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

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.

Conditions

• Hypoxia
• Hypercapnia

Interventions

DRUG

L-NMMA

See arm description.

DRUG

Ketorolac

See arm description.

DRUG

Ascorbic Acid

See arm description.

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.

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)

Sponsors & Collaborators

• University of Wisconsin, Madison

  lead OTHER

Principal Investigators

• William G Schrage, PhD · University of Wisconsin, Madison

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

SINGLE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Max Age

45 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2020-12-01

Primary Completion

2021-12-01

Completion

2021-12-01

FDA Drug

Yes

Countries

• United States

Study Locations