Sympathetic Neurovascular Transduction: Role of Adrenergic Receptors and Sex Differences

NCT05997732 | Recruiting Phase 4

• 1 other identifier: Pro00126600
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The main purpose of this interventional study is to examine differences in resting blood pressure control between healthy males and females. The main questions it aims to answer are:

• Have a blood sample taken to measure circulating sex hormone and sympathetic transmitters.
• Receive very small doses of medications commonly used to adjust blood pressure through an artery in their arm. The effects of these medications will be short-acting and localized to the forearm.
• Have their sympathetic nervous activity directly measured through two very small needles (similar to acupuncture needles) in the side of their leg.
• Have their blood pressure and heart rate recorded, and forearm blood flow measured using ultrasound.

Conditions

Vasoconstriction; Vasodilation

Keywords

sympathetic nerve activity; sex differences; adrenergic receptors; neurovascular transduction

Outcome Measures

Primary Outcomes (7)

• Forearm blood flow

  Measured during resting baseline; changes during phenylephrine, isoproterenol, and norepinephrine infusion to determine agonist sensitivity.

  10 minutes per condition + 2 minutes per agonist dose = 60 minutes

• Forearm vascular resistance

  Measured during resting baseline; changes during phenylephrine, isoproterenol, and norepinephrine infusion to determine agonist sensitivity.

  10 minutes per condition + 2 minutes per agonist dose = 60 minutes

• Forearm vascular conductance

  Measured during resting baseline; changes during phenylephrine, isoproterenol, and norepinephrine infusion to determine agonist sensitivity.

  10 minutes per condition + 2 minutes per agonist dose = 60 minutes

• Arterial blood pressure

  Measured during resting baseline; changes during phenylephrine, isoproterenol, and norepinephrine infusion to determine agonist sensitivity.

  10 minutes per condition + 2 minutes per agonist dose = 60 minutes

• Muscle sympathetic nerve activity

  Resting baseline

  10 minutes per condition = 30 minutes

• Circulating sex hormone concentrations

  Blood samples

  2 minutes

• Circulating sympathetic neurotransmitter concentrations

  Blood sample

  2 minutes

Secondary Outcomes (1)

• Arterial-venous blood gas concentrations

  2 minutes per sample = 6 minutes

Study Arms (3)

Control Condition

EXPERIMENTAL

Normal saline will be infused through the brachial artery catheter at the same calculated rate as propranolol + phentolamine in the α+β-blockade condition to control for volumetric effects.

Drug: Phenylephrine Hydrochloride; Drug: Isoproterenol Hydrochloride; Drug: Norepinephrine Bitartrate

β-Adrenergic Blockade

EXPERIMENTAL

β-adrenoreceptors will be blocked locally in the forearm using propranolol. Normal saline will be co-infused at the calculated rate of phentolamine in the α+β-blockade condition to control for volumetric effects.

Drug: Norepinephrine Bitartrate; Drug: Propranolol Hydrochloride

α+β-Adrenergic Blockade

EXPERIMENTAL

α-adrenoreceptors will be blocked locally in the forearm using phentolamine. Propranolol will be co-infused to maintain β-blockade.

Drug: Phentolamine Mesylate; Drug: Phenylephrine Hydrochloride; Drug: Isoproterenol Hydrochloride; Drug: Propranolol Hydrochloride

Interventions

Phenylephrine Hydrochloride DRUG

Participants will receive three incremental doses via the brachial artery catheter to assess α1-adrenoreceptor mediated vasoconstriction.

Control Condition

Isoproterenol Hydrochloride DRUG

Participants will receive four incremental doses via the brachial artery catheter to assess β-adrenoreceptor mediated vasodilation.

Control Condition

Norepinephrine Bitartrate DRUG

Participants will receive three incremental doses via the brachial artery catheter to assess nonspecific adrenoreceptor activation.

Control Condition; β-Adrenergic Blockade

Propranolol Hydrochloride DRUG

Propranolol will be continuously infused through the brachial artery catheter to induce β-adrenergic blockade locally in the forearm.

β-Adrenergic Blockade

Phentolamine Mesylate DRUG

Phentolamine will be continuously infused through the brachial artery catheter to induce α-adrenergic blockade locally in the forearm.

α+β-Adrenergic Blockade

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Between ages 18-40 years
• No diagnosed medical history of cardiovascular, respiratory, nervous system, or metabolic disease.
• Females must be pre-menopausal.
• Prior to study visit: abstained from caffeine, alcohol, strenuous exercise, and medication not taken regularly for at least 12 hours.

You may not qualify if:

• Current diagnosis of cardiovascular, respiratory, nervous system, or metabolic disease that may impact blood pressure regulation. This will be assessed on a case-by-case basis by the study physician.
• Participants with bleeding or clotting disorders, or those currently taking blood thinners.
• Participants currently taking beta-agonist inhalers i.e. Ventolin (at least not in the last 24 hours).
• Females who are pregnant, confirmed by a pregnancy test.
• Females who have are less than 1 year postpartum or are breastfeeding.
• Females who are post-menopausal.
• Participants that are classified as obese (body mass index \> 30 kg ⋅ m2).
• Those with a known allergy to sulfites, or other components of the supplied solution of study drugs.
• Participants taking medications that are contraindicated with any of the study drugs, such as monoamine oxidase (MAO) inhibitors or tricyclic antidepressants.
• Participants who have not adhered to the pre-testing guidelines related to diet, alcohol or exercise will not be excluded, but will be rescheduled for a different day. This is to reduce experimental variability.

Sponsors & Collaborators

• University of Alberta: lead

Study Sites (1)

University of Alberta

Edmonton, Alberta, T6G 2R3, Canada

RECRUITING

Related Publications (5)

• Hart EC, Charkoudian N, Wallin BG, Curry TB, Eisenach JH, Joyner MJ. Sex differences in sympathetic neural-hemodynamic balance: implications for human blood pressure regulation. Hypertension. 2009 Mar;53(3):571-6. doi: 10.1161/HYPERTENSIONAHA.108.126391. Epub 2009 Jan 26.

  PMID: 19171792 BACKGROUND

• Steinback CD, Fraser GM, Usselman CW, Reyes LM, Julian CG, Stickland MK, Chari RS, Khurana R, Davidge ST, Davenport MH. Blunted sympathetic neurovascular transduction during normotensive pregnancy. J Physiol. 2019 Jul;597(14):3687-3696. doi: 10.1113/JP277714. Epub 2019 Jun 13.

  PMID: 31106429 BACKGROUND

• Fairfax ST, Holwerda SW, Credeur DP, Zuidema MY, Medley JH, Dyke PC 2nd, Wray DW, Davis MJ, Fadel PJ. The role of alpha-adrenergic receptors in mediating beat-by-beat sympathetic vascular transduction in the forearm of resting man. J Physiol. 2013 Jul 15;591(14):3637-49. doi: 10.1113/jphysiol.2013.250894. Epub 2013 May 7.

  PMID: 23652594 BACKGROUND

• Dinenno FA, Eisenach JH, Dietz NM, Joyner MJ. Post-junctional alpha-adrenoceptors and basal limb vascular tone in healthy men. J Physiol. 2002 May 1;540(Pt 3):1103-10. doi: 10.1113/jphysiol.2001.015297.

  PMID: 11986395 BACKGROUND

• Hissen SL, Taylor CE. Sex differences in vascular transduction of sympathetic nerve activity. Clin Auton Res. 2020 Oct;30(5):381-392. doi: 10.1007/s10286-020-00722-0. Epub 2020 Aug 31.

  PMID: 32865664 BACKGROUND

MeSH Terms

Conditions

Aneurysm

Interventions

Phenylephrine; Isoproterenol; Norepinephrine; Propranolol; Phentolamine

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Catecholamines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Biogenic Monoamines; Biogenic Amines; Phenoxypropanolamines; Propanolamines; Propanols; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Sean van Diepen, MD, MSc

  University of Alberta

  PRINCIPAL INVESTIGATOR

• Craig Steinback, PhD

  University of Alberta

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Emily Vanden Berg, MSc

CONTACT

(780)-492-5553; ervanden@ualberta.ca

Nicholas Cheung, MSc

CONTACT

(780)-492-5553; nkcheung@ualberta.ca

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants will complete three pharmacological conditions, and serve as their own controls.

Study Record Dates

• First Submitted: August 2, 2023
• First Posted: August 18, 2023
• Study Start: October 31, 2023
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: January 8, 2026

Record last verified: 2026-01

Locations

CA (1)