Sympathetic Neurovascular Transduction: Role of Adrenergic Receptors and Sex Differences (STARS)

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:

1. Are there sex differences in the communication between the sympathetic nervous system (also known as the "fight or flight" response) and peripheral blood vessels (which influence systemic blood pressure)?
2. What is the role of specific vascular receptors that respond to sympathetic signals, and is it different between males and females?

Participants will complete one study visit of approximately 3 hours where they will:

• 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.

Study Overview

• Status: Recruiting
• Conditions: Vasodilation; Vasoconstriction
• Intervention / Treatment: Drug: Phenylephrine Hydrochloride; Drug: Isoproterenol Hydrochloride; Drug: Norepinephrine Bitartrate; Drug: Phenylephrine Hydrochloride; Drug: Isoproterenol Hydrochloride; Drug: Propranolol Hydrochloride; Drug: Propranolol Hydrochloride; Drug: Phentolamine Mesylate

Detailed Description

Blood pressure is in part regulated by activity of your sympathetic nervous system (also known as your "fight or flight" response). Sympathetic nerve activity affects the size of your blood vessels, which in turn will affect your blood pressure. This communication between sympathetic impulses and the resulting change in vascular resistance is termed "sympathetic neurovascular transduction". In other words, transduction represents the reactivity of the blood vessels in response to individual sympathetic bursts of activity.

Males and females regulate their blood pressure in different ways; for example, females tend to have lower blood pressure and sympathetic nerve activity than males. Females also appear to have less constriction of their blood vessels in response to stress. This may be due to differences in the receptors which are activated by the sympathetic nervous system. These receptors are called α and β-adrenergic receptors and are located on vascular smooth muscle cells. They respond to sympathetic neurotransmitters such as norepinephrine in opposite directions: α-adrenoreceptors cause vasoconstriction (and an increase in vascular resistance), and β-adrenoreceptors cause vasodilation (and a decrease in vascular resistance) in part through the endothelium-dependent nitric oxide pathway.

Current evidence suggests that β-adrenergic receptors are more sensitive in females and contribute to paradoxical vasodilation when α-adrenergic receptors are stimulated by norepinephrine from sympathetic bursts. It has also been suggested that estrogen interacts with adrenergic receptors, contributing to this sex difference. This study will contribute to the understanding of sex differences in cardiovascular physiology and may have implications for clinical cardiovascular conditions.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Emily Vanden Berg, MSc; Phone Number: (780)-492-5553; Email: ervanden@ualberta.ca
• Study Contact Backup: Name: Nicholas Cheung, MSc; Phone Number: (780)-492-5553; Email: nkcheung@ualberta.ca

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2R3
      • Recruiting
      • University of Alberta
      • Contact: Craig Steinback, PhD; Phone Number: (780)492-5553; Email: craig.steinback@ualberta.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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).
• Have a history of smoking regularly in the last 6 months (but nicotine substitutes (i.e. patch, gum) are not an exclusion criteria).
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Control Condition; 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; Participants will receive three incremental doses via the brachial artery catheter to assess α1-adrenoreceptor mediated vasoconstriction.; Drug: Isoproterenol Hydrochloride; Participants will receive four incremental doses via the brachial artery catheter to assess β-adrenoreceptor mediated vasodilation.; Drug: Norepinephrine Bitartrate; Participants will receive three incremental doses via the brachial artery catheter to assess nonspecific adrenoreceptor activation.; Drug: Phenylephrine Hydrochloride; Participants will receive one dose via the brachial artery catheter to evaluate the effectiveness of the α-adrenergic blockade.; Drug: Isoproterenol Hydrochloride; Participants will receive one dose via the brachial artery catheter to evaluate the effectiveness of the β-adrenergic blockade.
Experimental: β-Adrenergic Blockade; 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; Participants will receive three incremental doses via the brachial artery catheter to assess nonspecific adrenoreceptor activation.; Drug: Propranolol Hydrochloride; Propranolol will be continuously infused through the brachial artery catheter to induce β-adrenergic blockade locally in the forearm.; Drug: Propranolol Hydrochloride; Propranolol will be continuously co-infused with phentolamine to maintain the β-adrenergic blockade.
Experimental: α+β-Adrenergic Blockade; α-adrenoreceptors will be blocked locally in the forearm using phentolamine. Propranolol will be co-infused to maintain β-blockade.	Drug: Phenylephrine Hydrochloride; Participants will receive three incremental doses via the brachial artery catheter to assess α1-adrenoreceptor mediated vasoconstriction.; Drug: Isoproterenol Hydrochloride; Participants will receive four incremental doses via the brachial artery catheter to assess β-adrenoreceptor mediated vasodilation.; Drug: Phenylephrine Hydrochloride; Participants will receive one dose via the brachial artery catheter to evaluate the effectiveness of the α-adrenergic blockade.; Drug: Isoproterenol Hydrochloride; Participants will receive one dose via the brachial artery catheter to evaluate the effectiveness of the β-adrenergic blockade.; Drug: Propranolol Hydrochloride; Propranolol will be continuously infused through the brachial artery catheter to induce β-adrenergic blockade locally in the forearm.; Drug: Propranolol Hydrochloride; Propranolol will be continuously co-infused with phentolamine to maintain the β-adrenergic blockade.; Drug: Phentolamine Mesylate; Phentolamine will be continuously infused through the brachial artery catheter to induce α-adrenergic blockade locally in the forearm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arterial-venous blood gas concentrations	Blood sample during each condition	2 minutes per sample = 6 minutes

Collaborators and Investigators

• Sponsor: University of Alberta
• Investigators: Principal Investigator: Sean van Diepen, MD, MSc, University of Alberta; Principal Investigator: Craig Steinback, PhD, University of Alberta

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2023
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: August 2, 2023
• First Submitted That Met QC Criteria: August 11, 2023
• First Posted (Actual): August 18, 2023

Study Record Updates

• Last Update Posted (Actual): January 8, 2026
• Last Update Submitted That Met QC Criteria: January 5, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: sex differences; sympathetic nerve activity; neurovascular transduction; adrenergic receptors
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Aneurysm; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Hydrocarbons; Hydrocarbons, Cyclic; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Imidazoles; Amines; Catechols; Phenols; Benzene Derivatives; Alcohols; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Propanols; Ethanolamines; Biogenic Monoamines; Biogenic Amines; Catecholamines; Norepinephrine; Propranolol; Phenylephrine; Isoproterenol; Phentolamine
• Other Study ID Numbers: Pro00126600

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No