Vascular dysfunction is linked with increased free radical generation and is a major
contributor to the high mortality rates observed in diabetes. Several probable sources of free
radical generation have been suggested in diabetes, including cytochrome P450 (CYP)
monooxygenase-dependent pathways. CYP-mediated superoxide production reduces nitric
oxide (NO) bioavailability. In this study, we focus on the contribution of CYP
monooxygenase enzyme-generated reactive oxygen species in vascular dysfunction in an
experimental model of type II diabetes mellitus. The purpose of this study is to test the
hypothesis that sulfaphenazole treatment can restore diabetic endothelial function in db/db
mice.
Diabetic male mice (db/db strain) and their age-matched controls received daily
intraperitoneal injections of either the CYP 2C inhibitor sulfaphenazole (5 mg/kg) or saline
(vehicle control) for 8 weeks. Fasting plasma glucose levels were measured before starting,
during, and after finishing the treatment. As well, plasma levels of 8-isoprostane (as a
marker of oxidative stress) and nitrite levels of aortic tissue (as a marker of NO
bioavailability) were determined.
Although sulfaphenazole did not change endothelium-dependent vasodilation in WT mice,
it restored endothelial-mediated relaxation in treated db/db mice. We concluded that CYP
2C inhibition by sulfaphenazole reduces oxidative stress (measured as plasma levels of 8-isoprostane), increases NO bioavailability (measured as NOj) and restores endothelial
function in db/db mice without affecting plasma glucose levels.
Based on our findings, we speculate that inhibition of free radical generating CYP
monooxygenase enzymes restores endothelium-dependent vasodilation induced by
acetylcholine. In addition, it reduces oxidative stress and increases NO bioavailability.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:BVAU./4090 |
| Date | 11 1900 |
| Creators | Elmi, Shahrzad |
| Publisher | University of British Columbia |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | 1702930 bytes, application/pdf |
Page generated in 0.0012 seconds