Refractory blood pressure in female SHR to increased oxidative stress is not mediated by NO or by upregulation of renal antioxidant enzymes

Department of Physiology and Biophysics and The Women's Health Research Center, University of Mississippi Medical Center, Jackson, Mississippi Submitted July 31, 2009 ; accepted in final form November 30, 2009 There is a sex difference in the blood pressure (BP) responses to prooxidants and antioxidants in the spontaneously hypertensive rat (SHR). In contrast to males, BP in female SHR does not decrease in response to antioxidants, such as tempol or apocynin, or increase in response to the prooxidant, molsidomine. Molsidomine decreases BP and increases expression of antioxidants in male Wistar-Kyoto rats (WKY), but not male SHR. The present study tested the hypothesis that the mechanism responsible for the lack of a pressor response to molsidomine in females is due to higher endogenous nitric oxide (NO) or to compensatory upregulation of renal antioxidant enzymes. Female SHR were treated with molsidomine in the presence or absence of nitro- L -arginine methyl ester ( L -NAME) for 2 wk. Molsidomine increased nitrate/nitrite (NO x ) and F2-isoprostane (F2-IsoP) excretion, whereas L -NAME reduced NO x but increased F-Isop. Molsidomine and L -NAME together further reduced NO x and increased F2-IsoP. Molsidomine alone had no effect on BP; L -NAME alone increased BP. The combination of molsidomine and L -NAME did not increase BP above L -NAME alone levels. Whole body and renal oxidative stress increased, while renal cortical Cu,Zn-SOD expression was downregulated and catalase was upregulated by molsidomine; glutathione peroxidase expression was unaffected. These data support our previous studies suggesting that BP in female SHR is independent of either increases or decreases in oxidative stress. The mechanisms responsible for the sex difference in BP response to increase or decrease of oxidative stress are not due to increased NO in females or to compensatory upregulation of antioxidant enzymes in response to increases in oxidants. F2-isoprostanes; lucigenin chemiluminescence; sexual dimorphism; hypertension; catalase; prooxidant Address for reprint requests and other correspondence: J. F. Reckelhoff, Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505 (e-mail: jreckelhoff{at}physiology.umsmed.edu ).