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

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 α-epithelial Na ⁺ channel content (α-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 α-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.