Diesel Exhaust Inhalation, Systemic Nitric Oxide Inhibition and Cardiac Output

Study Overview
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Brief Summary
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Exposure to combustion-derived fine particulate air pollution is associated with cardiovascular mortality and morbidity. In previous studies, exposure to diesel exhaust (a major constituent of urban particulate air pollution) has been shown to impair two important functions of the vascular endothelium: vascular vasomotor function and endogenous fibrinolysis. Our subsequent studies suggest this impairment of vascular function is mediated by a reduction in nitric oxide bioavailability. In this study we aim to investigate the cardiovascular responses to systemic nitric oxide synthase inhibition following exposure to dilute diesel exhaust.

Official Title
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Diesel Exhaust Inhalation, Systemic Nitric Oxide Inhibition and Cardiac Output

Conditions
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Vascular Function in Healthy Volunteers

Intervention / Treatment
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* Drug: Intravenous infusion of L-NMMA and Nor-epinephrine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy volunteers Non smokers No regular medication (except oral contraceptive) No recent respiratory tract infection (within 6 weeks) Exclusion Criteria: History of asthma or respiratory disease Smoking history Pregnancy (positive urinary pregnancy test)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Diesel exhaust exposure<br>1 hour exposure to dilute diesel exhaust   300 mcg/m3 - during intermittent exercise | Drug: Intravenous infusion of L-NMMA and Nor-epinephrine<br>* Intravenous infusion of 3mg/kg L-NMMA (L-NG-monomethyl arginine; NO synthase inhibitor) and nor-epinephrine at 50 ng/kg/min. Each infusion to run over 15 mins and separated by 45 min to allow return to baseline. Drugs infused in a randomised order. During the study, blood pressure will be measured invasively using an intra-arterial radial artery cannula, central arterial stiffness measured using peripheral arterial tonometry and cardiac output using thoracic bioimpedance.<br>* Other names: L-NMMA: Clinalfa Basic, Bachem, Germany;|
| Experimental: Air exposure<br>1 hour exposure to filtered air during intermittent exercise | Drug: Intravenous infusion of L-NMMA and Nor-epinephrine<br>* Intravenous infusion of 3mg/kg L-NMMA (L-NG-monomethyl arginine; NO synthase inhibitor) and nor-epinephrine at 50 ng/kg/min. Each infusion to run over 15 mins and separated by 45 min to allow return to baseline. Drugs infused in a randomised order. During the study, blood pressure will be measured invasively using an intra-arterial radial artery cannula, central arterial stiffness measured using peripheral arterial tonometry and cardiac output using thoracic bioimpedance.<br>* Other names: L-NMMA: Clinalfa Basic, Bachem, Germany;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood pressure response to NO inhibition |  | Blood pressure will be measured continuously through the vascular study using intra-arterial monitoring | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heart rate response to systemic nitric oxide inhibition |  | Heart rate will be measured continuously throughout the study period using continous electrocardiography | 
| Central arterial stiffness following NO inhibition |  | Measured at baseline, and every 5 minutes during the 2-hour vascular study | 
| Cardiac output during NO inhibition |  | Measured at baseline, and every 5 minutes during the 2-hour vascular study | 
| Plasma nitrite (NO) concentrations |  | Measured at baseline, and every 15 minutes during the 2-hour vascular study | 
| Platelet activation and platelet-monocyte binding |  | Measured at baseline, and every 30 minutes during the 2-hour vascular study | 
| Heart rate variability |  | Heart rate will be measured continuously throughout the study period using continous electrocardiography, and HRV subsequently determined for the whole study period and the 2-hour vascular study separately | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nitric oxide, Diesel exhaust, Air pollution, Cardiac output, Healthy volunteers