Bhatia K, Elmarakby AA, El-Remessey A, Sullivan JC. Oxidative stress contributes to sex differences in angiotensin II-mediated hypertension in spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 302: R274 -R282, 2012. First published November 2, 2011; doi:10.1152/ajpregu.00546.2011.-NADPH oxidase has been implicated in ANG II-induced oxidative stress and hypertension in males; however, the contribution of oxidative stress to ANG II hypertension in females is unknown. In the present study, we tested the hypothesis that greater antioxidant capacity in female spontaneously hypertensive rats (SHR) blunts ANG II-induced oxidative stress and hypertension relative to males. Whole body and renal cortical oxidative stress levels were assessed in female and male SHR left untreated or following 2 wk of chronic ANG II infusion. Chronic ANG II infusion increased NADPH oxidase enzymatic activity in the renal cortex of both sexes; however, this increase only reached significance in female SHR. In contrast, male SHR demonstrated a greater increase in all measurements of reactive oxygen species production in response to chronic ANG II infusion. ANG II infusion increased plasma superoxide dismutase activity only in female SHR (76 Ϯ 9 vs. 190 Ϯ 7 Units·ml Ϫ1 ·mg Ϫ1 , P Ͻ 0.05); however, cortical antioxidant capacity was unchanged by ANG II in either sex. To assess the functional implication of alterations in NADPH enzymatic activity and oxidative stress levels following ANG II infusion, additional experiments assessed the ability of the in vivo antioxidant apocynin to modulate ANG II hypertension. Apocynin significantly blunted ANG II hypertension in male SHR (174 Ϯ 2 vs. 151 Ϯ 1 mmHg, P Ͻ 0.05), with no effect in females (160 Ϯ 11 vs. 163 Ϯ 10 mmHg). These data suggest that ANG II hypertension in male SHR is more dependent on increases in oxidative stress than in female SHR. superoxide; kidney; apocynin; NADPH oxidase THE RENIN-ANGIOTENSIN-ALDOSTERONE system (RAAS) is important in the regulation of body fluid and blood pressure homeostasis, and overactivation of the RAAS contributes to the development of numerous pathophysiological processes (20,21,40). There is an expanding literature regarding sex differences in the expression of RAAS components, as well as in functional responses to RAAS activation to both acute and chronic ANG II infusion (24,25,36,38,46). We recently published that greater levels of the vasodilatory peptide ANG (1-7) contribute to sex differences in the hypertensive response to chronic ANG II infusion in spontaneously hypertensive rats (SHR), although it is unknown whether there are additional molecular mechanism(s) contributing to sex differences in the blood pressure response to ANG II. Activation of angiotensin type 1 (AT 1 ) receptors mediate most well-known biological functions of ANG II, including the stimulation of oxidative stress, and female SHR have fewer AT 1 receptors than male SHR (43). However, little is known regarding the relative contribution of ANG II-mediated oxidative ...