Reflex Responses to Intermittent Hypoxia in Humans: Mechanisms and Consequences

Sponsor

University of Missouri-Columbia (Other)

Overall Status

Completed

CT.gov ID

NCT05146089

Collaborator

National Heart, Lung, and Blood Institute (NHLBI) (NIH), Mayo Clinic (Other)

Enrollment

Locations

Arm

51.7

Actual Duration (Months)

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Sleep Apnea Healthy Vasoconstriction Vasodilation	Other: Hypoxic exposure Other: modified Oxford test Drug: Oral Bosentan 62.5 mg Other: Hypoxic ventilatory response test	Early Phase 1

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 Design

Study Type:

Interventional

Actual Enrollment :

54 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Subjects will be asked to complete 1 1-hour screening visit, 1 overnight at-home monitoring, and 1 (women) or 2 (men) 5-hour study visits. Subjects will not be blinded to study condition and all subjects will serve as their own controls. All study visits will be separated by a minimum of 1 week and will occur at the same time of day.Subjects will be asked to complete 1 1-hour screening visit, 1 overnight at-home monitoring, and 1 (women) or 2 (men) 5-hour study visits. Subjects will not be blinded to study condition and all subjects will serve as their own controls. All study visits will be separated by a minimum of 1 week and will occur at the same time of day.

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

Reflex Responses to Intermittent Hypoxia in Humans: Mechanisms and Consequences

Actual Study Start Date :

Dec 20, 2016

Actual Primary Completion Date :

Sep 8, 2018

Actual Study Completion Date :

Apr 12, 2021

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Muscle sympathetic nerve activity (MSNA) [Change from baseline after hypoxia exposure]
MSNA burst incidence (bursts/100 heart beats)

Secondary Outcome Measures

Arterial blood pressure [Change from baseline after hypoxia exposure]
Systolic blood pressure, Diastolic blood pressure, Mean blood pressure

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Missouri-Columbia	Columbia	Missouri	United States	65211
2	Mayo Clinic	Rochester	Missouri	United States	55902

Sponsors and Collaborators

University of Missouri-Columbia
National Heart, Lung, and Blood Institute (NHLBI)
Mayo Clinic

Investigators

Principal Investigator: Jacqueline K Limberg, Ph.D., University of Missouri-Columbia

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Jacqueline K Limberg, PhD, Assistant Professor, University of Missouri-Columbia

ClinicalTrials.gov Identifier:

NCT05146089

Other Study ID Numbers:

2007973
K99HL130339
R00HL130339

First Posted:

Dec 6, 2021

Last Update Posted:

Dec 6, 2021

Last Verified:

Nov 1, 2021

Individual Participant Data (IPD) Sharing Statement:

Undecided

Plan to Share IPD:

Undecided

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Hypoxia

Bosentan

Study Results

No Results Posted as of Dec 6, 2021