title: Vascular responses to 8-nitro-cyclic GMP in non-diabetic and diabetic mice.
abstract: OBJECTIVE
  8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), formed nitric oxide (NO)-dependently, is a physiological second messenger, yet little is known about its role in the pathophysiology of vascular diseases. To study the pharmacological activity of 8-nitro-cGMP in diabetic mice, we compared its effects on vascular reactivity of aortas from non-diabetic and diabetic mice.
  
  
  METHODS
  Vascular tension recording was performed in thoracic aortic rings from wild-type (C57BL/6), non-diabetic db/+ and obese/diabetic db/db mice. Endothelial NO synthase (eNOS) uncoupling and superoxide were tested by Western blot and dihydroethidium fluorescence respectively.
  
  
  RESULTS
  8-Nitro-cGMP, at concentrations up to 10 µM, enhanced phenylephrine-induced contractions in aortas from C57BL/6 and db/+ mice, but not from db/db mice. This enhancement was not observed with 8-bromo-cGMP. Pretreatment of aortas from C57BL/6 and db/+ mice with l-NAME (100 µM), superoxide dismutase (100 U·mL(-1) ) or tiron (1 mM), abolished 8-nitro-cGMP-induced enhancement of the phenylephrine contraction. In 8-nitro-cGMP (10 µM)-treated C57BL/6 aortas, eNOS dimer/monomer ratio was significantly decreased and vascular superoxide production increased, suggesting that 8-nitro-cGMP-induced superoxide production via eNOS uncoupling may mediate the enhancement of the phenylephrine contraction. At higher concentrations (>10 µM), 8-nitro-cGMP produced relaxation of the phenylephrine-contracted aortas from C57BL/6, db/+ and db/db mice. The 8-nitro-cGMP-induced relaxation in db/db mouse aortas was found to be resistant to a phosphodiesterase 5 inhibitor, zaprinast (1 µM).
  
  
  CONCLUSIONS
  The vasodilator effect of 8-nitro-cGMP may contribute to amelioration of the vascular endothelial dysfunction in diabetic mice, representing a novel pharmacological approach to prevent the complications associated with diabetes.
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Tokutomi
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Kataoka
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Taishi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Masaya
authors.initials: M
authors.lastname: Fukuda
authors.forename: Hisato
authors.initials: H
authors.lastname: Nako
authors.forename: Kensuke
authors.initials: K
authors.lastname: Toyama
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Dong
authors.forename: Khandaker Ahtesham
authors.initials: KA
authors.lastname: Ahmed
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sawa
authors.forename: Takaaki
authors.initials: T
authors.lastname: Akaike
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000503:physiopathology*; D015153:Blotting, Western; D006152:Cyclic GMP / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000150:complications*; D010656:Phenylephrine / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation
chemical_list: C525106:8-nitroguanosine 3',5'-cyclic monophosphate; D010656:Phenylephrine; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP