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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Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus.
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K+ is an endothelium-derived hyperpolarizing factor in rat arteries
Edwards, G., Dora, K. A., Gardener, M. J., Garland, C. J., & Weston, A. H. (1998) · Nature · doi:10.1038/24388 · Cited by 1,057
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Diabetes mellitus and free radicals
Wolff, S. P. (1993) · British Medical Bulletin · doi:10.1093/oxfordjournals.bmb.a072637 · Cited by 660
Moncada, S., Rees, D. D., Schulz, R., & Palmer, R. M. J. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.6.2166 · Cited by 489
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Impairment of endothelium‐dependent relaxation in aortae from spontaneously diabetic rats
Durante, W., Sen, A. K., & Sunahara, F. A. (1988) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1988.tb11548.x · Cited by 250
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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
Vanhoutte, P. M., Shimokawa, H., Tang, E. H. C., & Félétou, M. (2009) · Acta Physiologica · doi:10.1111/j.1748-1716.2009.01964.x · Cited by 824
Sivitz, W. I., & Yorek, M. A. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2531 · Cited by 742
Reactive oxygen species and endothelial function in diabetes
Fatehi‐Hassanabad, Z., Chan, C. B., & Furman, B. L. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.03.048 · Cited by 165
“ed by both nitric oxide and EDHF in the rat mesenteric vascular bed (Inkster et al., 2002).”
BackgroundEDHF: new therapeutic targets?
Félétou, M. (2004) · Pharmacological Research · doi:10.1016/j.phrs.2003.10.017 · Cited by 136
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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