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

July 26, 2021 updated by: Frank Dinenno, Colorado State University

Novel Role of Acetylcholine in Regulating Vascular Tone: Effects of Age and Exercise Training

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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

The ability of blood vessels to dilate is essential to ensure adequate blood flow and oxygen delivery to active muscle during exercise. With advancing age, exercising muscle loses the ability to overcome vasoconstriction from the sympathetic nervous system, which impairs blood flow and limits exercise tolerance. Thus, understanding the signaling mechanisms that underlie the ability of active muscle to limit sympathetic vasoconstriction will advance our understanding of blood flow regulation in humans and lay the foundation for new strategies to improve blood flow and exercise tolerance in aging and clinical populations.

Therefore, the purpose of this research is to investigate endogenous acetylcholine as an important signaling molecule that regulates blood flow during exercise. The studies will also determine whether a reduced contribution of acetylcholine explains blood flow impairments in older adults. Since exercise training is known to improve acetylcholine signaling, this research will also address whether a handgrip exercise training intervention will improve blood flow regulation. The expected outcomes will provide new insight to the basic physiology underlying vascular control in humans. Furthermore, the findings will provide insight to the age-related decline in blood flow regulation during exercise and will assess the use of an exercise intervention to improve functional outcomes in older individuals.

Participants will be asked to complete several study visits over the course of 8 weeks. Once study eligibility has been determined, participants will report to the Human Performance Clinical Research Laboratory at Colorado State University for a 3 hour visit to assess forearm exercise capacity. In a separate 5 hour visit following an overnight fast, a physician will place a catheter in the brachial artery of the non-dominant arm to assess vascular function. Participants will then complete 7 weeks of handgrip exercise training (four sessions per week) and return to the laboratory for follow-up visits to assess forearm exercise capacity and vascular function.

Study Type

Interventional

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Colorado
      • Fort Collins, Colorado, United States, 80523
        • Colorado State University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • age 18-35 OR 60-85

Exclusion Criteria:

  • 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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Handgrip Exercise Training Intervention

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
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.
Drug: Acetylcholine
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.
Other Names:
  • ACh
Drug: Adenosine Triphosphate
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.
Other Names:
  • ATP
Drug: Atropine
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.
Other Names:
  • Atropine Sulfate
Drug: Phenylephrine
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.
Other Names:
  • Phenylephrine Hydrochloride
Drug: Sodium Nitroprusside
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.
Other Names:
  • SNP

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Functional sympatholysis
Time Frame: Baseline (week 0) and post-intervention (week 8)
Change in sensitivity to phenylephrine during handgrip exercise compared to rest
Baseline (week 0) and post-intervention (week 8)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Flow-mediated dilation
Time Frame: Baseline (week 0), mid-intervention (week 4), and post-intervention (week 8)
Change in brachial artery diameter in response to increased shear rate
Baseline (week 0), mid-intervention (week 4), and post-intervention (week 8)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Colorado State University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 16, 2019

Primary Completion (Anticipated)

July 31, 2021

Study Completion (Anticipated)

July 31, 2021

Study Registration Dates

First Submitted

May 31, 2019

First Submitted That Met QC Criteria

May 31, 2019

First Posted (Actual)

June 4, 2019

Study Record Updates

Last Update Posted (Actual)

August 2, 2021

Last Update Submitted That Met QC Criteria

July 26, 2021

Last Verified

July 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ACh sympatholysis

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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