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

• 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 ]

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

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.

• 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)
• 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: 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)
  Intervention: Drug: Endothelin-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
  Intervention: Drug: BQ-123 and 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)
  Intervention: Drug: Endothelin-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
  Intervention: Drug: BQ-123 and BQ-788

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• 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.
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• 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.
• Langrish JP, Lundbäck M, Mills NL, Johnston NR, Webb DJ, Sandström 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. Epub 2009 Aug 17.

Inclusion Criteria:

• Healthy male volunteers

Exclusion Criteria:

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