Reflex Responses to Intermittent Hypoxia in Humans: Mechanisms and Consequences

The overall goal of this project is to better understand the effect of intermittent hypoxia (IH) on sympathetic neuronal discharge patterns in humans, as well as mechanisms that mediate persistent sympathoexcitation with IH.

Study Overview

• Status: Completed
• Conditions: Healthy; Sleep Apnea; Vasodilation; Vasoconstriction
• Intervention / Treatment: Other: Hypoxic exposure; Other: modified Oxford test; Drug: Oral Bosentan 62.5 mg; Other: Hypoxic ventilatory response test

Detailed Description

Sleep apnea is the most common form of sleep disordered breathing and patients with sleep apnea exhibit persistent activation of the sympathetic nervous system. Sympathoexcitation is also the final common pathway for a host of complications in conditions like obesity, hypertension, sleep apnea, and heart failure and plays a significant role in predicting negative clinical outcomes and deteriorating cardiovascular health. However, the mechanisms of sympathoexcitation with sleep apnea are poorly understood and thus make effective therapeutic approaches difficult to develop.

Intermittent hypoxia (IH) has been implicated in animal models as the primary stimulus for evoking increases in sympathetic activity with recurrent apneas. Thus, the overall goal of this application is to better understand the effect of IH on sympathetic discharge patterns in humans as well as the mechanisms mediating persistent sympathoexcitation with IH. By better understanding the effect of IH on sympathoexcitation, targeted therapeutic approaches might be devised to mitigate the effects of sympathetic over-activity on the cardiovascular system in conditions such as sleep apnea.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Columbia, Missouri, United States, 65211
      • University of Missouri-Columbia
    • Rochester, Missouri, United States, 55902
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• healthy adult men and women;
• 18-45 years of age;
• BMI <30 kg/m2;
• non-pregnant/non-breastfeeding;
• non-smokers.

Exclusion Criteria:

Subjects will be excluded if they are:

• taking any medications known to affect the cardiovascular or autonomic nervous system (e.g. alpha-blockers, beta-blockers, etc);
• Apnea Hypopnea Index >10 events/hr

Self-reported history of:

• hepatic, renal, pulmonary, cardiovascular, or neurological disease;
• stroke or neurovascular disease;
• bleeding/clotting disorders;
• sleep apnea or other sleep disorders;
• diabetes;
• smoking;
• history of alcoholism or substance abuse;
• hypertension.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Hypoxia Exposure; Men and women will be exposed to acute intermittent hypoxic episodes.

Other: Hypoxic exposure; 30 minutes of intermittent hypoxia achieved using breaths of low oxygen air (5% oxygen) followed by room air through a mask.; Other: modified Oxford test; An intravenous bolus of sodium nitroprusside (100 μg) will be given to decrease blood pressure, followed 1 minute later by a bolus of phenylephrine (150 μg) to increase blood pressure, occurring before and after intermittent hypoxia exposure.; Drug: Oral Bosentan 62.5 mg; Prior to completion of visit 2, male subjects will consume 62.5 mg twice daily for 3 days as well as the morning of the study visit (7 pills) at home and experimental sessions will be performed 3 hours after oral intake of the final dose.; Other: Hypoxic ventilatory response test; Hypoxia will be achieved using breaths of low oxygen air (5% oxygen) followed by room air through a mask. This will be repeated 4-5 times per test, occurring before and after intermittent hypoxia exposure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle sympathetic nerve activity (MSNA)	MSNA burst incidence (bursts/100 heart beats)	Change from baseline after hypoxia exposure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arterial blood pressure	Systolic blood pressure, Diastolic blood pressure, Mean blood pressure	Change from baseline after hypoxia exposure

Collaborators and Investigators

• Sponsor: University of Missouri-Columbia
• Collaborators: Mayo Clinic; National Heart, Lung, and Blood Institute (NHLBI)

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 20, 2016
• Primary Completion (ACTUAL): September 8, 2018
• Study Completion (ACTUAL): April 12, 2021

Study Registration Dates

• First Submitted: November 2, 2021
• First Submitted That Met QC Criteria: November 23, 2021
• First Posted (ACTUAL): December 6, 2021

Study Record Updates

• Last Update Posted (ACTUAL): December 6, 2021
• Last Update Submitted That Met QC Criteria: November 23, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Signs and Symptoms, Respiratory; Hypoxia; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan
• Other Study ID Numbers: 2007973; K99HL130339 (NIH); R00HL130339 (NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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