Sex Differences in Renal Medullary Endothelin Receptor Function in Angiotensin II Hypertensive Rats

We hypothesized that angiotensin (Ang) II hypertensive rats have impaired natriuresis after renal medullary endothelin (ET) B receptor stimulation that would be more evident in male versus female rats. Acute intramedullary infusion of the ETB agonist sarafotoxin 6c in normotensive male rats increased sodium excretion from 0.51 +/- 0.11 mu mol/min during baseline to 1.64 +/- 0.19 mu mol/min (P < 0.05) after S6c. After 2 weeks of Ang II infusion (260 ng/kg per minute SC), male rats had an attenuated natriuretic response to S6c of 0.62 +/- 0.16 mu mol/min during baseline versus 0.95 +/- 0.07 mu mol/min after S6c. In contrast, ETB-dependent natriuresis was similar in female hypertensive rats (0.48 +/- 0.07 versus 1.5 +/- 0.18 mu mol/min; P < 0.05) compared with normotensive controls (1.05 +/- 0.07 versus 2.14 +/- 0.24 mu mol/min; P < 0.05). Because ETA receptors also mediate natriuresis in normotensive female rats, we examined ETA receptor function in female Ang II hypertensive rats. Intramedullary infusion of ET-1 increased sodium excretion in both hypertensive and normotensive female rats, which was partially blocked by the ETA antagonist BQ-123. Maximum ETB receptor binding in inner medullary membrane preparations was comparable between vehicle and Ang II hypertensive females; however, maximum ETB binding was significantly lower in male hypertensive rats (1952 +/- 251 versus 985 +/- 176 fmol/mg; P < 0.05). These results indicate that renal ETB function is impaired in male Ang II hypertension attributed, at least in part, to a reduced number of ETB binding sites. Furthermore, renal ET receptor function is preserved in female rats during chronic Ang II infusion, suggesting that renal ET receptor function could serve to limit hypertension in females compared with males. (Hypertension. 2011;58:212-218.)