ToxSci Advance Access originally published online on January 11, 2006
Toxicological Sciences 2006 90(2):385-391; doi:10.1093/toxsci/kfj100
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Hypersensitivity of Prediabetic JCR:LA-cp Rats to Fine Airborne Combustion Particle-Induced Direct and Noradrenergic-Mediated Vascular Contraction
* Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, University of Alberta, Edmonton, Alberta, T6G 2P5, Canada; and Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
Received November 10, 2005; accepted January 4, 2006
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 U.S. powerplant on vascular function in a prediabetic, hyperinsulinemic model, the JCR:LA-cp rat. Residual oil fly ash leachate (ROFA-L) was studied using aortic rings from young-adult, obese, insulin-resistant rats 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 were determined. ROFA-L (12.5 µg ml–1) increased phenylephrine-mediated contraction in obese (p < 0.05), but not in lean rat aortae, with the effect being exacerbated by L-NAME, and it 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) aortae 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 prediabetic rats. These observations provide the first direct evidence of the causal properties of PM2.5 and identify the pathophysiological role of the early prediabetic state in susceptibility to environmentally induced cardiovascular disease. These are important implications for public health and public policy.
Key Words: fine particulate air pollution; insulin resistance; type 2 diabetes; vasculopathy; vasospasm; cardiovascular disease; JCR:LA-cp rat.