Lack of nitric oxide mediation of flow-dependent arteriolar dilation in type I diabetes is restored by sepiapterin

Zsolt Bagi, Akos Koller

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

The mechanisms leading to microangiopathy in diabetes mellitus have still not been clearly elucidated. We hypothesized that type I diabetes mellitus affects the endothelium and alters flow-dependent dilation of arterioles, an important mechanism involved in local regulation of blood flow. Isolated, pressurized gracilis muscle arterioles (inside diameter approximately 150 μm at 80 mm Hg) from rats with streptozotocin (STZ)-induced diabetes mellitus exhibited reduced dilations induced by increases in perfusate flow compared to those of normal rats (plasma glucose: 25.7 ± 0.7 vs. 6.4 ± 0.5 mmol/l; maximum increase in diameter: 15 ± 4 vs. 31 ± 3 μm, p < 0.05). In control arterioles, both nitric oxide (NO) and prostaglandins mediated the flow-dependent dilation, whereas flow-induced dilations of diabetic arterioles were unaffected by N ω -nitro-L-arginine methyl ester (L-NAME) and were abolished by indomethacin. Sepiapterin - precursor of the endothelial NO synthase (eNOS) cofactor tetrahydrobiopterin (BH 4 ) - restored the L-NAME-sensitive portion of flow-dependent dilations of diabetic arterioles. Furthermore, depletion of BH 4 by 2,4-diamino-6-hydroxypyrimidine (DAHP) in control arterioles also resulted in reduced flow-dependent dilations, which were restored by intraluminal sepiapterin [but not with superoxide dismutase (SOD) plus catalase (CAT) (SOD+CAT)] and then could be inhibited by L-NAME. Dilations induced by the NO donor sodium nitroprusside (SNP) were unaffected by L-NAME in diabetes mellitus arterioles or when eNOS was activated by intraluminal flow in DAHP-treated arterioles (with or without SOD+CAT). In contrast, pyrogallol (known to produce reactive oxygen species) substantially reduced acetylcholine- and SNP-induced dilation in a SOD+CAT-reversible manner. Collectively, these findings suggest that in diabetic arterioles, due to the reduced bioavailability of BH 4 , the synthesis of NO by eNOS is limited, resulting in a reduced flow-induced dilation, a mechanism that may also be responsible for the development of diabetic microangiopathy and exacerbation of other vascular diseases.

Original languageEnglish (US)
Pages (from-to)47-57
Number of pages11
JournalJournal of Vascular Research
Volume40
Issue number1
DOIs
StatePublished - Apr 1 2003
Externally publishedYes

Fingerprint

Arterioles
Type 1 Diabetes Mellitus
Dilatation
Nitric Oxide
NG-Nitroarginine Methyl Ester
Catalase
Superoxide Dismutase
Diabetes Mellitus
Nitroprusside
Nitric Oxide Synthase
Pyrogallol
sepiapterin
Diabetic Angiopathies
Experimental Diabetes Mellitus
Nitric Oxide Donors
Nitric Oxide Synthase Type III
Vascular Diseases
Indomethacin
Biological Availability
Acetylcholine

Keywords

  • Arteriole
  • Diabetes mellitus type I
  • Flow-induced dilation
  • Nitric oxide
  • Tetrahydrobiopterin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Lack of nitric oxide mediation of flow-dependent arteriolar dilation in type I diabetes is restored by sepiapterin. / Bagi, Zsolt; Koller, Akos.

In: Journal of Vascular Research, Vol. 40, No. 1, 01.04.2003, p. 47-57.

Research output: Contribution to journalArticle

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