title: Angiotensin II type 2 receptor-dependent increase in nitric oxide synthase activity in the endothelium of db/db mice is mediated via a MEK pathway.
abstract: Angiotensin II type 2 receptor (AT(2)R) stimulation may cause vasodilation. It could thereby contribute to the antihypertensive effects of angiotensin II type 1 receptor (AT(1)R) antagonists since AT(1)R blockade reportedly increases endogenous levels of Ang II, and this may then bind to the unblocked AT(2)R. Because this is potentially an important consideration in diabetes, we examined whether or not AT(2)R mediates vasorelaxation in db/db diabetic mice. We also examined if AT(2)R-mediated vasorelaxation is preserved after long-term treatment with the AT(1)R antagonist losartan. The effects of AT(2)R stimulation, with either Ang II or the selective agonist CGP-42112A, were studied in aortas from db/db mice (a type 2 diabetic model). CGP-42112A induced a concentration-dependent relaxation in db/db aortas (not in Lean aortas), and this was significantly weakened by the MEK-inhibitor PD98059. CGP-42112A-induced relaxations were increased by Ang II-stimulation (by the organ-culture method) or by AT(1)R blockade (by long-term losartan treatment) only in Lean aortas. Basal AT(2)R expression, and Ang II-stimulated MEK and eNOS phosphorylations were all increased in aortas from db/db (vs. Lean) mice. Long-term losartan treatment increased Ang II-stimulated MEK and eNOS phosphorylations in aortas from Lean, but not db/db, mice. Therefore, this study has provided evidence that AT(2)R-mediated NO production and vasorelaxation through a MEK pathway are enhanced (under basal conditions) in aortas from db/db (vs. Lean) mice. The preservation of such AT(2)R function during AT(1)R blockade needs to be considered in the search for a physiological role for AT(2)R.
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Tokyo 142-8501, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Taguchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Katsuo
authors.initials: K
authors.lastname: Kamata
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D005419:Flavonoids; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D044139:Receptor, Angiotensin, Type 2; D014665:Vasodilator Agents; D000804:Angiotensin II; C060894:CGP 42112A; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D020930:MAP Kinase Kinase Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse; D019808:Losartan; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one