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

Purpose

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	Intervention
Coronary Disease	Drug: Endothelin-1 Drug: BQ-123 and BQ-788

MedlinePlus related topics:

Air Pollution

Drug Information available for:

BQ 123

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Basic Science, Randomized, Double Blind (Subject, Investigator, Outcomes Assessor), Crossover Assignment

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

Further study details as provided by University of Edinburgh:

Primary Outcome Measures:

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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

24 hour mean blood pressure (ambulatory monitoring) [ Time Frame: 24 hours following the exposure ] [ Designated as safety issue: No ]
Systemic endothelin-1 and big endothelin-1 concentrations [ Time Frame: At baseline, and immediately, 1, 2, 3, 4, 6 and 24 hours after exposure ] [ Designated as safety issue: No ]
Changes in arterial stiffness (pulse-wave velocity) [ Time Frame: During and for the 1 hour after the exposure ] [ Designated as safety issue: No ]

Enrollment:	15
Study Start Date:	March 2008
Study Completion Date:	May 2008
Primary Completion Date:	May 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental 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
2: Experimental 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
3: Experimental 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
4: Experimental 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

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.

Eligibility

Ages Eligible for Study:	18 Years to 35 Years
Genders 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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00745693

Locations


Sweden, Västerbottens
	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, Törnqvist 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.

Törnqvist H, Mills NL, Gonzalez M, Miller MR, Robinson SD, Megson IL, Macnee W, Donaldson K, Söderberg S, Newby DE, Sandström 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. Epub 2007 Apr 19.

Calderón-Garcidueñas L, Vincent R, Mora-Tiscareño A, Franco-Lira M, Henríquez-Roldán C, Barragán-Mejía G, Garrido-García L, Camacho-Reyes L, Valencia-Salazar G, Paredes R, Romero L, Osnaya H, Villarreal-Calderón R, Torres-Jardón 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.

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.

Vincent R, Kumarathasan P, Goegan P, Bjarnason SG, Guénette J, Bérubé 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.

Responsible Party:	University of Edinburgh ( Dr Jeremy Langrish )
Study ID Numbers:	Res08/A116
First Received:	September 2, 2008
Last Updated:	September 4, 2008
ClinicalTrials.gov Identifier:	NCT00745693
Health Authority:	Sweden: Regional Ethical Review Board

Keywords provided by University of Edinburgh:

Endothelin

Air pollution

Diesel exhaust

Vascular function

exposure

Study placed in the following topic categories:

Coronary Disease

Tryptophan

BQ 788

Heart Diseases

Myocardial Ischemia

Vascular Diseases

Cyclo(Trp-Asp-Pro-Val-Leu)

Ischemia

Additional relevant MeSH terms:

Therapeutic Uses

Cardiovascular Diseases

Cardiovascular Agents

Antihypertensive Agents

Pharmacologic Actions

ClinicalTrials.gov processed this record on October 24, 2008

Sponsors and Collaborators:	University of Edinburgh Umeå University
Information provided by:	University of Edinburgh
ClinicalTrials.gov Identifier:	NCT00745693