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Am J Physiol Renal Physiol 293: F139-F147, 2007. First published March 20, 2007; doi:10.1152/ajprenal.00504.2006
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Aldosterone receptor antagonism exacerbates intrarenal angiotensin II augmentation in ANG II-dependent hypertension

Rudy M. Ortiz,1,2 Miguel L. Graciano,1 Dale Seth,1 Mouhamed S. Awayda,1,3 and L. Gabriel Navar1

1Department of Physiology and Renal and Hypertension Center, Tulane University Health Science Center, New Orleans, Louisiana; 2Division of Natural Sciences, University of California, Merced, California; and 3Department of Physiology and Biophysics, University of Buffalo, Buffalo, New York

Submitted 18 December 2006 ; accepted in final form 28 February 2007

Effects of aldosterone receptor (AR) blockade with eplerenone (epl) on renal Na+ excretion, arterial blood pressure, intra-adrenal and renal ANG II, and plasma aldosterone levels during ANG II-dependent hypertension were evaluated. Rats from one cohort (n = 10/group) 1) control, 2) control + epl (25 mg/day), 3) ANG II (60 ng/min), and 4) ANG II + epl were maintained in metabolic cages for 28 days for daily urine collections. Systolic blood pressure (SBP) was measured weekly by tail-cuff. In a second cohort (n = 12/group), daily SBP was measured by telemetry (n = 6 rats/group) 1) control, 2) ANG II, and 3) ANG II + epl. A diet containing epl (0.1%) was provided after 1 wk of ANG II infusion. Direct monitoring of BP by telemetry showed that epl delayed the onset of the increase in SBP by 2 days and slightly reduced SBP (186 ± 6 vs. 177 ± 8 mmHg). Epl transiently increased Na+ excretion within 24 h of treatment in both normo- and hypertensive rats; however, balance was reestablished within 5 days suggesting that alternative mechanisms for conserving Na+ are activated. Cortical {alpha}-epithelial Na+ channel content ({alpha}-ENaC) was not altered after 21 days of epl treatment. Epl exacerbated the ANG II-mediated increases in intrarenal ANG II (226 ± 16 vs. 365 ± 38 fmol/g) and further increased intra-adrenal ANG II (3.9 ± 0.3 vs. 8.2 ± 0.9 fmol/mg) and aldosterone (255 ± 55 vs. 710 ± 87 pmol/mg) content. Exacerbation of intrarenal ANG II levels likely contributes to the maintenance of {alpha}-ENaC protein content and thus Na+ reabsorption, which helps explain the ineffectiveness of AR blockade in reducing SBP in ANG II-infused models of hypertension.

eplerenone; mineralocorticoids; sodium; spironolactone



Address for reprint requests and other correspondence: R. M. Ortiz, Division of Natural Sciences, Univ. of California, PO Box 2039, Merced, CA 95344 (e-mail: rortiz{at}ucmerced.edu)




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