Effects of trientine, a metal chelator, on defective endothelium-dependent relaxation in the mesenteric vasculature of diabetic rats.

Melanie Evelyn Inkster, Mary Anne Cotter, Norman E Cameron

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Diabetes mellitus compromises endothelium-dependent relaxation of blood vessels. This has been linked to the generation of reactive oxygen species (ROS), which neutralise nitric oxide (NO) and interfere with vasodilator function. Experiments using chelators have emphasised the importance of ROS produced by transition metal catalysed reactions. However, particularly for the small arteries and arterioles that control microcirculatory blood flow, NO is not the only endothelium-derived mediator; endothelium-derived hyperpolarizing factor (EDHF) has a major role. EDHF-mediated vasodilation is severely curtailed by diabetes; however, little information exists on the underlying pathophysiology. Deficits in the EDHF system, alone or in combination with the NO system, are crucial for the development of diabetic microvascular complications. To further elucidate the mechanisms involved, the aim was to examine the effects of diabetes and preventive and intervention chelator therapy with trientine on a preparation that has well-defined NO and EDHF-mediated responses, the rat mesenteric vascular bed.

In phenylephrine-preconstricted preparations, maximum vasodilation to acetylcholine was reduced by 35 and 44% after 4 and 8 weeks of streptozotocin-induced diabetes, respectively. Trientine treatment over the first 4 weeks gave 72% protection; intervention therapy over the final 4 weeks prevented deterioration and corrected the initial deficit by 68%. These responses depend on both NO and EDHE When the latter mechanism was isolated by NO synthase inhibition, diabetic deficits of 53.4 (4 weeks) and 65.4% (8 weeks) were revealed, that were 65% prevented and 50% corrected by trientine treatment. Neither diabetes nor trientine altered vascular smooth muscle responses to the NO donor, sodium nitroprusside (SNP). Thus, the data suggest that metal catalysed ROS production makes a substantial contribution to defects in both the EDHF and NO endothelial mechanisms in diabetes, which has therapeutic implications for microvascular complications.

Original languageEnglish
Pages (from-to)1091-1099
Number of pages9
JournalFree Radical Research
Volume36
Issue number10
DOIs
Publication statusPublished - 2002

Keywords

  • diabetes mellitus
  • rat
  • nitric oxide
  • endothelium-derived hyperpolarizing factor (EDHF)
  • diabetic complications
  • microangiopathy
  • isolated resistance arteries
  • nitric-oxide synthase
  • alpha-lipoic acid
  • corpus cavernosum
  • L-arginine
  • hyperpolarizing factors
  • neurovascular function
  • impaired contraction
  • radical scavengers
  • peripheral-nerve

Cite this

Effects of trientine, a metal chelator, on defective endothelium-dependent relaxation in the mesenteric vasculature of diabetic rats. / Inkster, Melanie Evelyn; Cotter, Mary Anne; Cameron, Norman E.

In: Free Radical Research, Vol. 36, No. 10, 2002, p. 1091-1099.

Research output: Contribution to journalArticle

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abstract = "Diabetes mellitus compromises endothelium-dependent relaxation of blood vessels. This has been linked to the generation of reactive oxygen species (ROS), which neutralise nitric oxide (NO) and interfere with vasodilator function. Experiments using chelators have emphasised the importance of ROS produced by transition metal catalysed reactions. However, particularly for the small arteries and arterioles that control microcirculatory blood flow, NO is not the only endothelium-derived mediator; endothelium-derived hyperpolarizing factor (EDHF) has a major role. EDHF-mediated vasodilation is severely curtailed by diabetes; however, little information exists on the underlying pathophysiology. Deficits in the EDHF system, alone or in combination with the NO system, are crucial for the development of diabetic microvascular complications. To further elucidate the mechanisms involved, the aim was to examine the effects of diabetes and preventive and intervention chelator therapy with trientine on a preparation that has well-defined NO and EDHF-mediated responses, the rat mesenteric vascular bed.In phenylephrine-preconstricted preparations, maximum vasodilation to acetylcholine was reduced by 35 and 44{\%} after 4 and 8 weeks of streptozotocin-induced diabetes, respectively. Trientine treatment over the first 4 weeks gave 72{\%} protection; intervention therapy over the final 4 weeks prevented deterioration and corrected the initial deficit by 68{\%}. These responses depend on both NO and EDHE When the latter mechanism was isolated by NO synthase inhibition, diabetic deficits of 53.4 (4 weeks) and 65.4{\%} (8 weeks) were revealed, that were 65{\%} prevented and 50{\%} corrected by trientine treatment. Neither diabetes nor trientine altered vascular smooth muscle responses to the NO donor, sodium nitroprusside (SNP). Thus, the data suggest that metal catalysed ROS production makes a substantial contribution to defects in both the EDHF and NO endothelial mechanisms in diabetes, which has therapeutic implications for microvascular complications.",
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