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Trial record 25 of 279 for:    Cerebral Hypoxia

Impact of NOS, COX, and ROS Inhibition on Cerebral Blood Flow Regulation

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ClinicalTrials.gov Identifier: NCT03066115
Recruitment Status : Not yet recruiting
First Posted : February 28, 2017
Last Update Posted : October 26, 2017
Sponsor:
Information provided by (Responsible Party):
University of Wisconsin, Madison

Brief Summary:

Elucidating cerebrovascular control mechanisms during physiologic stress may help identify novel therapeutic targets aimed at preventing or reducing the impact of cerebrovascular disease. The physiological stressors of hypoxia and hypercapnia will be utilized to elicit increases in cerebral blood flow (CBF), and intravenously infused drugs will allow for the testing of potential mechanisms of cerebrovascular control. Specifically, the contributions of nitric oxide synthase (NOS), cyclooxygenase (COX), and reactive oxygen species (ROS) to hypoxic and hypercapnic increases in CBF will be examined. The concept that these mechanisms interact in a compensatory fashion to ensure adequate CBF during both hypoxia and hypercapnia will also be tested.

~25 young, healthy men and women will be tested at rest and during hypoxia and hypercapnia. Subjects will participate in two randomized, counterbalanced study visits under the following conditions: inhibition of NOS, NOS-COX, and NOS-COX-ROS or inhibition of COX, COX-NOS, COX-NOS-ROS. During hypoxia, arterial oxygen saturation will be lowered to 80% and end-tidal carbon dioxide will be maintained at basal levels. During hypercapnia arterial carbon dioxide will be increased ~10 mmHg above basal levels and arterial oxygen saturation will be maintained. Blood flow velocity will be measured with transcranial Doppler ultrasound in the anterior (middle cerebral artery; MCA) and posterior (basilar artery; BA) circulations as a surrogate for CBF.

It is hypothesized that both NOS and COX independently contribute to hypoxic and hypercapnic vasodilation in the MCA and BA, combined NOS-COX contribute to hypoxic and hypercapnic vasodilation in MCA and BA to a greater extent than either NOS or COX alone, and NOS-COX-ROS contribute to hypoxic and hypercapnic vasodilation in the MCA and BA to a greater extent than NOS-COX.


Condition or disease Intervention/treatment Phase
Hypoxia Hypercapnia Drug: L-NMMA Drug: Ketorolac Drug: Ascorbic Acid Procedure: Intravenous Catheter Procedure: Transcranial Doppler Ultrasound Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
Official Title: Contributions of Nitric Oxide Synthase, Cyclooxygenase, and Reactive Oxygen Species to Regional Cerebrovascular Control During Hypoxia and Hypercapnia
Estimated Study Start Date : December 1, 2020
Estimated Primary Completion Date : December 1, 2021
Estimated Study Completion Date : December 1, 2021

Arm Intervention/treatment
Experimental: NOS, COX, and ROS Inhibition
Subjects will receive L-NMMA, ketorolac, then ascorbic acid via intravenous catheter. L-NMMA will have a 3 mg kg-1 loading dose over 5-minutes (36 mg kg-1 hr-1), followed by a maintenance dose of 1 mg kg-1 hr-1. Ketorolac will have a 0.3 mg kg-1 loading dose over 5 minutes (3.6 mg kg-1 hr-1) with a minimum loading dose of 15 mg. This will be followed by a maintenance dose of 0.03 mg kg-1 hr-1. Ascorbic acid will have a loading dose of 0.035 g kg fat-free mass-1 over 5-minutes (0.42 g kg fat-free mass-1 hr-1), followed by a maintenance dose of 0.060 g kg fat-free mass-1 hr-1. Cerebral blood flow velocity will be measured throughout the drug infusions via transcranial Doppler ultrasound.
Drug: L-NMMA
See arm description.
Other Name: NOS Inhibition

Drug: Ketorolac
See arm description.
Other Name: COX Inhibition

Drug: Ascorbic Acid
See arm description.
Other Name: ROS Inhibition

Procedure: Intravenous Catheter
Two intravenous catheters will be placed for each study visit. One catheter will be used for the intravenous infusion of study drugs (L-NMMA, Ketorolac, and Ascorbic Acid). The second catheter will be used to draw intermittent blood samples at 8-specific time points throughout each study visit to ensure pharmaceutical efficacy and examine systemic physiologic blood variables of interest.
Other Name: Cath

Procedure: Transcranial Doppler Ultrasound
MCAv will be measured via the transtemporal window while BAv will be measured through the transforaminal window with 2-MHz transcranial Doppler ultrasound probes (TCD, Neurovision model 500M, Multigon Industries, Inc.; Yonkers, NY, USA)
Other Name: Ultrasound

Experimental: COX, NOS, and ROS Inhibition

Subjects will receive ketorolac, L-NMMA, then ascorbic acid via intravenous catheter.

Ketorolac will have a 0.3 mg kg-1 loading dose over 5 minutes (3.6 mg kg-1 hr-1) with a minimum loading dose of 15 mg. This will be followed by a maintenance dose of 0.03 mg kg-1 hr-1. L-NMMA will have a 3 mg kg-1 loading dose over 5-minutes (36 mg kg-1 hr-1), followed by a maintenance dose of 1 mg kg-1 hr-1. Ascorbic acid will have a loading dose of 0.035 g kg fat-free mass-1 over 5-minutes (0.42 g kg fat-free mass-1 hr-1), followed by a maintenance dose of 0.060 g kg fat-free mass-1 hr-1. Cerebral blood flow velocity will be measured throughout the drug infusions via transcranial Doppler ultrasound.

Drug: L-NMMA
See arm description.
Other Name: NOS Inhibition

Drug: Ketorolac
See arm description.
Other Name: COX Inhibition

Drug: Ascorbic Acid
See arm description.
Other Name: ROS Inhibition

Procedure: Intravenous Catheter
Two intravenous catheters will be placed for each study visit. One catheter will be used for the intravenous infusion of study drugs (L-NMMA, Ketorolac, and Ascorbic Acid). The second catheter will be used to draw intermittent blood samples at 8-specific time points throughout each study visit to ensure pharmaceutical efficacy and examine systemic physiologic blood variables of interest.
Other Name: Cath

Procedure: Transcranial Doppler Ultrasound
MCAv will be measured via the transtemporal window while BAv will be measured through the transforaminal window with 2-MHz transcranial Doppler ultrasound probes (TCD, Neurovision model 500M, Multigon Industries, Inc.; Yonkers, NY, USA)
Other Name: Ultrasound




Primary Outcome Measures :
  1. Change in cerebral blood flow velocity in the middle cerebral artery [ Time Frame: Through study completion (up to 1 year) ]
    How cerebral blood flow velocity changes during hypoxia or hypercapnia with COX, NOS, and ROS inhibition in the middle cerebral artery as measured by transcranial Doppler ultrasound.


Secondary Outcome Measures :
  1. Change in cerebral blood flow velocity in the basilar artery [ Time Frame: Through study completion (up to 1 year) ]
    How cerebral blood flow velocity changes during hypoxia or hypercapnia with COX, NOS, and ROS inhibition in the basilar artery as measured by transcranial Doppler ultrasound.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Age: 18 ≤ years ≤ 45
  2. Free of disease and otherwise healthy as determined by health history questionnaire
  3. Not currently taking medication with the exception of birth control as determined by health history questionnaire
  4. Low to moderate physical activity will be permitted and assessed by a physical activity questionnaire (≤ 4 hours of physical activity/week)
  5. Body mass index (BMI) < 25 kg/m2
  6. Resting blood pressure <140/<90 mmHg (lowest of three measures)
  7. Resting heart rate <100 bpm
  8. Resting pulse oximetry oxygen saturation (SPO2) >95%
  9. Fasting venous blood values (average of two measures)

    1. Glucose <100 mg/dL
    2. Creatinine < 1.5 mg/dL
    3. Total cholesterol <200 mg/dL

    i. HDL cholesterol >40 mg/dL (men) ii. HDL cholesterol >50 mg/dL (women) iii. LDL cholesterol < 130 mg/dL d. Triglycerides <150 mg/dL

  10. Subjects must be willing to report to the laboratory on all study days after completing

    1. Minimum 10-hour fast
    2. Minimum 18-hours abstention from exercise, alcohol, caffeine, and non-steroidal anti-inflammatory drugs (i.e. aspirin, ibuprofen, and naproxen)
  11. Additionally, women will

    1. Have a regular menstrual cycle (self-report)
    2. Be studied (study visit 1 and study visit 2) on days 1-5 of menstrual cycle (self- report).

Exclusion Criteria:

  1. Coronary artery disease
  2. Stroke
  3. Heart attack
  4. Heart valve disease
  5. Congestive heart failure
  6. Previous heart surgery
  7. Lung disease
  8. Peripheral vascular disease
  9. Gastrointestinal (GI) bleeding
  10. Allergy or Intolerance to Aspirin or NSAIDS
  11. History of renal/kidney disease, insufficiency, or injury
  12. Smoke or use tobacco within the last year
  13. Subject has an abnormality or contraindication to study participation, which is not covered in the eligibility criteria.

Additionally, women will be excluded if they are

  1. Pregnant (as determined by a urine pregnancy test on screening and study days)
  2. Currently breastfeeding (self-report)
  3. Post-menopausal (self-report)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03066115


Contacts
Contact: William G Schrage, PhD 608-262-7715 wschrage@wisc.edu
Contact: Garrett L Peltonen, MS 608-263-6308 glpeltonen@wisc.edu

Locations
United States, Wisconsin
University of Wisconsin, Madison
Madison, Wisconsin, United States, 53706
Sponsors and Collaborators
University of Wisconsin, Madison
Investigators
Principal Investigator: William G Schrage, PhD University of Wisconsin, Madison

Responsible Party: University of Wisconsin, Madison
ClinicalTrials.gov Identifier: NCT03066115     History of Changes
Other Study ID Numbers: 2016-1014
First Posted: February 28, 2017    Key Record Dates
Last Update Posted: October 26, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Wisconsin, Madison:
Cerebral blood flow
Cyclooxygenase
Nitric oxide synthase
Reactive Oxygen Species

Additional relevant MeSH terms:
Hypoxia
Hypercapnia
Signs and Symptoms, Respiratory
Signs and Symptoms
Ketorolac
Ketorolac Tromethamine
omega-N-Methylarginine
Nitric Oxide
Ascorbic Acid
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Bronchodilator Agents
Autonomic Agents
Anti-Asthmatic Agents
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Neurotransmitter Agents
Endothelium-Dependent Relaxing Factors
Vasodilator Agents
Gasotransmitters