title: Altered nitric oxide bioavailability contributes to diesel exhaust inhalation-induced cardiovascular dysfunction in man.
abstract: BACKGROUND
  Diesel exhaust inhalation causes cardiovascular dysfunction including impaired vascular reactivity, increased blood pressure, and arterial stiffness. We investigated the role of nitric oxide (NO) bioavailability in mediating these effects.
  
  
  RESULTS
  In 2 randomized double-blind crossover studies, healthy nonsmokers were exposed to diesel exhaust or filtered air. Study 1: Bilateral forearm blood flow was measured during intrabrachial infusions of acetylcholine (ACh; 5 to 20 μg/min) and sodium nitroprusside (SNP; 2 to 8 μg/min) in the presence of the NO clamp (NO synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) 8 μg/min coinfused with the NO donor SNP at 90 to 540 ng/min to restore basal blood flow). Study 2: Blood pressure, arterial stiffness, and cardiac output were measured during systemic NO synthase inhibition with intravenous l-NMMA (3 mg/kg). Following diesel exhaust inhalation, plasma nitrite concentrations were increased (68±48 versus 41±32 nmol/L; P=0.006) despite similar l-NMMA-induced reductions in basal blood flow (-20.6±14.7% versus -21.1±14.6%; P=0.559) compared to air. In the presence of the NO clamp, ACh and SNP caused dose-dependent vasodilatation that was not affected by diesel exhaust inhalation (P>0.05 for both). Following exposure to diesel exhaust, l-NMMA caused a greater increase in blood pressure (P=0.048) and central arterial stiffness (P=0.007), but reductions in cardiac output and increases in systemic vascular resistance (P>0.05 for both) were similar to those seen with filtered air.
  
  
  CONCLUSIONS
  Diesel exhaust inhalation disturbs normal vascular homeostasis with enhanced NO generation unable to compensate for excess consumption. We suggest the adverse cardiovascular effects of air pollution are, in part, mediated through reduced NO bioavailability.
  
  
  BACKGROUND
  URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT00845767 and NCT01060930.
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Langrish
authors.forename: Jon
authors.initials: J
authors.lastname: Unosson
authors.forename: Jenny
authors.initials: J
authors.lastname: Bosson
authors.forename: Stefan
authors.initials: S
authors.lastname: Barath
authors.forename: Ala
authors.initials: A
authors.lastname: Muala
authors.forename: Scott
authors.initials: S
authors.lastname: Blackwell
authors.forename: Stefan
authors.initials: S
authors.lastname: Söderberg
authors.forename: Jamshid
authors.initials: J
authors.lastname: Pourazar
authors.forename: Ian L
authors.initials: IL
authors.lastname: Megson
authors.forename: Andrew
authors.initials: A
authors.lastname: Treweeke
authors.forename: Thomas
authors.initials: T
authors.lastname: Sandström
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
authors.forename: Anders
authors.initials: A
authors.lastname: Blomberg
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Mills
mesh_terms: D000328:Adult; D000393:Air Pollutants / Q000009:adverse effects*; D001120:Arginine / Q000097:blood; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005542:Forearm / Q000098:blood supply*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000008:administration & dosage; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D059289:Vascular Stiffness; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage; D001335:Vehicle Emissions / Q000633:toxicity*; D055815:Young Adult
chemical_list: D000393:Air Pollutants; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009573:Nitrites; D014665:Vasodilator Agents; D001335:Vehicle Emissions; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase