Aldosterone receptor antagonism exacerbates intrarenal angiotensin II augmentation in ANG II-dependent hypertension

Am J Physiol Renal Physiol. 2007 Jul;293(1):F139-47. doi: 10.1152/ajprenal.00504.2006. Epub 2007 Mar 20.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Glands / drug effects
  • Adrenal Glands / metabolism
  • Angiotensin II / physiology*
  • Animals
  • Blood Pressure / drug effects
  • Blotting, Western
  • Body Weight / drug effects
  • Diet
  • Drinking / physiology
  • Eating / physiology
  • Electrolytes / metabolism
  • Epithelial Sodium Channels / metabolism
  • Hematocrit
  • Hormones / blood
  • Hypertension, Renal / metabolism*
  • Hypertension, Renal / pathology
  • Kidney / drug effects
  • Kidney / metabolism*
  • Kidney / pathology
  • Kidney Cortex / metabolism
  • Male
  • Mineralocorticoid Receptor Antagonists*
  • Rats
  • Rats, Sprague-Dawley
  • Sodium / blood
  • Sodium / metabolism
  • Sodium / urine
  • Sodium Chloride / pharmacology

Substances

  • Electrolytes
  • Epithelial Sodium Channels
  • Hormones
  • Mineralocorticoid Receptor Antagonists
  • Angiotensin II
  • Sodium Chloride
  • Sodium