Vascular Dysfunction in Hypertensive Postmenopausal Women
| Status: | Recruiting |
|---|---|
| Conditions: | High Blood Pressure (Hypertension), Peripheral Vascular Disease |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 50 - 70 |
| Updated: | 10/5/2018 |
| Start Date: | September 1, 2017 |
| End Date: | December 31, 2019 |
| Contact: | Megan Wenner, Ph.D |
| Email: | mwenner@udel.edu |
| Phone: | 3028317343 |
Losartan and ET-1 Mediated Constriction in Postmenopausal Women With High Blood Pressure
The purpose of this study is to investigate the role of ET-1 in mediating vasoconstrictor
tone in hypertensive postmenopausal women (PMW) alone and in combination with a commonly
prescribed Angiotensin II (ANG II) antagonist. The long term goal is to understand the
mechanisms contributing to hypertension (HTN) in PMW. This study is the first step in
reaching our goal.
tone in hypertensive postmenopausal women (PMW) alone and in combination with a commonly
prescribed Angiotensin II (ANG II) antagonist. The long term goal is to understand the
mechanisms contributing to hypertension (HTN) in PMW. This study is the first step in
reaching our goal.
Cardiovascular disease (CVD) is the leading cause of death in women, and mortality from CVD
is higher in PMW compared to age-matched men. PMW are at a greater risk for developing HTN, a
major risk factor for CVD. They are also more likely to have uncontrolled or resistant HTN
despite medication.
ANG II is a common therapeutic target for the treatment HTN. ANG II blockade is highly
effective in normalizing blood pressure (BP) in hypertensive male rats, but does not reduce
BP to the same degree in hypertensive post menopausal female rats. Endothelin-1 (ET-1)
receptor antagonists reduce BP in hypertensive postmenopausal female rats, but have no effect
on males. Thus the mechanisms contributing to HTN in female rats and likely women,
particularly after menopause, are complex, multifactorial and not completely understood.
After menopause, the vasoconstrictor effects of both ANG II and ET-1 are amplified in animal
models. As such, these two predominant pathways may contribute to the high incidence of HTN
in PMW. ET-1 is a potent vasoconstrictor produced and released by endothelial cells that
binds to two receptor subtypes, ET-A and ET-B. While both receptors are located on vascular
smooth muscle (VSM) and mediate vasoconstriction, ET-B receptors are also located on the
endothelium and mediate vasodilation via nitric oxide.
Importantly, the production of ET-1 and expression of ET-A and B receptors can be modulated
by hormones such as estradiol and ANG II. Estradiol attenuates ET-1 production, and reduces
ET-1 mediated vasoconstriction via an ET-B receptor mechanism in vitro. Thus, decline in
estradiol after menopause may enhance vasoconstrictor tone via ET-1 and lead to HTN. ET-1
also potentiates the vasoconstrictor effects of ANG II since the vasoconstrictor and
hypertensive effects of ANG II are ameliorated by ET-1 receptor blockade. Additionally, ANG
II stimulates the synthesis of ET-1 and upregulates ET-A and ET-B receptor expression on VSM.
The ANG II receptor antagonist Losartan reduces ET-A and ET-B receptor expression and
attenuates the constrictor effects of ET-1 in a diabetic rat model. Therefore, ET-1 is an
important independent factor contributing to HTN in PMW, but therapeutic agents targeting
both ANG II and ET-1 may have greater efficacy given their interactions.
The investigators propose a comprehensive assessment of vascular function by measuring blood
flow responses in the cutaneous circulation during perfusion of ET-1 receptor antagonists via
microdialysis, combined with measures of intracellular protein and receptor expression of
endothelial cells and skin punch biopsies collected from normotensive and hypertensive PMW.
Investigators central hypothesis is that hypertensive PMW have greater ET-1 mediated
vasoconstrictor tone due to increased ET-1 expression, down-regulation of ET-B receptors on
endothelial cells and up-regulation of both ET-A and ET-B receptors on VSM leading to
increased vasoconstriction and HTN. Investigators further hypothesize that ANG II exacerbates
the increase in ET-1, and ET-A and ET-B receptor expression contributing to exaggerated
constriction with HTN in PMW.
is higher in PMW compared to age-matched men. PMW are at a greater risk for developing HTN, a
major risk factor for CVD. They are also more likely to have uncontrolled or resistant HTN
despite medication.
ANG II is a common therapeutic target for the treatment HTN. ANG II blockade is highly
effective in normalizing blood pressure (BP) in hypertensive male rats, but does not reduce
BP to the same degree in hypertensive post menopausal female rats. Endothelin-1 (ET-1)
receptor antagonists reduce BP in hypertensive postmenopausal female rats, but have no effect
on males. Thus the mechanisms contributing to HTN in female rats and likely women,
particularly after menopause, are complex, multifactorial and not completely understood.
After menopause, the vasoconstrictor effects of both ANG II and ET-1 are amplified in animal
models. As such, these two predominant pathways may contribute to the high incidence of HTN
in PMW. ET-1 is a potent vasoconstrictor produced and released by endothelial cells that
binds to two receptor subtypes, ET-A and ET-B. While both receptors are located on vascular
smooth muscle (VSM) and mediate vasoconstriction, ET-B receptors are also located on the
endothelium and mediate vasodilation via nitric oxide.
Importantly, the production of ET-1 and expression of ET-A and B receptors can be modulated
by hormones such as estradiol and ANG II. Estradiol attenuates ET-1 production, and reduces
ET-1 mediated vasoconstriction via an ET-B receptor mechanism in vitro. Thus, decline in
estradiol after menopause may enhance vasoconstrictor tone via ET-1 and lead to HTN. ET-1
also potentiates the vasoconstrictor effects of ANG II since the vasoconstrictor and
hypertensive effects of ANG II are ameliorated by ET-1 receptor blockade. Additionally, ANG
II stimulates the synthesis of ET-1 and upregulates ET-A and ET-B receptor expression on VSM.
The ANG II receptor antagonist Losartan reduces ET-A and ET-B receptor expression and
attenuates the constrictor effects of ET-1 in a diabetic rat model. Therefore, ET-1 is an
important independent factor contributing to HTN in PMW, but therapeutic agents targeting
both ANG II and ET-1 may have greater efficacy given their interactions.
The investigators propose a comprehensive assessment of vascular function by measuring blood
flow responses in the cutaneous circulation during perfusion of ET-1 receptor antagonists via
microdialysis, combined with measures of intracellular protein and receptor expression of
endothelial cells and skin punch biopsies collected from normotensive and hypertensive PMW.
Investigators central hypothesis is that hypertensive PMW have greater ET-1 mediated
vasoconstrictor tone due to increased ET-1 expression, down-regulation of ET-B receptors on
endothelial cells and up-regulation of both ET-A and ET-B receptors on VSM leading to
increased vasoconstriction and HTN. Investigators further hypothesize that ANG II exacerbates
the increase in ET-1, and ET-A and ET-B receptor expression contributing to exaggerated
constriction with HTN in PMW.
Inclusion Criteria: - Women.
- > 1year post menopausal.
- Age range 50-70 years
- Resting ECG in normal limits
- Standard blood chemistry within normal limits
- Systolic blood pressure: <130mm Hg for normotensives; >130mm Hg for hypertensives.
- Diastolic blood pressure: < 80mm Hg for normotensives; > 80mm Hg for hypertensives.
Exclusion Criteria:
- History of cardiovascular disease
- Blood clots or stroke
- Cancer
- Diabetes
- Kidney or Liver disease
- Obesity (BMI>35kg/m2)
- Pregnant/Breast feeding
- Current use of hormone therapy
- Current use of tobacco products
- High cholesterol
- Current use of anti-hypertensive meds
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