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(Na)V) in female, but not male, wt rats (Delta U(Na)V: 0.41+/-0.07 versus -0.04+/-0.06 micromol/min, respectively). The endothelin B receptor agonist sarafotoxin 6c produced similar increases in U(Na)V in both male (Delta 0.58+/-0.15 micromol/min) and female (Delta 0.67+/-0.18 micromol/min) wt rats. Surprisingly, ET-1 markedly increased U(Na)V in female (Delta 0.70+/-0.11 micromol/min) but not male sl/sl rats (Delta 0.00+/-0.05 micromol/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(Na)V observed in female rats. Gonadectomy eliminated the sex difference in the U(Na)V 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.