Contribution of Endothelin A Receptors in Endothelin 1-Dependent Natriuresis in Female Rats

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 (UNaV) in female, but not male, wt rats (Delta UNaV: 0.41 +/- 0.07 versus -0.04 +/- 0.06 mu mol/min, respectively). The endothelin B receptor agonist sarafotoxin 6c produced similar increases in UNaV in both male (Delta 0.58 +/- 0.15 mu mol/min) and female (Delta 0.67 +/- 0.18 mu mol/min) wt rats. Surprisingly, ET-1 markedly increased UNaV in female (Delta 0.70 +/- 0.11 mu mol/min) but not male sl/sl rats (Delta 0.00 +/- 0.05 mu mol/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 UNaV observed in female rats. Gonadectomy eliminated the sex difference in the UNaV 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. (Hypertension. 2009; 53[part 2]: 324-330.)