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ToxSci Advance Access published online on January 11, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj100
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received November 10, 2005
Accepted January 4, 2006

Environmental Toxicology

Hypersensitivity of Pre-diabetic JCR:LA-cp Rats to Fine Airborne Combustion Particle-induced Direct and Noradrenergic-Mediated Vascular Contraction

Spencer D. Proctor 1, Kevin L. Dreher 2, Sandra E. Kelly 1, and James C. Russell 1 *

1 Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, University of Alberta, Edmonton, AB, T6G 2P5, Canada
2 Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA

* To whom correspondence should be addressed.
James C. Russell, E-mail: Jim.Russell{at}ualberta.ca


  Abstract

Particulate matter with mean aerodynamic diameter 2.5 µm (PM2.5), from diesel exhaust, coal or residual oil burning and from industrial plants, is a significant component of airborne pollution. Type 2 diabetes is associated with enhanced risk of adverse cardiovascular events following exposure to PM2.5. Particle properties, sources and pathophysiological mechanisms responsible are unknown. We studied effects of residual oil fly ash (ROFA) from a large US power plant on vascular function in a pre-diabetic, hyperinsulinaemic model, the JCR:LA-cp rat. ROFA leachate (ROFA-L) was studied using aortic rings from young adult obese insulin resistant and lean normal rats in vitro. Contractile response to phenylephrine and relaxant response to acetylcholine were determined in the presence and absence of L-NAME (NG- nitro-L-arginine methyl ester). In a separate series of studies, the direct contractile effects of ROFA-L on repeated exposure determined. ROFA-L (12.5 ìg ml-1) increased phenylephrine-mediated contraction in obese (P<0.05), but not in lean rat aortae, with the effect being exacerbated by LNAME, and reduced acetylcholine-mediated relaxation of both obese and lean aortae (P<0.0001). Initial exposure of aortae to ROFA-L caused a small contractile response (<0.05 g), which was markedly greater on second exposure in the obese (~0.6 g, P<0.0001), but marginal in lean (~0.1 g) aortae. Our data demonstrate that bioavailable constituents of oil combustion particles enhance noradrenergic-mediated vascular contraction, impair endothelium-mediated relaxation, and induce direct vasocontraction in pre-diabetic rats. These observations provide the first direct evidence of the causal properties of PM2.5 and identify the pathophysiological role of the early pre-diabetic state in susceptibility to environmentally induced cardiovascular disease. There are important implications for public health and public policy.

Keywords: fine particulate air pollution; insulin resistance; type 2 diabetes; vasculopathy; vasospasm; cardiovascular disease; JCR:LA-cp rat.
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