Endothelin ET_B receptors contribute to sex differences in blood pressure elevation in angiotensin II hypertensive rats on a high-salt diet

Female rats are more resistant to blood pressure increases induced by high salt (HS) intake or angiotensin (Ang) II infusion. Because endothelin ET_B receptors on endothelial and epithelial cells mediate tonic vasodilation and sodium excretion, we hypothesized that ET_B receptors limit the hypertensive response and renal injury induced by HS diet alone or with chronic AngII infusion (AngII/HS) in female compared with male rats. A 4 week HS diet (4% NaCl) did not significantly change blood pressure (measured by telemetry) in either male or female Sprague-Dawley rats. Administration of the ET_B receptor antagonist A-192621 (1, 3 and 10 mg/kg per day in food) during HS feeding caused a dose-dependent increase in blood pressure in both sexes. In AngII/HS rats, males had a larger increase in blood pressure than females. The increase in blood pressure produced by ET_B receptor blockade in male AngII/HS rats was not significant. However, A-192621 treatment resulted in a significant further increase in blood pressure in female AngII/HS rats. Male rats had consistently higher protein excretion rates before and during AngII/HS, but this was not significantly affected by ET_B receptor blockade in either sex. In conclusion, ET_B receptors play a significantly greater beneficial role in protecting female compared with male rats against AngII-induced hypertension and may contribute to the sex differences in AngII-induced hypertension.