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 ETBagonist sarafotoxin 6c in normotensive male rats increased sodium excretion from 0.51±0.11 μmol/min during baseline to 1.64±0.19 μmol/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 μmol/min during baseline versus 0.95±0.07 μmol/min after S6c. In contrast, ETB-dependent natriuresis was similar in female hypertensive rats (0.48±0.07 versus 1.5±0.18 μmol/min;P<0.05) compared with normotensive controls (1.05±0.07 versus 2.14±0.24 μmol/min;P<0.05). Because ETAreceptors also mediate natriuresis in normotensive female rats, we examined ETAreceptor 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 ETAantagonist BQ-123. Maximum ETBreceptor binding in inner medullary membrane preparations was comparable between vehicle and Ang II hypertensive females; however, maximum ETBbinding was significantly lower in male hypertensive rats (1952±251 versus 985±176 fmol/mg;P<0.05). These results indicate that renal ETBfunction is impaired in male Ang II hypertension attributed, at least in part, to a reduced number of ETBbinding 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.