Sexual dimorphism in the renin-angiotensin system in aging spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 291: R383-R390, 2006. First published March 30, 2006 doi:10.1152/ajpregu.00510.2005.-In young adult spontaneously hypertensive rats (SHR), mean arterial pressure (MAP) is higher in males than in females and inhibition of the renin-angiotensin system (RAS) eliminates this sex difference. After cessation of estrous cycling in female SHR, MAP is similar to that in male SHR. The purpose of this study was to determine the role of the RAS in maintenance of hypertension in aging male and female SHR. At 16 mo of age, MAP was similar in male and female SHR (183 Ϯ 5 vs. 193 Ϯ 8 mmHg), and chronic losartan (40 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 po for 3 wk) reduced MAP by 52% (to 90 Ϯ 8 mmHg, P Ͻ 0.05 vs. control) in males and 37% (to 123 Ϯ 11 mmHg, P Ͻ 0.05 vs. control) in females (P Ͻ 0.05, females vs. males). The effect of losartan on angiotensin type 1 (AT1) receptor blockade was similar: MAP responses to acute doses of ANG II (62.5-250 ng/kg) were blocked to a similar extent in losartan-treated males and females. F2-isoprostane excretion was reduced with losartan more in males than in females. There were no sex differences in plasma renin activity, plasma angiotensinogen or ANG II, or renal expression of AT1 receptors, angiotensin-converting enzyme, or renin. However, renal angiotensinogen mRNA and protein expression was higher in old males than females, whereas renal ANG II was higher in old females than males. The data show that, in aging SHR, when blood pressures are similar, there remains a sexual dimorphism in the response to AT1 receptor antagonism, and the differences may involve sex differences in mechanisms responsible for oxidative stress with aging. sex differences; angiotensin type 1 receptor; angiotensinogen; angiotensin II; oxidative stress MEN ARE AT GREATER RISK for cardiovascular and renal disease than are women of similar ages. Men also have higher blood pressures than women (22). However, these sex differences change after menopause, when the risk for cardiovascular disease increases for women (1) and the prevalence of hypertension becomes similar in men and women (1). Reasons for the change in cardiovascular disease risk and the prevalence of hypertension after menopause are not clear.A key system for modulating blood pressure and body fluid volume is the renin-angiotensin system (RAS). Most of the known effects of angiotensin II (ANG II) are mediated through the angiotensin type 1 (AT 1 ) receptor, e.g., vasoconstriction, aldosterone and vasopressin release, salt and water retention, sympathetic activation, and oxidative stress. Sex differences in the RAS have been described previously for humans and animals (10, 19). For example, the spontaneously hypertensive rat (SHR) is a hypertensive model that exhibits sex differences in blood pressure similar to humans. Blood pressure is higher in male than in female SHR before 9 mo of age (16). However, after cessation of estrous cycling in...

Men have higher blood pressure than women, and androgens and oxidative stress have been implicated as playing roles in this sexual dimorphism. The spontaneously hypertensive rat (SHR) is an animal model of both androgen- and oxidative stress-mediated hypertension. Therefore, the present studies were performed to test the hypothesis that androgens cause hypertension in SHR in part by stimulating superoxide production via NADPH oxidase. Castration of male SHR reduced blood pressure by 15% and attenuated both basal and NADPH-stimulated superoxide production in kidney cortical homogenates. Expression of p47(phox) and gp91(phox) but not p22(phox) subunits of NADPH oxidase were significantly lower in kidney cortex from castrated males compared with intact males. Moreover, inhibition of NADPH oxidase with apocynin caused approximately 15 mmHg reduction in blood pressure and reduced basal and NADPH-stimulated superoxide production in intact male SHR, but had no effect on blood pressure or superoxide production in castrated males. These data support the hypothesis that androgens cause oxidative stress and thereby increase blood pressure in male SHR via an NADPH oxidase-dependent mechanism.

No abstract