The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.
Effects of Trientine, a Metal Chelator, on Defective Endothelium-dependent Relaxation in the Mesenteric Vasculature of Diabetic Rats
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 EDHF. 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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“Because metal chelators and hydroxyl radical scavengers have also been demonstrated to be effective in preventing diabetes-induced vascular and neural dysfunction, it is likely that the formation of hydroxyl radicals also contributes to impairment of vascular reactivity and nerve function in diabetes (46–51, 145).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [145]
In the citing paper
“Cameron and colleagues (46, 48–50, 145) demonstrated that treating diabetic rats with α-lipoic acid or the metal chelators, hydroxyethyl starch deferoxamine or trientine, prevented the diabetes-induced impairment in vascular relaxation associated with hyperalgesia and neurovascular deficits.”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [145]
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Endothelial dysfunction and vascular disease - a 30th anniversary update
Vanhoutte, P. M., Shimokawa, H., Feletou, M., & Tang, E. H. C. (2017) · Acta Physiologica · doi:10.1111/apha.12646 · Cited by 937
“…thus scavenging of NO and increased presence of peroxynitrite (Cosentino et al. 1997, Mayhan & Patel 1998, Graier et al. 1999, Maejima et al. 2001, Inkster et al. 2002, Pannirselvam et al. 2002, Pacher & Szabo 2006, Duncan et al. 2007, Quijano et al. 2007, Gao et al. 2008, L€uscher & Steffel…”
BackgroundEndothelial dysfunction and vascular disease
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“ed by both nitric oxide and EDHF in the rat mesenteric vascular bed (Inkster et al., 2002).”
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“Studies with transition metal chelators have provided additional evidence for a link between altered transition metal regulation and the pathogenesis of diabetes in animal models.([69-72]) For example, administration of an iron chelator and a copper chelator in a 2-week experiment in diabetic rats was reported to amel…”
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Self-citationReactive oxygen‐derived free radicals are key to the endothelial dysfunction of diabetes
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“What information is currently available about the dosage and tolerability of trientine in diabetes? In previous nonclinical studies [5,7,34,35], trientine dosages have been equivalent on a mg-per-kg basis in rats to those employed in the current study and in our recently reported 12-month clinical trial [12].”
BackgroundResultBaynes, J., & Murray, D. B. (2009) · Experimental Diabetes Research · doi:10.1155/2009/696378 · Cited by 32
Yorek, M. A. (2015) · The Review of Diabetic Studies · doi:10.1900/rds.2015.12.13 · Cited by 31
“Cameron and colleagues have demonstrated that treatment of diabetic rats with αlipoic acid, or the metal chelators hydroxyethyl starch deferoxamine, or trientine prevent the diabetes-induced impairment in vascular relaxation associated with hyperalgesia and neurovascular deficits [54, 55, 65-67].”
BackgroundInhibition of acetylcholine-induced EDHF response by elevated glucose in rat mesenteric artery
Özkan, M. H., & Uma, S. (2005) · Life Sciences · doi:10.1016/j.lfs.2005.02.036 · Cited by 29
Treatment for Diabetic Peripheral Neuropathy: What have we Learned from Animal Models?
Yorek, M. A. (2021) · Current Diabetes Reviews · doi:10.2174/1573399817666210504101609 · Cited by 26
Matsumoto, T., Kobayashi, T., & Kamata, K. (2006) · Current Cardiology Reviews · doi:10.2174/157340306778019405 · Cited by 22
“Moreover, treatment with folate, with an aldose-reductase inhibitor, with calcium dobesilate (an angioprotective agent), with evening primrose oil (an -6 -linoleic acid-containing oil), or with trientine (a metal chelator) restores impaired EDHF-mediated responses in diabetic states [26, 52, 74-76].”
Regulation of lens aldose reductase activity by nitric oxide
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“The effects of Trientine, which are attributed to protection against the harmful effects of oxidative stress, may imply potential therapeutic approaches for diabetic microangiopathy and vasculopathy (96).”
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Metadata
- Authors
- Inkster, M. E., Cotter, M. A., & Cameron, N. E.
- Affiliations
- University of Aberdeen (GB)
- Venue
- Free Radical Research
- Publisher
- Informa UK Limited
- Published
- 2002-01
- Volume
- 36
- Issue
- 10
- Pages
- 1091-1099
- ISSN
- 1029-2470 (ISSN-L)
- 1071-5762
- OpenAlex
- W1987191170
- Cited by
- 26
- References
- 54
- Citations by year
- 2025: 1 · 2023: 1 · 2021: 1 · 2015: 3 · 2014: 1 · 2013: 1
- FWCI
- 1.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology (medical) › 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
- triethylenetetramine, metal chelators, endothelium-dependent relaxation, diabetes mellitus, endothelium-derived hyperpolarizing factor, nitric oxide, reactive oxygen species, transition metal catalysis, mesenteric vasculature, streptozotocin-induced diabetes, acetylcholine, sodium nitroprusside, nitric oxide synthase, diabetic microvascular complications, vascular smooth muscle
- MeSH terms
- Acetylcholine, Animals, Biological Factors, Chelating Agents, Diabetes Mellitus, Experimental, Endothelium, Vascular, Enzyme Inhibitors, Male, Nitric Oxide, Nitroprusside, Phenylephrine, Splanchnic Circulation, Trientine, Vasoconstrictor Agents, Vasodilation, Rats, Sprague-Dawley, Nitric Oxide Synthase, Nitroarginine, Nitric Oxide Donors, Rats
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