Sympathetic Neurovascular Transduction: Role of Adrenergic Receptors and Sex Differences

Study Overview
=================
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: 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)? 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.

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.

Official Title
-----------------
Sympathetic Neurovascular Transduction: Role of Adrenergic Receptors and Sex Differences

Conditions
-----------------
Vasoconstriction, Vasodilation

Intervention / Treatment
-----------------
* Drug: Phenylephrine Hydrochloride
* Drug: Isoproterenol Hydrochloride
* Drug: Norepinephrine Bitartrate
* Drug: Propranolol Hydrochloride
* Drug: Phentolamine Mesylate
* Drug: Phenylephrine Hydrochloride
* Drug: Isoproterenol Hydrochloride
* Drug: Propranolol Hydrochloride


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Participants will complete three pharmacological conditions, and serve as their own controls.
Masking: None (Open Label)


Arms and Interventions

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

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
sympathetic nerve activity, sex differences, adrenergic receptors, neurovascular transduction