| 17069868 |
Awe SO, Adeagbo AS, D'Souza SE, Bhatnagar A, Conklin DJ: Acrolein induces vasodilatation of rodent mesenteric bed via an EDHF-dependent mechanism. Toxicol Appl Pharmacol. 2006 Dec 15;217(3):266-76. Epub 2006 Aug 26.
Acrolein is generated endogenously during lipid peroxidation and inflammation and is an environmental pollutant. Protein adducts of acrolein are detected in atherosclerotic plaques and neurons of patients with Alzheimer's disease. To understand vascular effects of acrolein exposure, we studied acrolein vasoreactivity in perfused rodent mesenteric bed. Acrolein induced endothelium-dependent vasodilatation that was more robust and more sensitive than dilation induced by 4-hydroxy-trans-2-nonenal, trans-2-hexenal, or propionaldehyde. Acrolein-induced vasodilatation was mediated by K (+)-sensitive components, e.g., it was abolished in 0 [K (+)](o) buffer or in 3 mM tetrabutylammonium, inhibited 75% in 50 microM ouabain, and inhibited 64% in 20 mM K (+) buffer. Moreover, combined treatment with the Ca (2+)-activated K (+) channel inhibitors 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34, 100 nM) and apamin (5 microM) significantly reduced vasodilatation without altering sensitivity to acrolein. However, acrolein-induced % dilation was unaffected by l-NAME or indomethacin pretreatment indicating mechanistic independence of NO and prostaglandins. Moreover, acrolein induced vasodilatation in cirazoline-precontracted mesenteric bed of eNOS-null mice confirming eNOS independence. Pretreatment with 6-(2-propargyloxyphenyl) hexanoic acid (PPOH 50 microM), an epoxygenase inhibitor, or the superoxide dismutase mimetic Tempol (100 microM) significantly attenuated acrolein-induced vasodilatation. Collectively, these data indicate that acrolein stimulates mesenteric bed vasodilatation due to endothelium-derived signal (s) that is K (+)-, ouabain-, PPOH-, and Tempol-sensitive, and thus, a likely endothelium-derived hyperpolarizing factor (EDHF). These data indicate that low level acrolein exposure associated with vascular oxidative stress or inflammation stimulates vasodilatation via EDHF release in medium-sized arteries--a novel function. |
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