Renin-Angiotensin System Angiotensin (1-7) Receptor Antagonism Equalizes Angiotensin II–Induced Hypertension in Male and Female Spontaneously Hypertensive Rats

Females are less sensitive to the hypertensive effects of angiotensin II compared with males, although the molecular mechanisms responsible are unknown. We hypothesize that differential activation of angiotensin II, angiotensin (1-7), angiotensin II type 1, angiotensin II type 2, and mas levels in the renal cortex of male and female spontaneously hypertensive rats contribute to sex differences in the blood pressure response to angiotensin II infusion. Males had a greater increase in blood pressure after angiotensin II infusion than females (males: 150 2 to 186 3 mm Hg; females: 137 3 to 160 4 mm Hg; P 0.05). Angiotensin II infusion resulted in comparable increases in plasma and renal cortical angiotensin II levels in both sexes. Renal cortical angiotensin (1-7) levels were higher in female rats under basal conditions (195 10 versus 67 11 ng/g of cortex; P 0.05) and after angiotensin II infusion (281 25 versus 205 47 ng/g of cortex; P 0.05) compared with male rats. In the renal cortex of male rats, angiotensin II infusion decreased angiotensin II type 1 protein expression and increased angiotensin II type 2 expression with no change in mas expression. In female rats there was an increase in mas receptor protein expression with angiotensin II infusion, although angiotensin II type 1 and angiotensin II type 2 expressions were unchanged. Male and female rats were then treated with the angiotensin (1-7) mas receptor antagonist A-779 in the absence and presence of angiotensin II. A-779 equalized the blood pressure response to angiotensin II in males and females (blood pressure at the end of treatment: males, 166 4 mm Hg; females, 164 5 mm Hg). In conclusion, angiotensin (1-7) contributes to the sex difference in angiotensin II–induced increases in blood pressure in spontaneously hypertensive rats. (Hypertension. 2010;56:658-666.)