title: Contribution of endothelin 1 to the vascular effects of diesel exhaust inhalation in humans.
abstract: Diesel exhaust inhalation impairs vascular function, and, although the underlying mechanism remains unclear, endothelin (ET) 1 and NO are potential mediators. The aim of this study was to identify whether diesel exhaust inhalation affects the vascular actions of ET-1 in humans. In a randomized, double-blind crossover study, 13 healthy male volunteers were exposed to either filtered air or dilute diesel exhaust (331+/-13 microg/m(3)). Plasma concentrations of ET-1 and big-ET-1 were determined at baseline and throughout the 24-hour study period. Bilateral forearm blood flow was measured 2 hours after the exposure during infusion of either ET-1 (5 pmol/min) or the ET(A) receptor antagonist, BQ-123 (10 nmol/min) alone and in combination with the ET(B) receptor antagonist, BQ-788 (1 nmol/min). Diesel exhaust exposure had no effect on plasma ET-1 and big-ET-1 concentrations (P>0.05 for both) or 24-hour mean blood pressure or heart rate (P>0.05 for all). ET-1 infusion increased plasma ET-1 concentrations by 58% (P<0.01) but caused vasoconstriction only after diesel exhaust exposure (-17% versus 2% after air; P<0.001). In contrast, diesel exhaust exposure reduced vasodilatation to isolated BQ-123 infusion (20% versus 59% after air; P<0.001) but had no effect on vasodilatation to combined BQ-123 and BQ-788 administration (P>0.05). Diesel exhaust inhalation increases vascular sensitivity to ET-1 and reduces vasodilatation to ET(A) receptor antagonism despite unchanged plasma ET-1 concentrations. Given the tonic interaction between the ET and NO systems, we conclude that diesel exhaust inhalation alters vascular reactivity to ET-1 probably through its effects on NO bioavailability.
authors.affiliation: Centre for Cardiovascular Sciences, University of Edinburgh, 49 Little France Crescent, Edinburgh, United Kingdom. jeremy.langrish@ed.ac.uk
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Langrish
authors.forename: Magnus
authors.initials: M
authors.lastname: Lundbäck
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Mills
authors.forename: Neil R
authors.initials: NR
authors.lastname: Johnston
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
authors.forename: Thomas
authors.initials: T
authors.lastname: Sandström
authors.forename: Anders
authors.initials: A
authors.lastname: Blomberg
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000502:physiology; D001916:Brachial Artery / Q000187:drug effects / Q000502:physiology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood* / Q000502:physiology; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D044022:Receptor, Endothelin A / Q000502:physiology; D044023:Receptor, Endothelin B / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D001335:Vehicle Emissions
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D001335:Vehicle Emissions; D009569:Nitric Oxide; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)