Neurovascular Adaptations in Aging Women

Overseen By Jacqueline K Limberg

Age: 18 - 65

Sex: Female

Trial Phase: Phase < 1

Sponsor: University of Missouri-Columbia

Must not be taking: Metabolic, Autonomic, Respiratory, others

Disqualifiers: Pregnancy, BMI ≥30, Smoking, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

64 Participants Needed

Trial Summary

What is the purpose of this trial?

Our goal is to enhance our understanding of early vascular adaptations in aging women with an emphasis on the sympathetic nervous system.

Do I need to stop my current medications to join the trial?

Yes, you will need to stop taking medications that affect metabolic, autonomic, or respiratory functions, as well as oral hormonal contraceptives if used in the last 6 months.

What data supports the effectiveness of the drug in the clinical trial 'Neurovascular Adaptations in Aging Women'?

Research shows that estradiol, a component of the treatment, can enhance cardiovascular reflexes and autonomic tone, which are important for heart health. Additionally, estradiol has been found to increase blood flow and reduce vascular resistance, suggesting potential benefits for neurovascular health. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Research suggests that estrogen and related compounds can affect blood vessel function and heart rate responses, but these studies are mostly in animals. Estrogen seems to enhance blood vessel relaxation and may influence heart rate control, but more human studies are needed to fully understand safety. ^{1 6 7 8 9}

How does this drug differ from other treatments for neurovascular adaptations in aging women?

This drug combination is unique because it targets multiple pathways involved in blood vessel function and blood pressure regulation, particularly in postmenopausal women. Estrogen in the treatment helps modulate sympathetic nerve activity and nitric oxide production, which are crucial for maintaining blood vessel health and reducing hypertension (high blood pressure) risks associated with menopause. ^{1 10 11 12 13}

Eligibility Criteria

This trial is for aging women who are interested in participating in a study focused on understanding how their blood circulation and nervous system change with age. Specific eligibility criteria have not been provided.

Inclusion Criteria

I was assigned female at birth.

Exclusion Criteria

I have used hormone replacement therapy in the past.

I was assigned male at birth.

Pregnancy or breastfeeding

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo assessments to study early vascular adaptations with an emphasis on the sympathetic nervous system

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Acetylcholine
• Estrogen
• Isoproterenol
• Nitroprusside
• Norepinephrine

Trial Overview The trial is testing the effects of various substances, including Nitroprusside, Norepinephrine, Acetylcholine, Isoproterenol, and Estrogen on the sympathetic nervous system and blood circulation in aging women.

Participant Groups

Group I: Women Experimental Treatment 5 Interventions

Women will be 18-55 years of age

Acetylcholine is already approved in United States, European Union for the following indications:

Approved in United States as Miochol-E System Pak for:

• Anterior segment surgery where rapid miosis may be required

Approved in European Union as Acetylcholine for:

• Anterior segment surgery where rapid miosis may be required

Who Is Running the Clinical Trial?

University of Missouri-Columbia

Lead Sponsor

Trials

387

Recruited

629,000+

Findings from Research

Ovariectomized female rats and male rats showed increased arterial reactivity to constricting agents compared to normal female rats, indicating that the absence of female sex hormones may heighten cardiovascular risk.

Both normal and ovariectomized female rats exhibited enhanced relaxation responses to sodium nitroprusside compared to male rats, suggesting that female hormones may help maintain vasodilatory function even after menopause.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of male gender and female sex hormone deficiency on the vascular responses of the rat in vitro. Nevala, R., Paakkari, I., Tarkkila, L., et al.[2014]

Low-dose estrogen therapy significantly improves autonomic tone and enhances baroreflex sensitivity in ovariectomized female rats, suggesting potential cardiovascular benefits for postmenopausal women.

The effects of estrogen on heart rate control are mediated through estrogen receptors, as blocking these receptors with ICI 182,780 negated the positive changes, indicating the importance of receptor activation for cardiovascular effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute injection of 17beta-estradiol enhances cardiovascular reflexes and autonomic tone in ovariectomized female rats. Saleh, TM., Connell, BJ., Saleh, MC.[2019]

In a study of 32 young women, progesterone was found to blunt the sensitivity of the carotid-vasomotor baroreflex, while estradiol enhanced this sensitivity, indicating that these hormones have opposing effects on vascular responses.

Higher levels of estradiol were linked to an increased rise in mean arterial pressure and a greater decrease in femoral vascular conductance during baroreflex testing, suggesting that estradiol may play a role in enhancing cardiovascular responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term administration of progesterone and estradiol independently alter carotid-vasomotor, but not carotid-cardiac, baroreflex function in young women. Brunt, VE., Miner, JA., Kaplan, PF., et al.[2021]

Nitric oxide (NO) plays a significant role in maintaining basal endometrial blood flow in ovariectomized rats, as shown by the reduction in blood flow when NO synthesis was inhibited with L-NAME.

Estradiol 17beta (E2beta) effectively increases endometrial blood flow and reduces vascular resistance, but its effects are negated when NO synthesis is inhibited, suggesting that other mechanisms may be responsible for E2beta's action on blood flow.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulation of endometrial blood flow in ovariectomized rats: assessment of the role of nitric oxide. Zhang, RS., Guth, PH., Scremin, OU., et al.[2019]

Chronic administration of estrogen and the selective estrogen receptor modulator LY117018 significantly enhances the release of nitric oxide in rat aorta, suggesting a potential mechanism for improved vascular function.

Ovariectomized rats treated with estrogen showed greater relaxation responses to acetylcholine compared to those treated with both progesterone and estrogen, indicating that estrogen alone may be more effective in promoting endothelial function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estrogen and selective estrogen receptor modulator LY117018 enhance release of nitric oxide in rat aorta. Rahimian, R., Laher, I., Dube, G., et al.[2014]

Estrogen enhances baroreflex heart rate responses to certain stimuli (like ANG II and phenylephrine) primarily through the estrogen receptor-alpha (ERalpha) subtype, as shown in a study involving ovariectomized female mice.

In the absence of ERalpha, the facilitation of these baroreflex responses by estrogen is lost, indicating that ERalpha plays a crucial role in the central modulation of heart rate responses to blood pressure changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estrogen receptor-alpha mediates estrogen facilitation of baroreflex heart rate responses in conscious mice. Pamidimukkala, J., Xue, B., Newton, LG., et al.[2020]

In a study of 146 participants (73 normotensive and 73 hypertensive), it was found that menopause is linked to a significant decline in endothelium-dependent vasodilation, particularly in women, indicating that endogenous estrogens may protect against endothelial dysfunction.

Before menopause, normotensive women showed no endothelial dysfunction, while hypertensive women experienced less severe age-related impairment compared to men; however, post-menopause, their endothelial function declined similarly to that of men.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Menopause is associated with endothelial dysfunction in women. Taddei, S., Virdis, A., Ghiadoni, L., et al.[2019]

Estrogen appears to negatively affect the hypotensive (blood pressure-lowering) effects of alpha2-receptor agonists like alpha-methyldopa in female rats, suggesting a complex interaction between estrogen and cardiovascular control mechanisms.

In ovariectomized (Ovx) rats, the hypotensive response to alpha-methyldopa was enhanced, but this effect was reversed with estrogen replacement, indicating that estrogen plays a crucial role in modulating the effectiveness of certain antihypertensive medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential modulation by estrogen of alpha2-adrenergic and I1-imidazoline receptor-mediated hypotension in female rats. El-Mas, MM., Abdel-Rahman, AA.[2019]

Chronic treatment with 17beta-estradiol (E(2)beta) significantly enhances the ability of acetylcholine (ACh) to induce relaxation in isolated rat anterior cerebral small arteries, indicating improved endothelial function.

The mechanism behind this potentiation appears to involve increased production and release of nitric oxide (NO) from endothelial cells, which is crucial for the relaxation response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estrogen-induced augmentation of endothelium-dependent nitric oxide-mediated vasodilation in isolated rat cerebral small arteries. Momoi, H., Ikomi, F., Ohhashi, T.[2019]

Menopause and male gender are linked to reduced nitric oxide (NO) activity in arteries, which may increase cardiovascular risk, as shown in a study involving 41 participants (15 premenopausal women, 12 postmenopausal women, and 14 men).

Estrogen replacement therapy for two weeks significantly restored vascular NO activity in postmenopausal women to levels similar to premenopausal women, indicating its potential role in mitigating cardiovascular risks associated with menopause.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of the menopause, gender, and estrogen replacement therapy on vascular nitric oxide activity. Majmudar, NG., Robson, SC., Ford, GA.[2013]

In female rats, estrogen plays a crucial role in enhancing the expression of β1- and β3-adrenoceptors, leading to greater vasorelaxation and reduced vasoconstriction compared to males; this effect is diminished after ovariectomy, which removes the ovaries and decreases estrogen levels.

The study found that these sex-specific differences in vascular response are also present in human mammary arteries, where women exhibit higher levels of β1- and β3-adrenoceptors than men, suggesting that estrogen's influence on vascular tone regulation is a common mechanism across species.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estrogen determines sex differences in adrenergic vessel tone by regulation of endothelial β-adrenoceptor expression. Riedel, K., Deussen, AJ., Tolkmitt, J., et al.[2020]

Estrogen plays a crucial role in regulating blood pressure by influencing the sympathetic nervous system, and its deficiency during menopause leads to increased sympathetic nerve activity, which may contribute to higher blood pressure in postmenopausal women.

Menopause is associated with heightened alpha-adrenergic vasoconstriction and reduced nitric oxide release, which together may cause elevated resting blood pressure and exaggerated responses to stress and exercise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autonomic regulation of blood pressure in menopause. Vongpatanasin, W.[2009]

Oestrogen deficiency in ovariectomized (OVX) rats leads to reduced expression of neuronal nitric oxide synthase (nNOS) in skeletal muscle, resulting in increased sympathetic vasoconstriction during exercise.

Chronic treatment with 17beta-oestradiol can reverse the effects of oestrogen deficiency, restoring nNOS levels and improving the modulation of vasoconstriction in exercising skeletal muscle.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impaired vasomodulation is associated with reduced neuronal nitric oxide synthase in skeletal muscle of ovariectomized rats. Fadel, PJ., Zhao, W., Thomas, GD.[2018]

References

1. Poland pubmed.ncbi.nlm.nih.gov

The effects of male gender and female sex hormone deficiency on the vascular responses of the rat in vitro. [2014]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Acute injection of 17beta-estradiol enhances cardiovascular reflexes and autonomic tone in ovariectomized female rats. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Short-term administration of progesterone and estradiol independently alter carotid-vasomotor, but not carotid-cardiac, baroreflex function in young women. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Regulation of endometrial blood flow in ovariectomized rats: assessment of the role of nitric oxide. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Estrogen and selective estrogen receptor modulator LY117018 enhance release of nitric oxide in rat aorta. [2014]

6. United States pubmed.ncbi.nlm.nih.gov

Estrogen receptor-alpha mediates estrogen facilitation of baroreflex heart rate responses in conscious mice. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Menopause is associated with endothelial dysfunction in women. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Differential modulation by estrogen of alpha2-adrenergic and I1-imidazoline receptor-mediated hypotension in female rats. [2019]

9. Japan pubmed.ncbi.nlm.nih.gov

Estrogen-induced augmentation of endothelium-dependent nitric oxide-mediated vasodilation in isolated rat cerebral small arteries. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Effects of the menopause, gender, and estrogen replacement therapy on vascular nitric oxide activity. [2013]

11. United States pubmed.ncbi.nlm.nih.gov

Estrogen determines sex differences in adrenergic vessel tone by regulation of endothelial β-adrenoceptor expression. [2020]

12. United States pubmed.ncbi.nlm.nih.gov

Autonomic regulation of blood pressure in menopause. [2009]

13. England pubmed.ncbi.nlm.nih.gov

Impaired vasomodulation is associated with reduced neuronal nitric oxide synthase in skeletal muscle of ovariectomized rats. [2018]