Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation through nitric oxide/O2- imbalance in insulin-resistant rat aorta.

• K Shinozaki

  Third Department of Medicine, Shiga University of Medical Science, Otsu, Japan.

• A Kashiwagi

  Third Department of Medicine, Shiga University of Medical Science, Otsu, Japan.

• Y Nishio

  Third Department of Medicine, Shiga University of Medical Science, Otsu, Japan.

• T Okamura

  Third Department of Medicine, Shiga University of Medical Science, Otsu, Japan.

• Y Yoshida

  Third Department of Medicine, Shiga University of Medical Science, Otsu, Japan.

• M Masada

  Third Department of Medicine, Shiga University of Medical Science, Otsu, Japan.

• N Toda

  Third Department of Medicine, Shiga University of Medical Science, Otsu, Japan.

• R Kikkawa

  Third Department of Medicine, Shiga University of Medical Science, Otsu, Japan.

抄録

To investigate underlying mechanisms responsible for the impaired nitric oxide (NO)-dependent vascular relaxation in the insulin-resistant state, we examined production of both NO and superoxide anion radical (O2-) and those modulating factors in aortas obtained from normal (CTR), insulin-treated (INS), or high fructose-fed (FR) rats. FR rats showed insulin resistance with endogenous hyperinsulinemia, whereas INS rats showed normal insulin sensitivity. Only FR aortic strips with endothelium elicited impaired relaxation in response to either acetylcholine or calcium ionophore A23187. Endothelial NO synthase (eNOS) activity and its mRNA levels were increased only in vessels from INS rats (P < 0.001), whereas eNOS activity in FR rats was decreased by 58% (P < 0.05) when compared with CTR rats. NO production from aortic strips stimulated with A23187 was significantly lower in FR than CTR rats. In contrast, A23187-stimulated O2- production was higher (P < 0.01) in FR than CTR rats. These differences were abolished when aortic strips were preincubated in the media including (6R)-5,6,7,8-tetrahydrobiopterin (BH4), an active cofactor for eNOS. Furthermore, as compared with CTR rats, aortic BH4 contents in FR rats were decreased (P < 0.001), whereas the levels of 7,8-dihydrobiopterin, the oxidized form of BH4, were increased, with opposite results in INS rats. These results indicate that insulin resistance rather than hyperinsulinemia itself may be a pathogenic factor for decreased vascular relaxation through impaired eNOS activity and increased oxidative breakdown of NO due to enhanced formation of O2- (NO/O2- imbalance), which are caused by relative deficiency of BH4 in vascular endothelial cells.

収録刊行物

• Diabetes

  Diabetes 48 (12), 2437-2445, 1999-12-01

  American Diabetes Association

キーワード

• Endocrinology, Diabetes and Metabolism
• Internal Medicine

詳細情報

• CRID: 1362544419276053632
• NII論文ID: 30026272274
• NII書誌ID: AA00628057
• DOI: 10.2337/diabetes.48.12.2437
• ISSN: 1939327X
• ISSN: 00121797
• ISSN: http://id.crossref.org/issn/00121797
• Web Site: https://journals.org/diabetes/diabetes/article-pdf/48/12/2437/364071/10580434.pdf
• Web Site: https://diabetesjournals.org/diabetes/article-pdf/48/12/2437/364071/10580434.pdf
• データソース種別:
  • Crossref
  • CiNii Articles