title: Impaired vascular function in normoglycemic mice prone to autoimmune diabetes: role of nitric oxide.
abstract: Type 1 diabetes is an immuno-inflammatory condition which increases the risk of cardiovascular disease, particularly in young adults. This study investigated whether vascular function is altered in mice prone to autoimmune diabetes and whether the nitric oxide (NO)-cyclic GMP axis is involved. Aortic rings suspended in organ chambers and precontracted with phenylephrine were exposed to cumulative concentrations of acetylcholine. To investigate the role of NO, some experiments were performed in the presence of either 1400W (N-(3-aminomethyl)benzyl-acetamidine hydrochloride), a selective inhibitor of the iNOS-isoform, L-NAME (N(G)-nitro-L-arginine methyl ester hydrochloride), an inhibitor of all three NOS-isoforms, or ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), a selective inhibitor of guanylate cyclase. Moreover, contractility to phenylephrine, big endothelin-1, and endothelin-1 was assessed and histological analysis and iNOS immunohistochemistry were performed. Endothelium-dependent relaxation was reduced in prediabetic NOD mice (78+/-4 vs. 88+/-2%, respectively, P<0.05 vs. control) despite normal plasma glucose levels (n.s. vs. control). Preincubation with 1400W further attenuated responses in prediabetic (P<0.05 vs. untreated) but not in diabetic or in control mice. In contrast, basal NO bioactivity remained unaffected until the onset of diabetes in NOD mice. Contractile responses to big endothelin-1 and endothelin-1 were reduced in prediabetic animals (P<0.05 vs. control), whereas in diabetic mice only responses to big endothelin-1 were decreased (P<0.05 vs. control). These data demonstrate that endothelium-dependent and -independent vascular function in NOD mice is abnormal already in prediabetes in the absence of structural injury. Early proinflammatory activation due to iNOS in diabetes-prone NOD mice appears to be one of the mechanisms contributing to impaired vasoreactivity.
authors.affiliation: Department of Medicine, Internal Medicine I, Medical Policlinic, University Hospital Zurich, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Traupe
authors.forename: Philipp C
authors.initials: PC
authors.lastname: Nett
authors.forename: Beat
authors.initials: B
authors.lastname: Frank
authors.forename: Luigi
authors.initials: L
authors.lastname: Tornillo
authors.forename: Regina
authors.initials: R
authors.lastname: Hofmann-Lehmann
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Terracciano
authors.forename: Matthias
authors.initials: M
authors.lastname: Barton
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D010477:Perfusion; D010656:Phenylephrine / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester