Sex differences in the development of hypertension and cardiovascular disease have been well described in humans and in animal models. Low dose AngII infusion is known to induce a neurogenic hypertension via CNS actions on circumventricular organs in the brainstem and hypothalamus. An increasing body of evidence has shown that Angll central and peripheral effects involve activation of reactive oxygen. Similarly, central peripheral studies with estrogen and testosterone have shown that many of their cardiovascular related effects may be related their modulation of the generation of reactive oxygen species (ROS) and nitric oxide (NO). Recent data from our laboratory have shown that low-dose infusion of AngII results in hypertension WT male mice but not in intact WT females. Further, we have new preliminary data showing that AngII induced hypertension in males is blocked by central infusions of the adrogen receptor flutamide and by central infusion of the superoxide dismutase (SOD) mimetic tempol and that males show greater levels of intracellular ROS in CVO neurons following Ang II long-term infusion than females. This proposal will use brainstem slices of circumventricular organs key to AngII hypertension, state-of-the-art imaging techniques, real-time RT-PCR, adeno-vector gene transfer and telemetry measurements of conscious blood pressure recordings to test the general hypothesis that sex and sex steroids modulate the central actions of Angll via interactions with free radical and NO generating pathways within the circumventricular organs of the brainstem and hypothalamus. This hypothesis will be tested with 4 specific aims:
Specific Aim 1. Determine the roles of nNOS and SOD on AngII induced increases in [Ca++]i in the brainstem and forebrain CVO brain slices from male and female mice.
Specific Aim 2 : Determine the effects of sex and sex steroids on AngII induced release of intracellular ROS in the brainstem and forebrain CVOs of male and female mice.
Specific Aim 3 : Determine the effects of sex and sex steroids on expression of SOD, nNOS and AT1 receptors in the brainstem and forebrain CVOs of males and females mice.
Specific Aim 4 : Determine the role of SOD and nNOS in AngII induced hypertension in WT males and females.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062261-09
Application #
7324837
Study Section
Special Emphasis Panel (ZRG1-CVS-C (03))
Program Officer
Thrasher, Terry N
Project Start
2000-02-15
Project End
2009-11-30
Budget Start
2007-12-15
Budget End
2009-11-30
Support Year
9
Fiscal Year
2008
Total Cost
$349,641
Indirect Cost
Name
University of Iowa
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Sandberg, Kathryn; Ji, Hong; Hay, Meredith (2015) Sex-specific immune modulation of primary hypertension. Cell Immunol 294:95-101
Schiller, Crystal Edler; O'Hara, Michael W; Rubinow, David R et al. (2013) Estradiol modulates anhedonia and behavioral despair in rats and negative affect in a subgroup of women at high risk for postpartum depression. Physiol Behav 119:137-44
Xue, Baojian; Beltz, Terry G; Yu, Yang et al. (2011) Central interactions of aldosterone and angiotensin II in aldosterone- and angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol 300:H555-64
Xue, Baojian; Badaue-Passos Jr, Daniel; Guo, Fang et al. (2009) Sex differences and central protective effect of 17beta-estradiol in the development of aldosterone/NaCl-induced hypertension. Am J Physiol Heart Circ Physiol 296:H1577-85
Xue, Baojian; Singh, Minati; Guo, Fang et al. (2009) Protective actions of estrogen on angiotensin II-induced hypertension: role of central nitric oxide. Am J Physiol Heart Circ Physiol 297:H1638-46
Xue, Baojian; Zhao, Yuanzi; Johnson, Alan Kim et al. (2008) Central estrogen inhibition of angiotensin II-induced hypertension in male mice and the role of reactive oxygen species. Am J Physiol Heart Circ Physiol 295:H1025-H1032
Xue, B; Johnson, A K; Hay, M (2007) Sex differences in angiotensin II- induced hypertension. Braz J Med Biol Res 40:727-34
Xue, Baojian; Pamidimukkala, Jaya; Lubahn, Dennis B et al. (2007) Estrogen receptor-alpha mediates estrogen protection from angiotensin II-induced hypertension in conscious female mice. Am J Physiol Heart Circ Physiol 292:H1770-6
Pamidimukkala, Jaya; Xue, Baojian; Newton, Leslie G et al. (2005) Estrogen receptor-alpha mediates estrogen facilitation of baroreflex heart rate responses in conscious mice. Am J Physiol Heart Circ Physiol 288:H1063-70
Xue, Baojian; Pamidimukkala, Jaya; Hay, Meredith (2005) Sex differences in the development of angiotensin II-induced hypertension in conscious mice. Am J Physiol Heart Circ Physiol 288:H2177-84

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