Cellular basis of endothelial dysfunction in small mesenteric arteries from spontaneously diabetic (db/db -/-) mice: Role of decreased tetrahydrobiopterin bioavailability

Malarvannan Pannirselvam, Subodh Verma, Todd J. Anderson, Christopher Triggle

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134 Citations (Scopus)

Abstract

1. Endothelium-dependent and -independent regulation of vascular tone in small mesenteric arteries (SMA) from control (db/db +/?) and diabetic (db/db -/-) mice was compared. 2. Phenylephrine-induced maximum contraction, but not sensitivity, of SMA in db/db -/compared to db/db +/? Was enhanced. 3. Acetylcholine (ACh), but not sodium nitroprusside (SNP), -induced relaxation was reduced in SMA from db/db -/- compared to db/db +/?. 4. ACh-induced relaxation of SMA was inhibited by a combination of Nω-nitro-L-arginine and indomethacin in db/db +/?, but not in db/db -/-. 5. Acute incubation of SMA with tetrahydrobiopterin (BH4, 10 μM) and sepiapterin (100 μM) enhanced ACh-induced relaxation in SMA from db/db -/-, but not from db/db +/? 2, 4-diamino-6-hydroxypyrimidine, an inhibitor of GTP cyclohydrolase I, (10 mM), impaired the sensitivity of SMA from db/db +/? To ACh, which was restored by co-incubation with BH4 (10 μM). 6. BH4 and superoxide dismutase (SOD, 150 u ml-1), either alone or in combination, had no effect on either ACh or SNP-induced relaxation in SMA from eNOS -/- mice. 7. Incubation of SMA with SOD (150 iu ml-1), catalase (200 iu ml-1) and L-arginine (1 mM) had no effect on ACh-induced relaxation of SMA. However, the combination of polyethylene glycol-SOD (200 iu mi-1) and catalase (80 u ml-1) improved the sensitivity of ACh-induced relaxation in db/db -/-, but not in db/db +/?. 8. These data suggest that increased production of superoxide anions and decreased availability of BH4 result in an 'uncoupling' of nitric oxide synthase and endothelial dysfunction in SMA from db/db -/- mice.

Original languageEnglish
Pages (from-to)255-263
Number of pages9
JournalBritish Journal of Pharmacology
Volume136
Issue number2
Publication statusPublished - 1 Jan 2002
Externally publishedYes

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Keywords

  • db/db mouse
  • Endothelial dysfunction
  • Endothelial nitric oxide synthase
  • eNOS knock out mice
  • Superoxide anions
  • Tetrahydrobiopterin
  • Type II diabetes

ASJC Scopus subject areas

  • Pharmacology

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