Contributions of Nitric Oxide Synthase, Cyclooxygenase, and Reactive Oxygen Species to Regional Cerebrovascular Control During Hypoxia and Hypercapnia
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Change in cerebral blood flow velocity in the middle cerebral artery
研究概览
简要总结
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.
详细描述
Specific Aims:
1A. Determine the independent contributions of NOS and COX to hypoxic and hypercapnic vasodilation in the MCA of young, healthy adults.
1B. Determine the combined contribution of NOS and COX to hypoxic and hypercapnic vasodilation in the MCA of young, healthy adults.
- C. Determine the combined contribution of NOS, COX, and ROS to hypoxic and hypercapnic vasodilation in the MCA of young, healthy adults.
- A. Determine the independent contributions of NOS and COX to hypoxic and hypercapnic vasodilation in the BA of young, healthy adults.
2B. Determine the combined contribution of NOS and COX to hypoxic and hypercapnic vasodilation in the BA of young, healthy adults.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age: 18 ≤ years ≤ 45
- •Free of disease and otherwise healthy as determined by health history questionnaire
- •Not currently taking medication with the exception of birth control as determined by health history questionnaire
- •Low to moderate physical activity will be permitted and assessed by a physical activity questionnaire (≤ 4 hours of physical activity/week)
- •Body mass index (BMI) < 25 kg/m2
- •Resting blood pressure <140/<90 mmHg (lowest of three measures)
- •Resting heart rate <100 bpm
- •Resting pulse oximetry oxygen saturation (SPO2) >95%
- •Fasting venous blood values (average of two measures)
- •Glucose <100 mg/dL
- •Creatinine < 1.5 mg/dL
- •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
- •Subjects must be willing to report to the laboratory on all study days after completing
- •Minimum 10-hour fast
- •Minimum 18-hours abstention from exercise, alcohol, caffeine, and non-steroidal anti-inflammatory drugs (i.e. aspirin, ibuprofen, and naproxen)
- •Additionally, women will
- •Have a regular menstrual cycle (self-report)
- •Be studied (study visit 1 and study visit 2) on days 1-5 of menstrual cycle (self- report).
排除标准
- •Coronary artery disease
- •Heart attack
- •Heart valve disease
- •Congestive heart failure
- •Previous heart surgery
- •Lung disease
- •Peripheral vascular disease
- •Gastrointestinal (GI) bleeding
- •Allergy or Intolerance to Aspirin or NSAIDS
- •History of renal/kidney disease, insufficiency, or injury
- •Smoke or use tobacco within the last year
- •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
- •Pregnant (as determined by a urine pregnancy test on screening and study days)
- •Currently breastfeeding (self-report)
- •Post-menopausal (self-report)
研究组 & 干预措施
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.
干预措施: L-NMMA (Drug)
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.
干预措施: Ketorolac (Drug)
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.
干预措施: Ascorbic Acid (Drug)
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.
干预措施: Intravenous Catheter (Procedure)
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.
干预措施: Transcranial Doppler Ultrasound (Procedure)
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.
干预措施: L-NMMA (Drug)
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.
干预措施: Ketorolac (Drug)
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.
干预措施: Ascorbic Acid (Drug)
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.
干预措施: Intravenous Catheter (Procedure)
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.
干预措施: Transcranial Doppler Ultrasound (Procedure)
结局指标
主要结局
Change in cerebral blood flow velocity in the middle cerebral artery
时间窗: 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.
次要结局
- Change in cerebral blood flow velocity in the basilar artery(Through study completion (up to 1 year))