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

• ClinicalTrials.gov Identifier: NCT00745693
• Recruitment Status: Completed
• First Posted: September 3, 2008
• Last Update Posted: September 5, 2008
• Sponsor: University of Edinburgh
• Collaborator: Umeå University
• Information provided by: University of Edinburgh

Study Description

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

Condition or disease	Intervention/treatment	Phase
Coronary Disease	Drug: Endothelin-1; Drug: BQ-123 and BQ-788	Not Applicable

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: The Effects of Diesel Exhaust Inhalation on Vascular Function - the Role of Endothelin
• Study Start Date: March 2008
• Actual Primary Completion Date: May 2008
• Actual Study Completion Date: May 2008

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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)	Drug: Endothelin-1; Intra-arterial infusion of Endothelin-1 at 5pmol/min for 1 hour during venous occlusion plethysmography; Other Names: ET-1; American Peptides - 88-1-10 (ET-1)
Experimental: 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	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; Other Names: American Peptides - 88-2-10 (BQ-123); American Peptides - 88-2-55 (BQ-788)
Experimental: 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)	Drug: Endothelin-1; Intra-arterial infusion of Endothelin-1 at 5pmol/min for 1 hour during venous occlusion plethysmography; Other Names: ET-1; American Peptides - 88-1-10 (ET-1)
Experimental: 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	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; Other Names: American Peptides - 88-2-10 (BQ-123); American Peptides - 88-2-55 (BQ-788)

Outcome Measures

Primary Outcome Measures :

1. Change in forearm blood flow following infusion of endothelin-1 or the endothelin receptor antagonists BQ-123 & BQ-788 [ Time Frame: 2 hours after exposure ]

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 35 Years (Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Healthy male volunteers

Exclusion Criteria:

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

Contacts and Locations

Locations

Sweden

Umeå University

Umeå, Västerbottens, Sweden, SE-901 87

Sponsors and Collaborators

University of Edinburgh

Umeå University

Investigators

• Principal Investigator: Jeremy P Langrish, MB BCh MRCP; University of Edinburgh
• Study Director: Anders Blomberg, MD; Umeå University
• Study Director: Thomas Sandström, MD; Umeå University
• Study Director: David E Newby, MD FRCP; University of Edinburgh

More Information

Publications:

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.

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.

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.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Dr Jeremy Langrish, University of Edinburgh
• ClinicalTrials.gov Identifier: NCT00745693
• Other Study ID Numbers: Res08/A116
• First Posted: September 3, 2008
• Last Update Posted: September 5, 2008
• Last Verified: September 2008

Keywords provided by University of Edinburgh:

Endothelin; Air pollution; Diesel exhaust; Vascular function; exposure

Additional relevant MeSH terms:

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; cyclo(Trp-Asp-Pro-Val-Leu); BQ 788; Antihypertensive Agents; Endothelin Receptor Antagonists; Molecular Mechanisms of Pharmacological Action; Endothelin B Receptor Antagonists