Impact of NOS, COX, and ROS Inhibition on Cerebral Blood Flow Regulation
Status:
Withdrawn
Trial end date:
2021-12-01
Target enrollment:
Participant gender:
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.