title: Endothelial nitric oxide and 15-lipoxygenase-1 metabolites independently mediate relaxation of the rabbit aorta.
abstract: Endothelial 15-lipoxygenase-1 (15-LO-1) metabolites of arachidonic acid (AA), 11,12,15-trihydroxyeicosatrienoic acid (THETA) and 15-hydroxy-11,12-epoxyeicosatrienoic acid (HEETA) and nitric oxide (NO) mediate relaxations to acetylcholine (ACH). However, interactions between NO and the 15-LO-1 pathway have not been explored. Therefore, the effect of physiological and pharmacological concentrations of NO on 15-LO activity and relaxation was studied in rabbit aorta. In indomethacin-treated aortic rings, maximal ACH relaxations of 91.3±4.0%, decreased to 54.5±3.0% by the NO synthase inhibitor, nitro-l-arginine (LNA), to 49.8±3% by the guanylate cyclase (GC) inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, to 63.7±4.9% by the lipoxygenase (LO) inhibitor, nordihydroguaiaretic acid (NDGA) and were completely inhibited by the combination of LNA and NDGA. AA relaxations were not affected by GC inhibition but were reduced by LO inhibition. The NO donor, dipropylenetriamine-NONOate (DPTA) caused concentration-related relaxations (EC(50)=4.7×10(-6)M). Aortic metabolism of (14)C-AA to THETA and HEETA was not altered by EC(50) concentrations of DPTA but were reduced 10-fold by 10(-3)M DPTA. In LNA-treated aorta, DPTA (3×10(-6)M) caused relaxations of 38.2.5±4%. Maximum relaxations to ACH did not differ in the presence and absence 3×10(-6)M DPTA (49.5±5% and 44.2±4%, respectively). These results indicate that NO and 15-LO-1 act in parallel to mediate ACH relaxations and NO does not alter 15-LO-1 activity.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Nitin T
authors.initials: NT
authors.lastname: Aggarwal
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Gauthier
authors.forename: William B
authors.initials: WB
authors.lastname: Campbell
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000475:Alkenes / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D007213:Indomethacin / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000475:Alkenes; D016859:Lipoxygenase Inhibitors; C453079:dipropylenetriamine-NONOate; D016718:Arachidonic Acid; D009569:Nitric Oxide; D001093:Arachidonate 15-Lipoxygenase; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D000109:Acetylcholine; D007213:Indomethacin