Acrolein induces vasodilatation of rodent mesenteric bed via an EDHF-dependent mechanism

• Published in: Toxicology and applied pharmacology Vol. 217; no. 3; pp. 266 - 276
• Main Authors: Awe, S.O., Adeagbo, A.S.O., D'Souza, S.E., Bhatnagar, A., Conklin, D.J.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 15-12-2006; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; ACROLEIN; Acrolein - toxicity; Aldehyde; Animals; Apamin - pharmacology; ARTERIES; Biological and medical sciences; Biological Factors - metabolism; BIOLOGICAL STRESS; Blood Vessels - drug effects; Blood Vessels - metabolism; CALCIUM IONS; Drug Interactions; ENDOTHELIUM; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; endothelium-derived hyperpolarization factor (EDHF); Endothelium-derived relaxing factor; eNOS-null mice; Environmental Pollutants - toxicity; HEXANOIC ACID; INFLAMMATION; Male; Medical sciences; Mesentery - blood supply; Mesentery - drug effects; MICE; Mice, Inbred C57BL; Mice, Knockout; NERVE CELLS; NERVOUS SYSTEM DISEASES; Nitric Oxide Synthase Type III - deficiency; Nitric Oxide Synthase Type III - genetics; OUABAIN; Ouabain-sensitive dilation; PATIENTS; POLLUTANTS; POTASSIUM; Potassium Channel Blockers - pharmacology; Potassium channels; Potassium Channels - drug effects; Potassium Channels - metabolism; POTASSIUM IONS; PROSTAGLANDINS; Pyrazoles - pharmacology; Rats; Rats, Sprague-Dawley; SENSITIVITY; SUPEROXIDE DISMUTASE; Toxicology; VASODILATION; Vasodilation - drug effects; Potassium channels; Endothelium-derived relaxing factor; Aldehyde; Ouabain-sensitive dilation; eNOS-null mice; endothelium-derived hyperpolarization factor (EDHF); Bed; Cardiotonic agent; Ouabain; Rodentia; Ionic channel; Inorganic element; Ouabain- sensitive dilation; Endothelium; Acrolein; Vertebrata; Mammalia; Mouse; Animal; Glycoside; Endothelium-derived hyperpolarization factor (EDHF); Endothelium derived relaxing factor; Mechanism of action; Potassium
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2006.08.008

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 μM ouabain, and inhibited 64% in 20 mM K
+ buffer. Moreover, combined treatment with the Ca
2+-activated K
+ channel inhibitors 1-[(2-chlorophenyl)diphenylmethyl]-1
H-pyrazole (TRAM-34, 100 nM) and apamin (5 μM) 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 μM), an epoxygenase inhibitor, or the superoxide dismutase mimetic Tempol (100 μM) 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.