Renal endothelin ETA/ETB receptor imbalance differentiates salt-sensitive from salt-resistant spontaneous hypertension

It is unclear why a subgroup of patients with essential hypertension develop salt-sensitive hypertension with progression of target organ damage over time. We evaluated the role of the renal endothelin (ET) system in the stroke-prone spontaneously hypertensive rat (SHRSP) model of salt-sensitive spontaneous hypertension (SS-SH) compared with the spontaneously hypertensive rat (SHR) model of salt-resistant spontaneous hypertension (SR-SH). Both strains were studied after either sham-operation on a normal diet (Sham) or after unilateral nephrectomy and high NaCl loading (NX-NaCl) with 4% NaCl in diet for 6 weeks (n = 10, respectively). Systolic blood pressure (SBP) increased only in SHRSP-NX-NaCl compared with SHRSP-Sham (250+/-6 versus 172+/-5 mm Hg, P<0.0001). SBP remained unchanged in SHR-NX-NaCl compared with SHR-Sham. In SHRSP-NX-NaCl animals, urinary albumin and ET-1 excretion, renal ET-1 mRNA expression, glomerulosclerosis index, and tubulointerstitial damage index were elevated compared with SHRSP-Sham (P<0.05, respectively), whereas no significant changes were found in SHR after NX-NaCl. Urinary sodium excretion (UNa+) was significantly reduced by 38% in SHRSP-NX-NaCl compared with SHR-NX-NaCl (P<0.005, respectively). SHR animals showed a similar increase in both renal ETA and ETB receptor densities after NX-NaCl (2.2-fold, P<0.05). In contrast, SHRSP-NX-NaCl developed a significantly more pronounced increase in ETA compared with ETB binding (4.7-fold versus 2.4-fold, P<0.05, compared with SHRSP-Sham, respectively), resulting in a significant 2.1-fold increase in ETA/ETB receptor ratio only in the SHRSP-NX-NaCl (P<0.05). Thus, activation of the renal ET system together with an increased ETA/ETB receptor ratio may contribute to the development and progression of SS-SH.