The long term goal of this project is to better understand the physiologic mechanisms of progesterone and a commonly-prescribed progestin on endothelial function and neural-vascular control in women. We will also explore potential interactions between the progestogens and estrogen on these physiologic mechanisms.
Our aim i s to investigate NO-dependent vasodilation in conduit and resistance vessels, to examine whether circulating levels of the vascular constrictor endothelin-1 is influenced by progestogens, and to investigate the effects of estrogen and progestogens on sympathetic outflow, baroreflex sensitivity, and vascular transduction. Our general approach is to suppress endogenous production of estrogen and progesterone using a gonadotropin-releasing hormone antagonist to create a hypoestrogen state. We will then administer progesterone or the progestin medroxyprogesterone acetate (MPA) alone or in combination with estrogen. The overall goal will be met by addressing the following specific aims: 1) Determine the acute effects of progesterone and MPA alone and in combination with estrogen on endothelium-dependent and endothelium-independent vasodilation in women. 2) Determine the acute effects of progesterone and MPA on sympathetic outflow, baroreflex sensitivity, and vascular transduction in women. 3) Determine the acute effects of progesterone and MPA on the contribution of nitric oxide and alpha-receptors to vasodilation and vasoconstriction in resistance vessels.PROJECT NARRATIVE Our current understanding of how natural and synthetic forms of progesterone impact the health of blood vessels and control of blood pressure in humans is lacking, despite the overwhelming use of these hormones in young and older women for contraceptive purposes, for hormone replacement therapy, and in the treatment of gynecological disorders. The goal of this project is to better understand how the natural and synthetic forms of progesterone impact blood vessel responsiveness and in the control of blood vessel tone by the sympathetic nervous system in women. We will also examine how these forms of progesterone interact with estrogen, with the goal to improve our understanding of the potential cardiovascular health benefits and risks of hormone therapy in both young and older women.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081671-04
Application #
8020971
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Goldberg, Suzanne H
Project Start
2008-02-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2011
Total Cost
$324,123
Indirect Cost
Name
University of Oregon
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
948117312
City
Eugene
State
OR
Country
United States
Zip Code
97403
Harvey, Ronee E; Hart, Emma C; Charkoudian, Nisha et al. (2015) Oral Contraceptive Use, Muscle Sympathetic Nerve Activity, and Systemic Hemodynamics in Young Women. Hypertension 66:590-7
Brunt, Vienna E; Fujii, Naoto; Minson, Christopher T (2015) Endothelial-derived hyperpolarization contributes to acetylcholine-mediated vasodilation in human skin in a dose-dependent manner. J Appl Physiol (1985) 119:1015-22
Zarling, Jacob A; Brunt, Vienna E; Vallerga, Anne K et al. (2015) Nitroxide pharmaceutical development for age-related degeneration and disease. Front Genet 6:325
Choi, Patricia J; Brunt, Vienna E; Fujii, Naoto et al. (2014) New approach to measure cutaneous microvascular function: an improved test of NO-mediated vasodilation by thermal hyperemia. J Appl Physiol (1985) 117:277-83
Carter, Jason R; Fu, Qi; Minson, Christopher T et al. (2013) Ovarian cycle and sympathoexcitation in premenopausal women. Hypertension 61:395-9
Brunt, Vienna E; Miner, Jennifer A; Kaplan, Paul F et al. (2013) Short-term administration of progesterone and estradiol independently alter carotid-vasomotor, but not carotid-cardiac, baroreflex function in young women. Am J Physiol Heart Circ Physiol 305:H1041-9
Brunt, Vienna E; Fujii, Naoto; Minson, Christopher T (2013) No independent, but an interactive, role of calcium-activated potassium channels in human cutaneous active vasodilation. J Appl Physiol (1985) 115:1290-6
Lakehomer, Hannah; Kaplan, Paul F; Wozniak, David G et al. (2013) Characteristics of scheduled bleeding manipulation with combined hormonal contraception in university students. Contraception 88:426-30
Fujii, Naoto; Reinke, Maggie C; Brunt, Vienna E et al. (2013) Impaired acetylcholine-induced cutaneous vasodilation in young smokers: roles of nitric oxide and prostanoids. Am J Physiol Heart Circ Physiol 304:H667-73
Smith, Michael M; Minson, Christopher T (2012) Obesity and adipokines: effects on sympathetic overactivity. J Physiol 590:1787-801

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