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

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 Na V) in female, but not male, wt rats (ΔU Na V: 0.41±0.07 versus −0.04±0.06 μmol/min, respectively). The endothelin B receptor agonist sarafotoxin 6c produced similar increases in U Na V in both male (Δ0.58±0.15 μmol/min) and female (Δ0.67±0.18 μmol/min) wt rats. Surprisingly, ET-1 markedly increased U Na V in female (Δ0.70±0.11 μmol/min) but not male sl/sl rats (Δ0.00±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 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.