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

NCT ID: NCT00745693

Last Updated: 2024-05-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-03-31
• Study Completion Date: 2008-05-31

Brief Summary

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

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.

Conditions

Coronary Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

1

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)

Group Type: EXPERIMENTAL

Endothelin-1

Intervention Type: DRUG

Intra-arterial infusion of Endothelin-1 at 5pmol/min for 1 hour during venous occlusion plethysmography

2

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

Group Type: EXPERIMENTAL

BQ-123 and BQ-788

Intervention Type: DRUG

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

3

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)

Group Type: EXPERIMENTAL

Endothelin-1

Intervention Type: DRUG

Intra-arterial infusion of Endothelin-1 at 5pmol/min for 1 hour during venous occlusion plethysmography

4

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

Group Type: EXPERIMENTAL

BQ-123 and BQ-788

Intervention Type: DRUG

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

Interventions

Endothelin-1

Intra-arterial infusion of Endothelin-1 at 5pmol/min for 1 hour during venous occlusion plethysmography

Intervention Type: DRUG

BQ-123 and BQ-788

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

Intervention Type: DRUG

Other Intervention Names

ET-1; American Peptides - 88-1-10 (ET-1); American Peptides - 88-2-10 (BQ-123); American Peptides - 88-2-55 (BQ-788)

Eligibility Criteria

Inclusion Criteria

• Healthy male volunteers

Exclusion Criteria

• Use of regular medication
• Cigarette smoking
• Significant occupational exposure to air pollution
• Intercurrent illness

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

Umeå University

OTHER

Sponsor Role: collaborator

University of Edinburgh

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jeremy P Langrish, MB BCh MRCP

Role: PRINCIPAL_INVESTIGATOR

University of Edinburgh

Anders Blomberg, MD

Role: STUDY_DIRECTOR

Umeå University

Thomas Sandström, MD

Role: STUDY_DIRECTOR

Umeå University

David E Newby, MD FRCP

Role: STUDY_DIRECTOR

University of Edinburgh

Locations

Umeå University

Umeå, Västerbottens, Sweden

Countries

Sweden

References

Mills NL, Tornqvist H, Robinson SD, Gonzalez M, Darnley K, MacNee W, Boon NA, Donaldson K, Blomberg A, Sandstrom T, Newby DE. Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis. Circulation. 2005 Dec 20;112(25):3930-6. doi: 10.1161/CIRCULATIONAHA.105.588962.

Reference Type: BACKGROUND

PMID: 16365212 (View on PubMed)

Tornqvist H, Mills NL, Gonzalez M, Miller MR, Robinson SD, Megson IL, Macnee W, Donaldson K, Soderberg S, Newby DE, Sandstrom T, Blomberg A. Persistent endothelial dysfunction in humans after diesel exhaust inhalation. Am J Respir Crit Care Med. 2007 Aug 15;176(4):395-400. doi: 10.1164/rccm.200606-872OC. Epub 2007 Apr 19.

Reference Type: BACKGROUND

PMID: 17446340 (View on PubMed)

Calderon-Garciduenas L, Vincent R, Mora-Tiscareno A, Franco-Lira M, Henriquez-Roldan C, Barragan-Mejia G, Garrido-Garcia L, Camacho-Reyes L, Valencia-Salazar G, Paredes R, Romero L, Osnaya H, Villarreal-Calderon R, Torres-Jardon R, Hazucha MJ, Reed W. Elevated plasma endothelin-1 and pulmonary arterial pressure in children exposed to air pollution. Environ Health Perspect. 2007 Aug;115(8):1248-53. doi: 10.1289/ehp.9641.

Reference Type: BACKGROUND

PMID: 17687455 (View on PubMed)

Peretz A, Sullivan JH, Leotta DF, Trenga CA, Sands FN, Allen J, Carlsten C, Wilkinson CW, Gill EA, Kaufman JD. Diesel exhaust inhalation elicits acute vasoconstriction in vivo. Environ Health Perspect. 2008 Jul;116(7):937-42. doi: 10.1289/ehp.11027.

Reference Type: BACKGROUND

PMID: 18629317 (View on PubMed)

Vincent R, Kumarathasan P, Goegan P, Bjarnason SG, Guenette J, Berube D, Adamson IY, Desjardins S, Burnett RT, Miller FJ, Battistini B. Inhalation toxicology of urban ambient particulate matter: acute cardiovascular effects in rats. Res Rep Health Eff Inst. 2001 Oct;(104):5-54; discussion 55-62.

Reference Type: BACKGROUND

PMID: 11833973 (View on PubMed)

Langrish JP, Lundback M, Mills NL, Johnston NR, Webb DJ, Sandstrom T, Blomberg A, Newby DE. Contribution of endothelin 1 to the vascular effects of diesel exhaust inhalation in humans. Hypertension. 2009 Oct;54(4):910-5. doi: 10.1161/HYPERTENSIONAHA.109.135947. Epub 2009 Aug 17.

Reference Type: DERIVED

PMID: 19687345 (View on PubMed)

Other Identifiers

Res08/A116

Identifier Type: -

Identifier Source: org_study_id