The Effects of Diesel Exhaust Inhalation on Vascular Function - the Role of Endothelin

Study Overview
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Brief Summary
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The purpose of this study is to identify the role of endothelin 1 (a natural vasoconstrictor) in the adverse vascular effects demonstrated after exposure to air pollution

Detailed Description
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Air pollution is a major problem, and can be linked to around 5% of all deaths worldwide each year. There are strong associations between air pollution exposure and heart disease but we do not yet understand how these harmful effects are mediated. Understanding this mechanism is likely to have a major impact on the way we treat patients with heart disease and have the potential to shape future environmental health policy. The upregulation of Endothelin-1 provides a plausible mechanism for these harmful effects, and we plan to investigate this in more depth in the human forearm following exposure to diesel exhaust.

Official Title
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The Effects of Diesel Exhaust Inhalation on Vascular Function - the Role of Endothelin

Conditions
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Coronary Disease

Intervention / Treatment
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* Drug: Endothelin-1
* Drug: BQ-123 and BQ-788


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male volunteers Exclusion Criteria: Use of regular medication Cigarette smoking Significant occupational exposure to air pollution Intercurrent illness

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

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: 1<br>1 hour exposure to filtered air, followed by forearm venous occlusion plethysmography at 2 hours after the exposure and infusion of endothelin-1 (5pmol/min) | Drug: Endothelin-1<br>* Intra-arterial infusion of Endothelin-1 at 5pmol/min for 1 hour during venous occlusion plethysmography<br>* Other names: American Peptides - 88-1-10 (ET-1);|
| Experimental: 2<br>1 hour exposure to filtered air, followed by forearm venous occlusion plethysmography at 2 hours after the exposure and infusion of endothelin receptor antagonists BQ-123 and BQ-788 | Drug: BQ-123 and BQ-788<br>* 1 hour intra-arterial infusion of BQ-123 at 10nmol/min followed by co-infusion of BQ-788 at 1nmol/min for a further hour during forearm venous occlusion plethysmography<br>* Other names: American Peptides - 88-2-55 (BQ-788);|
| Experimental: 3<br>1 hour exposure to dilute diesel exhaust (300mcg/m3), followed by forearm venous occlusion plethysmography at 2 hours after the exposure and infusion of endothelin-1 (5pmol/min) | Drug: Endothelin-1<br>* Intra-arterial infusion of Endothelin-1 at 5pmol/min for 1 hour during venous occlusion plethysmography<br>* Other names: American Peptides - 88-1-10 (ET-1);|
| Experimental: 4<br>1 hour exposure to dilute diesel exhaust (300mcg/m3), followed by forearm venous occlusion plethysmography at 2 hours after the exposure and infusion of endothelin receptor antagonists BQ-123 and BQ-788 | Drug: BQ-123 and BQ-788<br>* 1 hour intra-arterial infusion of BQ-123 at 10nmol/min followed by co-infusion of BQ-788 at 1nmol/min for a further hour during forearm venous occlusion plethysmography<br>* Other names: American Peptides - 88-2-55 (BQ-788);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in forearm blood flow following infusion of endothelin-1 or the endothelin receptor antagonists BQ-123 & BQ-788 |  | 2 hours after exposure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24 hour mean blood pressure (ambulatory monitoring) |  | 24 hours following the exposure | 
| Systemic endothelin-1 and big endothelin-1 concentrations |  | At baseline, and immediately, 1, 2, 3, 4, 6 and 24 hours after exposure | 
| Changes in arterial stiffness (pulse-wave velocity) |  | During and for the 1 hour after the exposure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endothelin, Air pollution, Diesel exhaust, Vascular function, exposure