title: Mechanisms of diesel-induced endothelial nitric oxide synthase dysfunction in coronary arterioles.
abstract: OBJECTIVE
  Increased air pollutants correlate with increased incidence of cardiovascular disease potentially due to vascular dysfunction. We have reported that acute diesel engine exhaust (DE) exposure enhances vasoconstriction and diminishes acetylcholine (ACh)-induced dilation in coronary arteries in a nitric oxide synthase (NOS)-dependent manner. We hypothesize that acute DE inhalation leads to endothelial dysfunction by uncoupling NOS.
  
  
  METHODS
  Rats inhaled fresh DE (300 µg particulate matter/m3) or filtered air for 5 hr. After off-gassing, intraseptal coronary arteries were isolated and dilation to ACh recorded using videomicroscopy.
  
  
  RESULTS
  Arteries from DE-exposed animals dilated less to ACh than arteries from air-exposed animals. NOS inhibition did not affect ACh dilation in control arteries but increased dilation in the DE group, suggesting NOS does not normally contribute to ACh-induced dilation in coronary arteries but does contribute to endothelial dysfunction after DE inhalation. Cyclooxygenase (COX) inhibition did not affect ACh dilation in the DE group, but combined inhibition of NOS and COX diminished dilation in both groups and eliminated intergroup differences, suggesting that the two pathways interact. Superoxide scavenging increased ACh dilation in DE arteries, eliminating differences between groups. Tetrahydrobiopterin (BH4) supplementation with sepiapterin restored ACh-mediated dilation in the DE group in a NOS-dependent manner. Superoxide generation (dihydroethidium staining) was greater in DE arteries, and superoxide scavenging, BH4 supplementation, or NOS inhibition reduced the signal in DE but not air arteries.
  
  
  CONCLUSIONS
  Acute DE exposure appears to uncouple NOS, increasing reactive oxygen species generation and causing endothelial dysfunction, potentially because of depletion of BH4 limiting its bioavailability.
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico, Health Sciences Center, Albuquerque, New Mexico 87131, USA.
authors.forename: Tom W
authors.initials: TW
authors.lastname: Cherng
authors.forename: Michael L
authors.initials: ML
authors.lastname: Paffett
authors.forename: Olan
authors.initials: O
authors.lastname: Jackson-Weaver
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Campen
authors.forename: Benjimen R
authors.initials: BR
authors.lastname: Walker
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Kanagy
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: D000393:Air Pollutants; D001335:Vehicle Emissions; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D000109:Acetylcholine