(Verbatim from the application): Men and hypertensive male rats have higher blood pressures (BP) than aged-matched women or female rats. The mechanisms responsible for these gender differences are unclear; however, recent studies by ourselves and other have strongly implicated androgens. The overall goal of this proposal is to investigate the mechanisms responsible for androgen-induced increases in BP. We hypothesize that the gender difference in BP is caused by androgen-induced increases in plasma renin activity (PRA) and angiotensin II (Ang II), leading to increases in sodium reabsorption and stimulation of oxidative stress, with increases in superoxide, reduction in NO, and production of peroxynitrite and vasoconstrictor F2-isoprostanes (IsoP), which potentiate the vasoconstrictor actions ofAng II.
In Specific Aim 1 the hypothesis will be tested in spontaneously hypertensive rats (SHR) that androgens stimulate the renin-angiotensin system (RAS) by increasing PRA which stimulates oxidative stress with increases in superoxide, reduction of NO and production of peroxynitrite and IsoP, by quantifying the components of the RAS (PRA, Ang II, angiotensinogen, aldosterone) and oxidative stress systems (superoxide, nitrate/nitrite for NO, IsoP, and nitrotyrosinated proteins in kidney for peroxynitrite).
In Specific Aim 2, we will test the hypothesis that androgen-induced activation of the RAS is necessary to mediate the gender differences in BP in SHR.
This aim will address whether the RAS plays an active or permissive role in the gender differences in BP control and evaluate possible mechanisms by which androgens could stimulate the RAS, by fixing or blocking components of the RAS.
In Specific Aim 3, we will test the hypothesis that components of the oxidative stress pathway mediate the gender differences in BP in SI-fR, by inhibiting synthesis or blocking the components of oxidative stress.
In Specific Aim 4, the hypothesis will be tested that androgens increase BP in normotensive rats by similar mechanisms as found in SHR: androgens stimulate the RAS leading to sodium reabsorption and oxidative stress and inactivation of NO.
This aim will also address why there are sensitivity differences in the pressor responses to androgens between SHR and normotensive rats.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066072-04
Application #
6744359
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Barouch, Winifred
Project Start
2001-05-01
Project End
2006-04-30
Budget Start
2004-05-01
Budget End
2006-04-30
Support Year
4
Fiscal Year
2004
Total Cost
$282,241
Indirect Cost
Name
University of Mississippi Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Reckelhoff, Jane F; Alexander, Barbara T (2018) Reproducibility in animal models of hypertension: a difficult problem. Biol Sex Differ 9:53
Ball, Jana P; Syed, Maryam; MaraƱon, Rodrigo O et al. (2017) Role and Regulation of MicroRNAs in Aldosterone-Mediated Cardiac Injury and Dysfunction in Male Rats. Endocrinology 158:1859-1874
Patil, Chetan N; Racusen, Lorraine C; Reckelhoff, Jane F (2017) Consequences of advanced aging on renal function in chronic hyperandrogenemic female rat model: implications for aging women with polycystic ovary syndrome. Physiol Rep 5:
Yanes Cardozo, Licy L; Romero, Damian G; Reckelhoff, Jane F (2017) Cardiometabolic Features of Polycystic Ovary Syndrome: Role of Androgens. Physiology (Bethesda) 32:357-366
Miller, Virginia M; Reckelhoff, Jane F (2016) Sex as a Biological Variable: Now What?! Physiology (Bethesda) 31:78-80
Dalmasso, Carolina; Maranon, Rodrigo; Patil, Chetan et al. (2016) Cardiometabolic Effects of Chronic Hyperandrogenemia in a New Model of Postmenopausal Polycystic Ovary Syndrome. Endocrinology 157:2920-7
Blenck, Christa L; Harvey, Pamela A; Reckelhoff, Jane F et al. (2016) The Importance of Biological Sex and Estrogen in Rodent Models of Cardiovascular Health and Disease. Circ Res 118:1294-312
McSweeney, Jean C; Rosenfeld, Anne G; Abel, Willie M et al. (2016) Preventing and Experiencing Ischemic Heart Disease as a Woman: State of the Science: A Scientific Statement From the American Heart Association. Circulation 133:1302-31
Tostes, Rita C; Carneiro, Fernando S; Carvalho, Maria Helena C et al. (2016) Reactive oxygen species: players in the cardiovascular effects of testosterone. Am J Physiol Regul Integr Comp Physiol 310:R1-14
Maranon, Rodrigo O; Reckelhoff, Jane F (2016) Mechanisms responsible for postmenopausal hypertension in a rat model: Roles of the renal sympathetic nervous system and the renin-angiotensin system. Physiol Rep 4:

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