The mesenteric vascular bed from the streptozotocin (STZ) diabetic model was used in this thesis to elucidate the mechanisms underlying diabetic vascular dysfunction. Treatment strategies targeting oxygen free radicals, angiotensin II, and lipids were investigated. In phenylephrine-preconstricted preparations, maximum vasodilation to acetylcholine, progressively deteriorated over 8 weeks of diabetes both before and after NO synthase inhibition which isolated the EDHF component. Chronic preventive treatment with silymarin, a free radical scavenger, or allopurinol, a xanthine oxidase inhibitor, partially protected against the development of 4-week diabetic deficits of the NO and EDHF systems. On the other hand, treatment with the semicarbizide-sensitive amine oxidase (SSAO) inhibitor, MDL74972A, only significantly improved the NO component. Preventive treatment with the transition metal chelator, trientine, produced significant protection of the NO and EDHF responses. Furthermore, intervention treatment not only protected against the development of an 8-week but also reversed some of the 4-week diabetic deficit. Both preventative and intervention treatments targeting angiotensin II production through either angiotensin-converting enzyme (ACE) inhibition with lisinopril or AT1 receptor blockade with candesartan provided some protection against the diabetic-induced decline in acetylcholine relaxations. Most notably, candesartan preventive treatment completely protected against a deficit in the EDHF response. Preventive treatment with rosuvastatin, a lipid-lowering drug, partially protected against the development of NO and EDHF deficits. The results show that experimental diabetes had deleterious effects on NO and EDHF-mediated vasodilation and suggest a role for free radicals, angiotensin II and lipids in this dysfunction.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:252115 |
| Date | January 2002 |
| Creators | Inkster, Melanie E. |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU160140 |
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