Loss of endothelin B receptor function impairs sodium excretion in a time- and sex-dependent manner

Abstract

Recent studies suggested a direct link between circadian rhythms and regulation of sodium excretion. Endothelin-1 (ET-1) regulates sodium balance by promoting natriuresis through the endothelin B receptor (ET_B) in response to increased salt in the diet, but the effect that the time of day has on this natriuretic response is not known. Therefore, this study was designed to test the hypothesis that ET_B receptor activation contributes to the diurnal control of sodium excretion and that sex differences contribute to this control as well. Twelve-hour urine collections were used to measure sodium excretion. On day 3 of the experiment, a NaCl load (900 μeq) was given by oral gavage either at Zeitgeber time [ZT] 0 (inactive period) or ZT12 (active period) to examine the natriuretic response to the acute salt load. Male and female ET_B-deficient (ET_B def) rats showed an impaired natriuretic response to a salt load at ZT0 compared with their respective transgenic controls (Tg cont). Male ET_B def rats showed a delayed natriuretic response to a salt load given at ZT12 compared with male Tg cont, a contrast to the prompt response shown by female ET_B def rats. Treatment with ABT-627, an ET_A receptor antagonist, improved the natriuretic response seen within the first 12 h of a ZT0 salt load in both sexes. These findings demonstrate that diurnal excretion of an acute salt load 1) requires ET-1 and the ET_B receptor, 2) is more evident in male vs. female rats, and 3) is opposed by the ET_A receptor.

Keywords: ETA receptors; ETB receptors; circadian rhythm; kidney; male and female; rats.

Fig. 1.

A: effect of an inactive period (ZT0) salt load on the rate of sodium excretion in males; n = 6–7 rats/group. P_Genotype = not significant (NS). P_Time < 0.05. P_{Genotype*Time} < 0.05. *P < 0.05 vs. transgenic control (Tg cont) 0–12. †P < 0.05 vs. Tg cont 12–24. B: effect of an active period (ZT12) salt load on the rate of sodium excretion in males; n = 5–6 rats/group. *P < 0.05 vs. Tg cont 0–12. †P < 0.05 vs. 12–24 Tg cont. P_Genotype = NS. P_Time < 0.05. P_{Genotype*Time} < 0.05 and effect of a salt load at ZT0 (C) and ZT12 (D) on change in mean arterial pressure (MAP) in males; n = 5–6 rats/group. C and D: P_Genotype, P_Time, and P_{Genotype*Time} = NS.

Fig. 2.

Effect of a salt load at ZT0 (A) and ZT12 (B) on the rate of sodium excretion in females and effect of a salt load at ZT0 (C) and ZT12 (D) on the change in MAP in females; n = 8–10 rats/group. A: P_Genotype = NS. P_Time = NS. P_{Genotype*Time} < 0.05. B: P_Genotype = NS. P_Time < 0.05. P_{Genotype*Time} = NS. For C and D, P_Genotype, P_Time, and P_{Genotype*Time} = NS.

Fig. 3.

Effect of a salt load at ZT0 (A) and ZT12 (B) on the rate of sodium excretion in males treated with ABT-627 and effect of a salt load at ZT0 (C) and ZT12 (D) on change in MAP in males treated with ABT-627; n = 6–7 rats/group. A: P_Genotype, P_Time, and P_{Genotype*Time} = NS. B: P_Genotype = NS. P_Time < 0.05. P_{Genotype*Time} = NS. C and D: P_Genotype, P_Time, and P_{Genotype*Time} = NS.

Fig. 4.

Effect of a salt load at ZT0 (A) and ZT12 (B) on the rate of sodium excretion in females treated with ABT-627 and effect of a salt load at ZT0 (C) and ZT12 (D) on change in MAP in females treated with ABT-627; n = 4–6 rats/group. A and B: P_Genotype = NS. P_Time < 0.05. P_{Genotype*Time} = NS. C: P_Genotype = 0.05. P_Time = NS. P_{Genotype*Time} = NS 4D: P_Genotype, P_Time, and P_{Genotype*Time} = NS. †P < 0.05 vs. Tg cont 12–24. *P < 0.05 vs. 0–12 Tg cont.