title: Ozone Inhalation Impairs Coronary Artery Dilation via Intracellular Oxidative Stress: Evidence for Serum-Borne Factors as Drivers of Systemic Toxicity.
abstract: Ambient ozone (O3) levels are associated with cardiovascular morbidity and mortality, but the underlying pathophysiological mechanisms driving extrapulmonary toxicity remain unclear. This study examined the coronary vascular bed of rats in terms of constrictive and dilatory responses to known agonists following a single O3 inhalation exposure. In addition, serum from exposed rats was used in ex vivo preparations to examine whether bioactivity and toxic effects of inhaled O3 could be conveyed to extrapulmonary systems via the circulation. We found that 24 h following inhalation of 1 ppm O3, isolated coronary vessels exhibited greater basal tone and constricted to a greater degree to serotonin stimulation. Vasodilation to acetylcholine (ACh) was markedly diminished in coronary arteries from O3-exposed rats, compared with filtered air-exposed controls. Dilation to ACh was restored by combined superoxide dismutase and catalase treatment, and also by NADPH oxidase inhibition. When dilute (10%) serum from exposed rats was perfused into the lumen of coronary arteries from unexposed, naïve rats, the O3-induced reduction in vasodilatory response to ACh was partially recapitulated. Furthermore, following O3 inhalation, serum exhibited a nitric oxide scavenging capacity, which may partially explain blunted ACh-mediated vasodilatory responses. Thus, bioactivity from inhalation exposures may be due to compositional changes of the circulation. These studies shed light on possible mechanisms of action that may explain O3-associated cardiac morbidity and mortality in humans.
authors.affiliation: *Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Paffett
authors.affiliation: *Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Zychowski
authors.affiliation: Departments of Biostatistics and Environmental & Occupational Health Sciences, School of Public Health, University of Washington, Seattle, Washington and.
authors.forename: Lianne
authors.initials: L
authors.lastname: Sheppard
authors.affiliation: Toxicology Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Robertson
authors.affiliation: *Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico.
authors.forename: John M
authors.initials: JM
authors.lastname: Weaver
authors.affiliation: *Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Selita N
authors.initials: SN
authors.lastname: Lucas
authors.affiliation: *Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, mcampen@salud.unm.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Campen
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage; D000818:Animals; D001769:Blood; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D019570:Inhalation Exposure; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D010126:Ozone / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000008:administration & dosage; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D012701:Serotonin; D010126:Ozone; D000109:Acetylcholine
keywords: cardiopulmonary; cardiovascular system; endothelium; inhalation toxicology; respiratory toxicology