Hypertension incidence rises sharply after menopause, implicating a beneficial effect of estrogen on blood pressure (BP) regulation. However, there still are large gaps in the understanding of the underlying mechanisms and treatment of postmenopausal hypertension. Using intraneural microelectrodes to record postganglionic SNA in normotensive postmenopausal women, the applicant recently provided direct evidence for a major sympathoinhibitory effect of estrogen. Chronic estrogen replacement decreased SNA by 30% and caused a small decrease in 24-hour ambulatory BP. The most fascinating aspect of the work is that these effects were much more robust with transdermal than oral estrogen. She now wants to investigate: 1) the clinical importance of her findings by studying postmenopausal hypertension; and 2) underlying mechanism causing a greater effect of transdermal than oral estrogen on SNA and BP. She hypothesizes that the mechanism involves first-pass hepatic metabolism of oral estrogen leading to decreased hepatic production of insulin-like growth factor and excessive deposition of fat in the liver and around the abdominal viscera, factors which are likely to stimulate SNA and negate a primary sympathoinhibitory action of estrogen. To test her mechanistic hypothesis, she will need to acquire new research skills including euglycemic clamps and nuclear magnetic resonance measurements of regional fat distribution. She will use these techniques in exploring other clinical factors, such as concomitant administration of androgenic progestins, that are likely to engage some of the same adverse metabolic mechanisms and negate the antihypertensive effect of estrogen replacement. Finally, the applicant will learn to perform complementary experiments in a conscious rat model to determine the extent to which decreased activity of the sympathetic nervous system causes the antihypertensive effect of estrogen. The long-term goal of her work would be the discovery the most effective estrogen preparation that can prevent or treat hypertension in women after menopause.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23RR016321-02
Application #
6623553
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Wilde, David B
Project Start
2002-05-01
Project End
2007-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
2
Fiscal Year
2003
Total Cost
$124,200
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Fadel, Paul J; Orer, Hakan S; Barman, Susan M et al. (2004) Fractal properties of human muscle sympathetic nerve activity. Am J Physiol Heart Circ Physiol 286:H1076-87
Vongpatanasin, Wanpen; Taylor, J Andrew; Victor, Ronald G (2004) Effects of cocaine on heart rate variability in healthy subjects. Am J Cardiol 93:385-8
Abbas, Aamer; Fadel, Paul J; Wang, Zhongyun et al. (2004) Contrasting effects of oral versus transdermal estrogen on serum amyloid A (SAA) and high-density lipoprotein-SAA in postmenopausal women. Arterioscler Thromb Vasc Biol 24:e164-7
Barman, Susan M; Fadel, Paul J; Vongpatanasin, Wanpen et al. (2003) Basis for the cardiac-related rhythm in muscle sympathetic nerve activity of humans. Am J Physiol Heart Circ Physiol 284:H584-97
Vongpatanasin, Wanpen; Tuncel, Meryem; Wang, Zhongyun et al. (2003) Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women. J Am Coll Cardiol 41:1358-63
Tuncel, Meryem; Wang, Zhongyun; Arbique, Debbie et al. (2002) Mechanism of the blood pressure--raising effect of cocaine in humans. Circulation 105:1054-9