Abstract—Renal medullary endothelin B receptors contribute to blood pressure regulation by facilitating salt excretion. Premenopausal females have relatively less hypertension than males; therefore, we examined whether there is a sex difference in the natriuretic response to renal medullary infusion of endothelin peptides in the rat. All of the experiments were conducted in anesthetized wild-type (wt) or endothelin B–deficient (sl/sl) rats. Infusion of endothelin 1 (ET-1) significantly increased sodium excretion (U_NaV) in female, but not male, wt rats (U_NaV: 0.41±0.07 versus -0.04±0.06 µmol/min, respectively). The endothelin B receptor agonist sarafotoxin 6c produced similar increases in U_NaV in both male (0.58±0.15 µmol/min) and female (0.67±0.18 µmol/min) wt rats. Surprisingly, ET-1 markedly increased U_NaV in female (0.70±0.11 µmol/min) but not male sl/sl rats (0.00±0.05 µmol/min). ET-1 had no effect on medullary blood flow in females, although medullary blood flow was significantly reduced to a similar extent in males of both strains. These results suggest that the lack of a natriuretic response to ET-1 in male rats is because of reductions in medullary blood flow. Treatment with ABT-627, an endothelin A receptor antagonist, or N^G-propyl-L-arginine, an NO synthase 1 inhibitor, prevented the increase in U_NaV observed in female rats. Gonadectomy eliminated the sex difference in the U_NaV and medullary blood flow response to ET-1. These findings demonstrate that there is no sex difference in endothelin B–dependent natriuresis, and the endothelin A receptor contributes to ET-1–dependent natriuresis in female rats, an effect that requires NO synthase 1. These findings provide a possible mechanism for why premenopausal women are more resistant to salt-dependent hypertension.