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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083947-07
Application #
8710314
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
2014-07-01
Budget End
2015-06-30
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Limberg, Jacqueline K; Ott, Elizabeth P; Holbein, Walter W et al. (2018) Pharmacological assessment of the contribution of the arterial baroreflex to sympathetic discharge patterns in healthy humans. J Neurophysiol 119:2166-2175
Miller, Virginia M; Kling, Juliana M; Files, Julia A et al. (2018) What's in a name: are menopausal ""hot flashes"" a symptom of menopause or a manifestation of neurovascular dysregulation? Menopause 25:700-703
Barnes, Jill N; Harvey, Ronée E; Miller, Kathleen B et al. (2018) Cerebrovascular Reactivity and Vascular Activation in Postmenopausal Women With Histories of Preeclampsia. Hypertension 71:110-117
Klassen, Stephen A; Limberg, Jacqueline K; Baker, Sarah E et al. (2018) The role of the paravertebral ganglia in human sympathetic neural discharge patterns. J Physiol 596:4497-4510
Baker, Sarah E; Limberg, Jacqueline K; Dillon, Gabrielle A et al. (2018) Aging Alters the Relative Contributions of the Sympathetic and Parasympathetic Nervous System to Blood Pressure Control in Women. Hypertension 72:1236-1242
Harvey, Ronée E; Barnes, Jill N; Hart, Emma C J et al. (2017) Influence of sympathetic nerve activity on aortic hemodynamics and pulse wave velocity in women. Am J Physiol Heart Circ Physiol 312:H340-H346
Ranadive, Sushant M; Harvey, Ronee E; Lahr, Brian D et al. (2017) Sympathetic responsiveness is not increased in women with a history of hypertensive pregnancy. Am J Physiol Regul Integr Comp Physiol 312:R49-R54
Al-Khateeb, Abdulrahman A; Limberg, Jacqueline K; Barnes, Jill N et al. (2017) Acute cyclooxygenase inhibition and baroreflex sensitivity in lean and obese adults. Clin Auton Res 27:17-23
Harvey, Ronée E; Johnson, Maja C; Ranadive, Sushant M et al. (2017) Aortic hemodynamics in postmenopausal women following cessation of hormone therapy. Physiol Rep 5:
Barnes, Jill N; Harvey, Ronée E; Zuk, Samantha M et al. (2017) Aortic hemodynamics and white matter hyperintensities in normotensive postmenopausal women. J Neurol 264:938-945

Showing the most recent 10 out of 55 publications