The overall goal of HL-83947 is to explore sympathetic regulation of blood pressure (BP) in humans. As a result of observations made over the last 5 years our renewal application is focused on novel ideas about the sympathetic nervous system and the rise in BP in postmenopausal women. It is well known that women have lower BP than men in early adulthood. However, this protection disappears at menopause, after which women have an accelerating risk of hypertension compared to men of similar age. Along these lines, we propose that there is a BP raising "double hit" in postmenopausal women that includes loss of ?-adrenergic vasodilation which normally offsets ?-adrenergic constriction in young women coupled with an age related rise in sympathetic vasoconstrictor activity. Together these factors cause a sympathetically mediated rise in blood pressure after menopause. In this context, the major ideas underpinning this application are: 1) after menopause there is a marked reduction in the NO component of ?-adrenergic vasodilation;2) this loss of ?-adrenergic vasodilation along with age related increases in sympathetic activity leads to increased sympathetic support of BP in postmenopausal women;3) these age related changes are caused in part by a loss of female reproductive hormones at menopause and can be attenuated by Menopausal Hormone Therapy (MHT);and 4) they can also be mitigated by regular exercise which can restore endothelial function and may reduce sympathetic activity in postmenopausal women. To address these ideas we will use an ensemble of experimental tools developed and mastered in our laboratory to explore the following specific aims:
Aim 1 will test whether forearm vasodilation to isoproterenol is blunted in postmenopausal women compared to young women, and whether this blunted vasodilation is due to a loss of the nitric oxide (NO) mediated component of ?-adrenergic vasodilation.
Aim 2 will test whether sympathetic support of blood pressure is related to MSNA in young and postmenopausal women. We will measure MSNA and arterial pressure before and during ganglionic blockade with trimethaphan.
Aim 3 will test whether exercise training augments endothelial and ?-adrenergic vasodilation and limits sympathetic support of blood pressure in postmenopausal women. We will also explore how training interacts with MHT. Importantly, most ideas about sympathetic and endothelial control of BP have undergone minimal or no direct testing in women and our preliminary data clearly show the need for more data especially in postmenopausal women. Since blood pressure control is a biomedically significant issue, the studies we propose are highly relevant to public health and also designed to provide basic mechanistic insight into an important and poorly understood cardiovascular risk factor in women.

Public Health Relevance

The overall goal of this application is to understand why blood pressure rises in postmenopausal women. While it is well known that women have lower blood pressure than men in early adulthood, this protection disappears at menopause. Following menopause women have an accelerating risk of hypertension compared to men of similar age. In this context, we propose that there is blood pressure raising double hit in postmenopausal women that includes loss of ?-adrenergic vasodilation via nitric oxide which normally offsets ?-adrenergic constriction in young women coupled with an age related rise in sympathetic vasoconstrictor activity. This double hit then causes a sympathetically mediated rise in blood pressure after menopause. Importantly, most ideas about sympathetic and endothelial control of BP have undergone minimal or no direct testing in women and our preliminary data clearly show the need for more data especially in postmenopausal women. Finally, since blood pressure control is a biomedically significant issue, the studies we propose are highly relevant to public health and also designed to provide basic mechanistic insight into an important and poorly understood cardiovascular risk factor in women.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL083947-06A1
Application #
8532123
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
2006-04-01
Project End
2017-06-30
Budget Start
2013-08-01
Budget End
2014-06-30
Support Year
6
Fiscal Year
2013
Total Cost
$388,963
Indirect Cost
$144,332
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Barnes, Jill N; Hart, Emma C; Curry, Timothy B et al. (2014) Aging enhances autonomic support of blood pressure in women. Hypertension 63:303-8
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Casey, Darren P; Curry, Timothy B; Charkoudian, Nisha et al. (2013) The effects of acute beta-adrenergic blockade on aortic wave reflection in postmenopausal women. Am J Hypertens 26:503-10
Carter, Jason R; Fu, Qi; Minson, Christopher T et al. (2013) Ovarian cycle and sympathoexcitation in premenopausal women. Hypertension 61:395-9
Curry, Timothy B; Somaraju, Madhuri; Hines, Casey N et al. (2013) Sympathetic support of energy expenditure and sympathetic nervous system activity after gastric bypass surgery. Obesity (Silver Spring) 21:480-5
Hart, Emma C; Charkoudian, Nisha; Joyner, Michael J et al. (2013) Relationship between sympathetic nerve activity and aortic wave reflection characteristics in postmenopausal women. Menopause 20:967-72
Vianna, Lauro C; Hart, Emma C; Fairfax, Seth T et al. (2012) Influence of age and sex on the pressor response following a spontaneous burst of muscle sympathetic nerve activity. Am J Physiol Heart Circ Physiol 302:H2419-27

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