Neurovascular Adaptations in Aging Women

Overseen By Jacqueline K Limberg

Age: 18+

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to better understand how blood vessels change in aging women, focusing on the role of the sympathetic nervous system, which controls the body's fight-or-flight response. Researchers will test how various treatments, such as hormones and other chemicals, affect these changes. Suitable participants have not undergone hormone therapy or significant surgeries like a hysterectomy and do not have conditions such as obesity or high blood pressure. As an Early Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants a chance to contribute to groundbreaking medical knowledge.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that acetylcholine can irritate the skin and eyes and may also affect the respiratory system. Estrogen carries some risks, as it has been linked to a higher chance of stroke and blood clots in older women. Isoproterenol can irritate the skin and eyes and is not recommended for individuals with certain heart conditions. Nitroprusside is toxic if swallowed and might irritate the skin and eyes. Lastly, norepinephrine, often used as a medicine, should be used carefully when combined with certain antidepressants.

The trial is in its early stages, so information on the safety of these treatments for this specific use is limited. However, many of these substances have been used in medical settings for other purposes, providing some context for their safety. Participants should consider these potential risks and discuss them with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for neurovascular changes in aging women because they each offer unique ways to impact the body's vascular system. Unlike traditional treatments that may not target the nuances of neurovascular health, acetylcholine and norepinephrine directly influence nerve signaling and blood vessel function, potentially providing more precise management. Estrogen, already known for its protective effects, is being evaluated for its specific role in vascular adaptations, which could lead to more personalized hormone-based therapies. Isoproterenol and nitroprusside work by affecting blood pressure and circulation, offering alternative mechanisms to improve vascular health. Together, these treatments could pave the way for better-targeted strategies to maintain vascular health in aging women.

What evidence suggests that this trial's treatments could be effective for neurovascular adaptations in aging women?

This trial will examine the effects of various treatments on neurovascular health in aging women. Research has shown that acetylcholine plays a crucial role in brain health as people age. It can help slow or improve memory and thinking problems in older adults, offering promise for aging women. Estrogen protects heart and brain health, particularly when taken during early menopause, and may reduce the risk of dementia. Studies have found that isoproterenol affects blood vessels differently based on age and gender, which could be significant for women's health as they age. Nitroprusside helps manage blood pressure, a common concern in older adults. Lastly, norepinephrine regulates blood flow and can predict certain heart-related responses, which is vital for maintaining heart health during aging. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

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.

Pregnancy or breastfeeding

Body mass index ≥30 kg/m2

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: Women Experimental Treatment 5 Interventions

Women will be 18-70 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+

American Heart Association (AHA)

Collaborator

Trials

2

Recruited

530+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

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]

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 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]

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]

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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC4573353/

Estrogen-Cholinergic Interactions: Implications for ...

The current data showed that anticholinergic blockade resulted in an “older” pattern of brain activation (Davis et al., 2008) for postmenopausal women and ...

2.

sciencedirect.com

sciencedirect.com/science/article/pii/S2211124725000208

A central role for acetylcholine in entorhinal cortex function ...

Our data demonstrate that alterations to the cholinergic EC are an early, conserved feature of cognitive aging across species and may serve as ...

3.

nature.com

nature.com/articles/s41392-025-02145-7

Antiageing strategy for neurodegenerative diseases

This integrated approach is a promising strategy to effectively prevent, pause or slow down the progression of neurodegenerative diseases.

4.

cell.com

cell.com/cell-reports/pdf/S2211-1247(25)00020-8.pdf

A central role for acetylcholine in entorhinal cortex function ...

Our data demonstrate that alterations to the cholinergic EC are an early, conserved feature of cognitive aging across species and may serve as ...

5.

link.springer.com

link.springer.com/article/10.1007/s40263-023-01017-4

Turning the Spotlight to Cholinergic Pharmacotherapy of ...

The data analysis revealed a slower decline or improvement in language performance among patients with neurodegenerative and vascular brain ...

6.

fishersci.com

fishersci.com/content/dam/fishersci/en_US/documents/programs/education/regulatory-documents/sds/chemicals/chemicals-a/S25652.pdf

Safety Data Sheet

Hazard statements: Causes skin irritation. Causes serious eye irritation. May cause respiratory irritation. Precautionary statements:.

7.

chemos.de

chemos.de/import/data/msds/GB_en/60-31-1-A0000619-GB-en.pdf

Safety Data Sheet: Acetylcholine chloride

Hazardous combustion products: see section 5. Personal protective equipment: see section 8. Incompatible materials: see section 10. Disposal considerations: see ...

8.

fishersci.com

fishersci.com/store/msds?partNumber=AAL0216814&productDescription=ACETYLCHOLINE+CHLRIDE+25G&vendorId=VN00024248&countryCode=US&language=en

Acetylcholine chloride

Precautionary Statements. Prevention. Wash face, hands and any exposed skin thoroughly after handling. Wear protective gloves/protective ...

9.

cdn.caymanchem.com

cdn.caymanchem.com/cdn/msds/23829m.pdf

Safety Data Sheet

Eye irritation 2A. H319 Causes serious eye irritation. Specific target organ toxicity (single exposure) 3 H335 May cause respiratory irritation.

10.

sigmaaldrich.com

sigmaaldrich.com/KR/ko/sds/sigma/a6625?srsltid=AfmBOooRluPBWvIeVft9xYiapdqv7JKM5T7az0isLcxc22k1KQuzKyIn

SAFETY DATA SHEET

OSHA: No component of this product present at levels greater than or equal to 0.1% is on OSHA's list of regulated carcinogens. Reproductive ...