Vascular responses to 8-nitro-cyclic GMP in non-diabetic and diabetic mice

Yoshiko Tokutomi, Keiichiro Kataoka, Eiichiro Yamamoto, Taishi Nakamura, Masaya Fukuda, Hisato Nako, Kensuke Toyama, Yi Fei Dong, Khandaker Ahtesham Ahmed, Tomohiro Sawa, Takaaki Akaike, Shokei Kim-Mitsuyama

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH 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. KEY 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 AND IMPLICATIONS 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.

Original languageEnglish
Pages (from-to)1884-1893
Number of pages10
JournalBritish Journal of Pharmacology
Volume162
Issue number8
DOIs
Publication statusPublished - 2011 Apr

Keywords

  • 8-nitro-cGMP
  • aorta
  • db/db mouse
  • eNOS
  • superoxide anions
  • vascular responses

ASJC Scopus subject areas

  • Pharmacology

Fingerprint Dive into the research topics of 'Vascular responses to 8-nitro-cyclic GMP in non-diabetic and diabetic mice'. Together they form a unique fingerprint.

Cite this