title: 4-Hydroxy-2-nonenal attenuates β2-adrenoceptor-mediated vasodilation of rat retinal arterioles.
abstract: 4-Hydroxy-2-nonenal (4-HNE) is a major reactive aldehyde formed by lipid peroxidation, and it plays an important role in the pathogenesis of several vascular diseases, including diabetes mellitus. In this study, we examined the effects of 4-HNE on the vasodilatory mechanisms of rat retinal arterioles. The retinal vasodilator responses were assessed by measuring the diameter of retinal arterioles in the fundus images. Intravitreal injection of 4-HNE significantly prevented the vasodilation of retinal arterioles induced by the β2-adrenoceptor agonist salbutamol but not the nitric oxide donor (±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR3). Iberiotoxin, an inhibitor of large-conductance KCa (BKCa) channels, significantly reduced the salbutamol-induced vasodilation of retinal arterioles. The vasodilator effect of BMS-191011, a BKCa channel opener, on retinal arterioles was significantly attenuated by 4-HNE. These results suggest that 4-HNE attenuates retinal vasodilator responses to β2-adrenoceptor agonists through the impairment of the BKCa pathway. The direct effect of 4-HNE on retinal blood vessels may, therefore, contribute to the retinal vascular dysfunction observed in patients with diabetes mellitus.
authors.affiliation: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Asami
authors.initials: A
authors.lastname: Mori
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takei
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakahara
authors.forename: Kunio
authors.initials: K
authors.lastname: Ishii
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D058449:Intravitreal Injections; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress; D017208:Rats, Wistar; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D012161:Retinal Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000447:Aldehydes; D051036:Large-Conductance Calcium-Activated Potassium Channels; D022702:Receptors, Adrenergic, beta-3; C027576:4-hydroxy-2-nonenal; D000420:Albuterol