA) isoform ligand. Cardiac function depends on NKA, which is regulated in part by endogenous digitalis-like ligands. Our goal was to study whether changes occur in MBG and endogenous ouabain (EO) production during cardiac remodelling in hypertensive DS, and whether these are associated with changes in myocardial NKA isoforms and sensitivity to MBG and ouabain.


METHODS
Changes in MBG and EO levels, changes in myocardial NKA isoform composition, and sensitivity to endogenous ligands during development of cardiac hypertrophy and the transition to heart failure were studied in DS rats with an 8% NaCl intake.


RESULTS
The animals developed compensated left ventricular hypertrophy after 4 weeks, which progressed to heart failure at 9-12 weeks. The hypertrophic stage was associated with increased plasma MBG levels (mean +/- SEM of 1.22 +/- 0.22 versus 0.31 +/- 0.03 nmol/l; P < 0.01), increased sensitivity of NKA to MBG, and an increased abundance of alpha1 NKA. Plasma levels of EO did not change, and the sensitivity of NKA to ouabain decreased. The transition to heart failure was accompanied by a decrease in alpha1 NKA, a reduction in plasma MBG, and decreased sensitivity of NKA to MBG. In addition, an increased abundance of ouabain-sensitive alpha3 NKA, a three-fold rise in plasma EO (1.01 +/- 0.13 versus 0.27 +/- 0.06 nmol/l), and a seven-fold increase in the ouabain sensitivity of NKA compared with controls were observed.


CONCLUSIONS
During cardiac hypertrophy and the transition to heart failure, a shift in endogenous NKA ligands production is linked to a shift in myocardial NKA isoforms.
Fedorova
Olga V
OV
Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA. FedorovO@grc.nia.nih.gov
Talan
Mark I
MI
Agalakova
Natalia I
NI
Lakatta
Edward G
EG
Bagrov
Alexei Y
AY
D000818:Animals; D002018:Bufanolides / Q000097:blood; D002303:Cardiac Output, Low / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000097:blood; D006973:Hypertension / Q000150:complications / Q000503:physiopathology*; D007527:Isoenzymes / Q000378:metabolism; D008024:Ligands; D008297:Male; D010042:Ouabain / Q000097:blood; D051381:Rats; D020303:Rats, Inbred Dahl; D012965:Sodium Chloride / Q000494:pharmacology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D002018:Bufanolides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008024:Ligands; C093896:marinobufagenin; D012965:Sodium Chloride; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase