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

• Status: Withdrawn
• Trial end date: 2021-12-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: University of Wisconsin, Madison
• Treatments: Ascorbic Acid; Ketorolac; Ketorolac Tromethamine; Nitric Oxide; omega-N-Methylarginine

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)