Sex Differences in Sympathetic Activity and Vascular Reactivity During Acute and Chronic Hypoxia.

This study aims to investigate sex differences in blood pressure control associated with exposure to acute hypoxia (low oxygen), and short term acclimatization to hypoxia at high altitude.

Study Overview

• Status: Completed
• Conditions: Vasodilation; Vasoconstriction
• Intervention / Treatment: Drug: Phenylephrine Hydrochloride; Other: Cold Pressor Test; Other: Isocapnic Acute Hypoxia; Other: Hyperoxia

Detailed Description

About 200 million people worldwide live at high altitudes. Millions of others travel to high altitude every year for work or travel. The low oxygen (or hypoxia) experienced at high altitudes causes considerable physiological stress, and the body adapts in order to maintain adequate oxygen delivery to its tissues. One of these adaptations is an increase in the activity of the sympathetic nervous system. This system is responsible for the "fight or flight" response. Sympathetic activity regulates the size of the blood vessels, which will affect blood pressure. Previous studies suggest that males and females regulate their blood pressure in different ways. Females tend to have lower resting sympathetic activity, and less vasoconstriction in response to stressors than males. Blood pressure changes are also influenced by levels of sex hormones; for example, estrogen may cause opposing vasodilation. Therefore, it is important to understand the differences in how males and females respond to low oxygen.

The main purpose of this study is to examine the differences between males and females in control of blood vessels during exposure to low oxygen. To study this question, we will test vasoreactivity to set physiological stressors in both males and females. Participants will be recruited at the Canadian sites, and we will test them while they breathe low oxygen for a short amount of time at low altitude. We will also perform assessments on the same participants during a two week stay at high altitude at White Mountain, CA, which is at an altitude of 3,800m. These data will have implications in the basic understanding of differences between male and female physiology. Specifically, to males and females living or travelling to high altitude.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3E 6K6
      • Mount Royal University
    • Edmonton, Alberta, Canada, T6G 2R3
      • University of Alberta

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Between ages of 18-50
• No medical history of cardiovascular, respiratory, nervous system, or metabolic disease
• Females must be pre-menopausal

Exclusion Criteria:

• Any known cardiovascular, respiratory, nervous system, or metabolic disease (however, participants with controlled arterial hypertension will not be excluded)
• Having travelled above 2,000m within 1 month of testing at low and high altitude
• Females who are pregnant, confirmed by a pregnancy test
• Females who are post-menopausal
• Participants that are classified as obese (body mass index > 30kg⋅m²)
• Have a history of smoking regularly in the last 6 months (but nicotine substitutes (patch, gum) not an exclusion criteria)
• Those with a known allergy to sulfites
• Participants taking monoamine oxidase (MAO) inhibitors or tricyclic antidepressants

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: Low Altitude; Participants will be assessed at an altitude of <1050m.	Drug: Phenylephrine Hydrochloride; Series of three incremental bolus injections to observe α1-adrenoreceptor mediated vasoconstriction.; Other Names: Neo-Synephrine; Other: Cold Pressor Test; Standardized sympathetic stressor involving submersion of the hand in ice-cold water for 3-minutes, aiming to elicit endogenous neurotransmitter release and blood pressure increases.; Other: Isocapnic Acute Hypoxia; During low altitude assessment, participants will be exposed to isocapnic hypoxia equivalent to 3,800m to assess responses to acute exposure.
Experimental: Early Acclimatization to High Altitude; Participants will be assessed on day 2 or 3 of a high-altitude expedition at 3,800m.	Drug: Phenylephrine Hydrochloride; Series of three incremental bolus injections to observe α1-adrenoreceptor mediated vasoconstriction.; Other Names: Neo-Synephrine; Other: Cold Pressor Test; Standardized sympathetic stressor involving submersion of the hand in ice-cold water for 3-minutes, aiming to elicit endogenous neurotransmitter release and blood pressure increases.; Other: Hyperoxia; During high altitude assessments, participants will breathe an oxygen concentration comparable to their end-tidal values at low altitude for the assessment of the influences of acclimatization.
Experimental: Late Acclimatization to High Altitude; Participants will be assessed on day 9 or 10 of a high-altitude expedition at 3,800m.	Drug: Phenylephrine Hydrochloride; Series of three incremental bolus injections to observe α1-adrenoreceptor mediated vasoconstriction.; Other Names: Neo-Synephrine; Other: Cold Pressor Test; Standardized sympathetic stressor involving submersion of the hand in ice-cold water for 3-minutes, aiming to elicit endogenous neurotransmitter release and blood pressure increases.; Other: Hyperoxia; During high altitude assessments, participants will breathe an oxygen concentration comparable to their end-tidal values at low altitude for the assessment of the influences of acclimatization.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in blood pressure	Phenylephrine sensitivity	18 minutes
Change in arterial blood flow	Phenylephrine sensitivity	18 minutes
Cold pressor test reactivity		4 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.
• Mazzeo RS, Child A, Butterfield GE, Mawson JT, Zamudio S, Moore LG. Catecholamine response during 12 days of high-altitude exposure (4, 300 m) in women. J Appl Physiol (1985). 1998 Apr;84(4):1151-7. doi: 10.1152/jappl.1998.84.4.1151.
• Purdy GM, James MA, Rees JL, Ondrus P, Keess JL, Day TA, Steinback CD. Spleen reactivity during incremental ascent to altitude. J Appl Physiol (1985). 2019 Jan 1;126(1):152-159. doi: 10.1152/japplphysiol.00753.2018. Epub 2018 Nov 21.
• Usselman CW, Gimon TI, Nielson CA, Luchyshyn TA, Coverdale NS, Van Uum SH, Shoemaker JK. Menstrual cycle and sex effects on sympathetic responses to acute chemoreflex stress. Am J Physiol Heart Circ Physiol. 2015 Mar 15;308(6):H664-71. doi: 10.1152/ajpheart.00345.2014. Epub 2014 Dec 19.

Study record dates

Study Major Dates

• Study Start (Actual): August 4, 2019
• Primary Completion (Actual): December 7, 2021
• Study Completion (Actual): September 9, 2022

Study Registration Dates

• First Submitted: August 4, 2021
• First Submitted That Met QC Criteria: August 10, 2021
• First Posted (Actual): August 11, 2021

Study Record Updates

• Last Update Posted (Actual): October 31, 2022
• Last Update Submitted That Met QC Criteria: October 27, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Signs and Symptoms, Respiratory; Hypoxia; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Cardiotonic Agents; Respiratory System Agents; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Nasal Decongestants; Adrenergic alpha-1 Receptor Agonists; Phenylephrine; Oxymetazoline; Synephrine
• Other Study ID Numbers: Pro00088122

Drug and device information, study documents

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