Loss of renal medullary endothelin B receptor function during salt deprivation is regulated by angiotensin II

Abstract

We have recently demonstrated that chronic infusion of exogenous ANG II, which induces blood pressure elevation, attenuates renal medullary endothelin B (ETB) receptor function in rats. Moreover, this was associated with a reduction of ETBreceptor expression in the renal inner medulla. The aim of this present work was to investigate the effect of a physiological increase in endogenous ANG II (low-salt diet) on the renal ET system, including ETBreceptor function. We hypothesized that endogenous ANG II reduces renal medullary ETBreceptor function during low-salt intake. Rats were placed on a low-salt diet (0.01–0.02% NaCl) for 2 wk to allow an increase in endogenous ANG II. In rats on normal-salt chow, the stimulation of renal medullary ETBreceptor by ETBreceptor agonist sarafotoxin 6c (S6c) causes an increase in water (3.6 ± 0.4 from baseline vs. 10.5 ± 1.3 μl/min following S6c infusion; P < 0.05) and sodium excretion (0.38 ± 0.06 vs. 1.23 ± 0.17 μmol/min; P < 0.05). The low-salt diet reduced the ETB-dependent diuresis (4.5 ± 0.5 vs. 6.1 ± 0.9 μl/min) and natriuresis (0.40 ± 0.11 vs. 0.46 ± 0.12 μmol/min) in response to acute intramedullary infusion of S6c. Chronic treatment with candesartan restored renal medullary ETBreceptor function; urine flow was 7.1 ± 0.9 vs. 15.9 ± 1.7 μl/min ( P < 0.05), and sodium excretion was 0.4 ± 0.1 vs. 1.1 ± 0.1 μmol/min ( P < 0.05) before and after intramedullary S6c infusion, respectively. Receptor binding assays determined that the sodium-depleted diet resulted in a similar level of ETBreceptor binding in renal inner medulla compared with rats on a normal-salt diet. Candesartan reduced renal inner medullary ETBreceptor binding (1,414 ± 95 vs. 862 ± 50 fmol/mg; P < 0.05). We conclude that endogenous ANG II attenuates renal medullary ETBreceptor function to conserve sodium during salt deprivation independently of receptor expression.