Abstract P045: Endothelin Receptor Blockade Eliminates Sex-differences In Natriuresis In Rats Acclimating To A High Salt Diet

Abstract

The current understanding of sodium (Na + ) handling, which is critical for blood pressure regulation, is based on studies done primarily in male (M) subjects. Our recent studies showed that female (F) Sprague Dawley (SD) rats reach a steady state in urinary Na + excretion after 1 day of increasing dietary Na + intake while M rats take 3-5 days. RNA sequencing data suggests that renal endothelin-1 (ET-1) signaling plays an important role in this difference, however, the role of ET receptors in sex-differences in acclimation to a high salt (HS) diet is not clear. We hypothesized that ET receptors mediate the advanced natriuretic capacity of F rats, compared to M rats, during acclimation to a HS diet. To test our hypothesis, M and F SD rats were implanted with telemeters and randomly assigned to treatment with A-182086, a dual antagonist of ET receptor A and B, or vehicle. After 2-3 days of treatment, rats were placed into metabolic cages and 24-hour urine samples were collected on a normal salt (NS, 0.3% NaCl) diet and after challenging rats with a HS (4% NaCl) diet for 1 day. Treatment with the ET receptor antagonist increased serum ET-1 and mean arterial pressure (MAP) to a comparable extent in both sexes (ET-1: M; 4.17 ± 0.65 vs 0.32 ± 0.02 pg/ml P=0.0004, F; 4.94 ± 1.01 vs 0.30 ± 0.01 pg/ml P<0.0001; MAP: M; 126 ± 2 vs 116 ± 3 mmHg P<0.0001, F; 114 ± 3 vs 107 ± 3 mmHg P<0.0043). On a NS and HS diet, F rats treated with A-182086 consumed more food than corresponding M rats (NS; P=0.0377, HS; P<0.0001), whereas vehicle-treated rats have no sex-difference in food intake. In vehicle-treated rats, urinary Na + excretion was higher in F compared to M rats on either NS or HS diet. Interestingly, ET receptor antagonism eliminates these sex differences in natriuresis during both dietary phases. In particular, A-182086 promotes urinary Na + excretion in M rats fed a HS diet (65.0 ± 2.3 vs 28.2 ± 4.6 % of Na + intake, P=0.0004). In conclusion, ET receptor antagonism eliminates sex-differences in natriuresis on NS and day 1 of HS. In opposition to our hypothesis, ET receptor antagonism promotes HS-induced natriuresis in M rats rather than attenuating the natriuretic capacity of F rats. A better mechanistic understanding of M-F differences in natriuresis could reveal sex-specific targets for hypertension treatment.