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Cited by 329Nitric Oxide and Endothelin EffectsCardiovascular Health and Disease PreventionEicosanoids and Hypertension Pharmacology

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

Shinozaki, K, Kashiwagi, A, Nishio, Y, Okamura, T, Yoshida, Y, Masada, M, Toda, N, Kikkawa, R·1999·Diabetes
DOI 10.2337/diabetes.48.12.2437
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Abstract

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.

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Authors
Shinozaki, K., Kashiwagi, A., Nishio, Y., Okamura, T., Yoshida, Y., Masada, M., Toda, N., & Kikkawa, R.
Affiliations
Shiga University of Medical Science (JP)
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
1999-12-01
Volume
48
Issue
12
Pages
2437-2445
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.48.12.2437
OpenAlex
W2141998216
Cited by
329
References
10
Citations by year
2026: 1 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 5 · 2020: 6 · 2019: 1 · 2018: 5 · 2017: 5 · 2016: 5 · 2015: 9 · 2014: 13 · 2013: 11 · 2012: 11
FWCI
9.51
Type
journal article
Language
en
Open access
closed
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
Keywords
insulin resistance, endothelium-dependent relaxation, nitric oxide, superoxide, biopterin, tetrahydrobiopterin, 7,8-dihydrobiopterin, endothelial nitric oxide synthase, oxidative stress, aorta, hyperinsulinemia, vascular dysfunction
MeSH terms
Calcimycin, Acetylcholine, Animals, Aorta, Thoracic, Ascorbic Acid, Biopterins, Blood Glucose, Blood Pressure, Endothelium, Vascular, Fructose, Hyperinsulinism, Insulin, Insulin Resistance, Isometric Contraction, Male, Muscle Relaxation, Muscle, Smooth, Vascular, Nitric Oxide, Nitroprusside, RNA, Messenger, Superoxides, Transcription, Genetic, Vasodilation, Rats, Sprague-Dawley, Nitric Oxide Synthase, Rats, Nitric Oxide Synthase Type III, In Vitro Techniques

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