Role of Acetylcholine in Blood Flow Regulation in Healthy Adults: Effects of Age and Exercise Training

NCT03972683 | Withdrawn Early Phase 1 FDA Drug

• 1 other identifier: ACh sympatholysis
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The overall goal of this study is to address fundamental questions regarding how the molecule acetylcholine interacts with the sympathetic nervous system to regulate blood flow and oxygen delivery to working skeletal muscle in young and older adults. With advancing age, blood vessels supplying active muscle lose their ability to override sympathetic constriction, which limits delivery of oxygen and results in fatigue. Findings from these studies will serve as the foundation for new strategies to improve regional blood flow regulation in older adults and clinical populations, which will increase quality of life and help to preserve functional independence.

Conditions

Vasoconstriction; Vasodilation

Keywords

Exercise

Outcome Measures

Primary Outcomes (1)

• Functional sympatholysis

  Change in sensitivity to phenylephrine during handgrip exercise compared to rest

  Baseline (week 0) and post-intervention (week 8)

Secondary Outcomes (1)

• Flow-mediated dilation

  Baseline (week 0), mid-intervention (week 4), and post-intervention (week 8)

Study Arms (1)

Handgrip Exercise Training Intervention

EXPERIMENTAL

Participants will visit the lab for baseline measurements designed to evaluate signaling mechanisms that regulate blood flow. A physician will place a catheter in the brachial artery for pharmacological infusions. The following drugs will be administered to each participant: acetylcholine, adenosine triphosphate, atropine, phenylephrine, and sodium nitroprusside (see Interventions for further details regarding each drug). The order of infusions will be randomized and blood flow will be allowed to return to baseline between each infusion (\~15 min) with the exception of atropine, which will be administered last owing to its longer half-life. Following baseline measurements, participants will complete a 7 week handgrip exercise training intervention, then they will return to the laboratory for post-training measurements. The post-training assessments will be performed in the same manner as the baseline visit; thus, the same drugs will be infused as described above.

Other: Handgrip Exercise Training; Drug: Acetylcholine; Drug: Adenosine Triphosphate; Drug: Atropine; Drug: Phenylephrine; Drug: Sodium Nitroprusside

Interventions

Handgrip Exercise Training OTHER

Signaling mechanisms that regulate blood flow will be studied before and after 7 weeks of handgrip exercise training with the non-dominant forearm. Training sessions will consist of 30 min of rhythmic contractions using a handgrip exercise device, and participants will complete four training sessions per week.

Handgrip Exercise Training Intervention

Acetylcholine DRUG

Vasodilatory sensitivity to acetylcholine will be assessed in dose-response fashion as a standard test of vascular function. Doses of 0.5, 1.5, and 15 μg/dl forearm volume/min will be infused via a brachial artery catheter for 4 min per dose.

Also known as: ACh

Handgrip Exercise Training Intervention

Adenosine Triphosphate DRUG

Vasodilatory sensitivity to adenosine triphosphate will be assessed during infusion of a dose of 10 μg/dl forearm volume/min administered via a brachial artery catheter over a total of 4 min.

Also known as: ATP

Handgrip Exercise Training Intervention

Atropine DRUG

Atropine will be used to inhibit muscarinic acetylcholine receptors in order to determine the contribution of acetylcholine to vasodilation during exercise. An initial dose of 0.2 mg will be infused via a brachial artery catheter over 3 min, then a maintenance dose of 0.067 mg will be infused over 1 min prior to each of 5 subsequent experimental trials.

Also known as: Atropine Sulfate

Handgrip Exercise Training Intervention

Phenylephrine DRUG

Vasoconstriction to phenylephrine will be used to assess sensitivity to alpha 1 adrenergic stimulation. Phenylephrine will be infused via a brachial artery catheter at 0.125 or 0.25 μg/dl forearm volume/min (18-35 and 60-85 age groups, respectively), adjusted according to forearm blood flow, for a total of 16 min.

Also known as: Phenylephrine Hydrochloride

Handgrip Exercise Training Intervention

Sodium Nitroprusside DRUG

Sodium nitroprusside will be infused via a brachial artery catheter as a control vasodilator to elevate resting forearm blood flow to a level similar to that during exercise. The dose will be adjusted to match forearm blood flow to a similar level as during handgrip exercise, with an anticipated average dose of 1 μg/dl forearm volume/min. The dose will be infused for a total of 14 min.

Also known as: SNP

Handgrip Exercise Training Intervention

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• age 18-35 OR 60-85

You may not qualify if:

• recent history of smoking
• body mass index greater than 30
• history of cardiovascular or metabolic disease, including hypertension or diabetes
• medications that may affect outcome measures, such as blood pressure medications or hormone replacement therapy
• high levels of exercise training, particularly with the forearm (such as weightlifting or rock-climbing)

Sponsors & Collaborators

• Colorado State University: lead

Study Sites (1)

Colorado State University

Fort Collins, Colorado, 80523, United States

Location

MeSH Terms

Conditions

Aneurysm; Motor Activity

Interventions

Acetylcholine; Adenosine Triphosphate; Atropine; Phenylephrine; Nitroprusside

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Behavior

Intervention Hierarchy (Ancestors)

Biogenic Amines; Amines; Organic Chemicals; Adenine Nucleotides; Purine Nucleotides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleotides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleotides; Atropine Derivatives; Tropanes; Azabicyclo Compounds; Aza Compounds; Belladonna Alkaloids; Solanaceous Alkaloids; Alkaloids; Bridged Bicyclo Compounds, Heterocyclic; Heterocyclic Compounds, Bridged-Ring; Ethanolamines; Amino Alcohols; Alcohols; Ferricyanides; Cyanides; Anions; Ions; Electrolytes; Inorganic Chemicals; Ferric Compounds; Iron Compounds; Hydrogen Cyanide; Nitrogen Compounds

Study Officials

• Frank Dinenno, PhD

  Colorado State University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: All participants will be studied before and after a handgrip exercise training intervention.

Study Record Dates

• First Submitted: May 31, 2019
• First Posted: June 4, 2019
• Study Start: April 16, 2019
• Primary Completion: July 31, 2021
• Study Completion: July 31, 2021
• Last Updated: August 2, 2021

Record last verified: 2021-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)