Acetylcholine for Blood Vessel Function

(CAP NOVA Trial)

Overseen By Anna Stanhewicz, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Iowa

Must not be taking: Stimulants, Antihypertensives, Statins

Disqualifiers: Cardiovascular, Metabolic, Renal, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

56 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how acetylcholine, a chemical in the body, affects blood flow in the skin. Researchers are testing a new method to measure the function of small blood vessels, which might help identify issues early. The study involves a simple procedure to deliver acetylcholine to a small area of skin and observe the blood vessels' response. Young adults who are generally healthy and not taking medications that affect blood vessels might be suitable for this trial.

As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking medical insights.

Will I have to stop taking my current medications?

The trial requires that you do not use medications that could affect blood vessel function, like stimulants or blood pressure medications, within 8 weeks before joining. If you're on such medications, you may need to stop them to participate.

What prior data suggests that this method is safe for assessing microvascular function?

Research has shown that acetylcholine affects blood vessels by causing them to widen, a process called vasodilation, which improves blood flow. In this study, the treatment uses a method called intradermal microdialysis, which is minimally invasive and targets a small area of the skin.

Other studies have linked acetylcholine to side effects like swelling and clouding of the eye's outer layer, but these are rare and specific to eye treatments. Since this study applies acetylcholine to the skin, the side effects might differ.

This trial is in an early phase, so the safety of the treatment is still under close examination. Participants' experiences will help researchers understand how well acetylcholine is tolerated when used in this manner. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using acetylcholine for blood vessel function because it offers a different approach compared to traditional treatments. Most treatments focus on controlling symptoms or risk factors like high blood pressure or cholesterol. But acetylcholine works by directly targeting the microvasculature, potentially improving blood flow through the skin's tiny blood vessels. This method uses intradermal microdialysis to deliver the treatment precisely where needed, which could lead to more effective management of microvascular issues. This unique delivery and action mechanism could provide a more targeted way to improve vascular health.

What evidence suggests that acetylcholine is effective for assessing microvascular function?

Research shows that acetylcholine helps widen blood vessels by utilizing nitric oxide, a natural substance in the body. This widening can lower blood pressure and improve blood flow. Studies indicate that acetylcholine plays a crucial role in how blood vessels react to changes in blood flow. It signals the cells lining the blood vessels to relax, allowing more blood to pass through. In simpler terms, acetylcholine keeps blood vessels flexible and responsive, which is important for healthy circulation. Participants in this trial will receive acetylcholine to assess its effects on microvascular endothelial function. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for young adults aged 18-30 who are interested in participating in a study examining blood vessel function in the skin. The study involves local heating of the skin and filling out surveys related to lifestyle factors like sleep, physical activity, and stress.

Inclusion Criteria

I am either a man or a woman.

Exclusion Criteria

Pregnancy (including a positive urine pregnancy test) or breast-feeding

Non-English-speaking. Participants need to understand English to follow instructions and comply with procedures conducted during the screening and experimental visits.

I have taken medication that could affect blood vessel function in the last 8 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants undergo baseline assessments including microvascular blood flow response to acetylcholine and local heat at 42°C and 39°C using laser-Doppler flowmetry and intradermal microdialysis.

1 day

1 visit (in-person, average of 4 hours)

Follow-up

Participants are monitored for any adverse effects and overall health status after the baseline assessment.

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Acetylcholine

Trial Overview The trial is testing how well blood vessels in the skin respond to heat as a way to assess nitric oxide-dependent dilation. It compares two different temperatures (39°C and 42°C) using intradermal microdialysis—a technique that delivers drugs directly into the skin.

How Is the Trial Designed?

Group I: assessment of microvascular endothelial function Experimental Treatment 1 Intervention

The investigators use intradermal microdialysis to deliver acetylcholine, L-NAME, and acetylcholine + L-NAME to the cutaneous microvasculature.

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 Iowa

Lead Sponsor

Trials

486

Recruited

934,000+

Published Research Related to This Trial

Acetylcholine (Ach) stimulates nitric oxide (NO) production in human brain microvascular endothelial cells through a calcium-dependent mechanism, specifically via M5 muscarinic receptors, which are crucial for this process.

The study reveals that the increase in intracellular calcium concentration induced by Ach is essential for NO release, highlighting the role of M5-mAchRs and calcium signaling in regulating cerebral blood flow.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muscarinic M5 receptors trigger acetylcholine-induced Ca2+ signals and nitric oxide release in human brain microvascular endothelial cells. Zuccolo, E., Laforenza, U., Negri, S., et al.[2020]

Acetylcholine is not only a key neurotransmitter in the nervous system but also plays significant roles in nonneuronal tissues, including red blood cells, where it regulates various physiological processes.

Recent research highlights the importance of acetylcholine in red blood cell functions such as rheology, ion concentration balance, nitric oxide metabolism, and protein phosphorylation, suggesting potential new therapeutic targets for vascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonneuronal cholinergic system in human erythrocytes: biological role and clinical relevance. de Almeida, JP., Saldanha, C.[2021]

Acetylcholine plays a crucial role in regulating blood vessel tone, which affects blood flow and pressure.

Understanding how acetylcholine influences blood vessel function can help in developing treatments for cardiovascular diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endothelial biology in humans: from acetylcholine testing in coronary arteries to personalized management of coronary heart disease. Berry, D.[2015]

Acetylcholine (ACh) induces three distinct types of vasomotion in porcine ear veins, with relaxation occurring at concentrations above 10(-9) M, which can be inhibited by atropine, indicating the involvement of muscarinic receptors.

The study found that intraluminal application of ACh resulted in stronger dilation and subsequent contraction compared to extraluminal application, suggesting that the receptors responsible for these responses are primarily located on the inside of the vessel wall.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of acetylcholine on different muscarinic receptors in the perfused porcine ear vein. Schneider, E., Felix, W.[2019]

Acetylcholine (ACh) can trigger calcium (Ca2+) influx in rabbit aortic endothelial cells without needing to deplete intracellular calcium stores, indicating a novel mechanism of action for ACh in these cells.

The study found that both ACh and sarcoplasmic-endoplasmic reticulum Ca2+ ATPase blockers activated Ca2+ influx through similar pathways, suggesting that receptor activation and intracellular calcium store depletion may engage the same Ca2+ entry mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple mechanisms of activating Ca2+ entry in freshly isolated rabbit aortic endothelial cells. Wang, X., van Breemen, C.[2019]

The M3 muscarinic acetylcholine receptor is crucial for mediating both vasodilation in intact ophthalmic arteries and vasoconstriction in arteries without endothelium, as shown in studies using M3 receptor-deficient mice and wild-type controls.

In endothelium-removed arteries, acetylcholine-induced vasoconstriction was significantly reduced in M3R(-/-) mice, highlighting the M3 receptor's role in cholinergic responses, while responses to other agents like nitric oxide remained unaffected, indicating a specific mechanism of action for the M3 receptor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of the M3 muscarinic acetylcholine receptor subtype in murine ophthalmic arteries after endothelial removal. Gericke, A., Steege, A., Manicam, C., et al.[2021]

Alzheimer's disease (AD) patients showed impaired blood flow regulation in the brain, indicated by increased damping in flow responses and lower resting flow velocities compared to healthy controls.

Treatment with acetylcholinesterase inhibitors (AChEI) like donepezil improved these blood flow responses in a dose-dependent manner, suggesting that enhancing cholinergic function may help restore blood supply to active neurons in AD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetylcholine esterase inhibitor donepezil improves dynamic cerebrovascular regulation in Alzheimer patients. Rosengarten, B., Paulsen, S., Molnar, S., et al.[2022]

Administration of recombinant choline acetyltransferase (ChAT) in mice with angiotensin II-induced hypertension significantly reduced blood pressure through nitric oxide-dependent vasodilation, demonstrating its potential as a therapeutic intervention.

A modified version of ChAT, PEG-ChAT, showed a longer-lasting effect on lowering blood pressure compared to regular ChAT, suggesting that enhancing the stability of ChAT could improve its efficacy in treating hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic administration of choline acetyltransferase decreases blood pressure in murine hypertension. Stiegler, A., Li, JH., Shah, V., et al.[2023]

Acetylcholine, traditionally thought to primarily cause blood vessel dilation, actually has a more complex role, often leading to constriction in many species, including humans, particularly in the coronary circulation.

The presence of both endothelium-derived relaxing factor (EDRF) and cholinergic constrictor receptors complicates our understanding of vascular responses, suggesting that cholinergic constriction may contribute to conditions like coronary artery spasm and sudden death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cholinergic constriction in the general circulation and its role in coronary artery spasm. Kalsner, S.[2019]

All five muscarinic receptor subtypes were found in murine ophthalmic arteries, with M(3) and M(5) receptors showing higher expression levels, indicating their potential importance in vascular function.

The study revealed that M(3) receptors play a crucial role in regulating the dilation of ophthalmic arteries in response to acetylcholine, as their absence significantly impaired this response, while M(5) receptors did not affect this mechanism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cholinergic responses of ophthalmic arteries in M3 and M5 muscarinic acetylcholine receptor knockout mice. Gericke, A., Mayer, VG., Steege, A., et al.[2021]

Acetylcholine (ACh) induces hyperpolarization and relaxation of the guinea pig coronary artery, but this effect is dependent on the presence of the endothelium, as removing it abolishes these responses.

The study suggests that ACh's ability to relax blood vessels involves both endothelial-derived factors stimulating guanylate cyclase and hyperpolarization of smooth muscle, highlighting the importance of endothelial function in vascular responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of ACh on electrical and mechanical activity in guinea pig coronary arteries. Keef, KD., Bowen, SM.[2017]

In a study involving 20 normotensive volunteers, both acetylcholine (ACh) and methacholine (MCh) caused dose-dependent vasodilation, with MCh being significantly more potent, likely due to the rapid degradation of ACh in plasma.

The findings suggest that the M3 muscarinic receptor subtype primarily mediates cholinergic vasodilation in the forearm resistance vasculature, as indicated by the rank order of potency of receptor antagonists used in the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo characterization of vasodilating muscarinic-receptor subtypes in humans. Bruning, TA., Hendriks, MG., Chang, PC., et al.[2019]

Acetylcholine causes a rapid dilation of cerebral blood vessels in guinea pigs, which is mediated by nitric oxide release and can be blocked by atropine, indicating its role in regulating blood flow.

In conditions where nitric oxide production is inhibited, acetylcholine can lead to a slow vasoconstriction, suggesting that under certain circumstances, it may worsen blood flow during brain ischemia due to endothelial damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitric oxide synthase inhibitors unmask acetylcholine-mediated constriction of cerebral vessels in the in vitro isolated guinea-pig brain. Librizzi, L., Folco, G., de Curtis, M.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5157078/

Acetylcholine released by endothelial cells facilitates flow ... The data reveal that cholinergic signalling is a key element to endothelial mechanosensitivity, and the autocrine action of ACh explains vascular flow‐mediated ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0026286224000980

Concentration-dependent microvascular responses to ... Lower concentrations of ACh as well as sterile water induced more pronounced non-specific vasodilatory responses compared to higher concentrations of ACh. This ...

3. nejm.org nejm.org/doi/full/10.1056/NEJM199007053230105

Abnormal Endothelium-Dependent Vascular Relaxation in ... The responses of blood flow and vascular resistance to acetylcholine were significantly reduced in the hypertensive patients (P<0.0001); maximal ...

4. withpower.com withpower.com/trial/early-phase-1-flow-mediated-vasodilatation-fmd-6-2024-a0481

Acetylcholine for Blood Vessel Function (CAP NOVA Trial) Research shows that Acetylcholine can lower blood pressure by causing blood vessels to widen through a process involving nitric oxide, a natural substance that ...

5. bmcoralhealth.biomedcentral.com bmcoralhealth.biomedcentral.com/articles/10.1186/s12903-024-05169-7

Dose-related effect of acetylcholine on human gingival blood ... This study investigates the dose-response relationship of acetylcholine (ACh) on healthy human gingival blood flow (GBF).

6. dailymed.nlm.nih.gov dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e701ef07-9499-4b56-931f-f4eb3eedbe24

E (acetylcholine chloride intraocular solution) 20 mg/2 mL ... Safety and effectiveness in pediatric patients have not been established. ADVERSE REACTIONS. Infrequent cases of corneal edema, corneal clouding, and corneal ...

7. reference.medscape.com reference.medscape.com/drug/miochol-e-acetylcholine-343661

Miochol E, (acetylcholine) dosing, indications, interactions, ... Medscape - Indication-specific dosing for Miochol E, (acetylcholine), frequency-based adverse effects, comprehensive interactions, contraindications, ...

8. drugs.com drugs.com/sfx/miochol-e-system-pak-side-effects.html

Miochol-E System Pak Side Effects Learn about the side effects of Miochol-E System Pak (acetylcholine), from common to rare, for consumers and healthcare professionals.

9. bausch.com bausch.com/globalassets/pdf/packageinserts/pharma/miochol-e-acetylcholine-chloride-intraocular-solution.pdf

Miochol™-E (acetylcholine chloride intraocular solution) 20 ... Safety and effectiveness in pediatric patients have not been established. ADVERSE REACTIONS. Infrequent cases of corneal edema, corneal clouding, and corneal ...