Sulfaphenazole treatment restores endothelium-dependent vasodilation in diabetic mice.

Abstract

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 monooxygenase enzyme-generated reactive oxygen species in vascular dysfunction in an experimental model of diabetes mellitus type II. Diabetic male mice (db/db strain) and their age-matched controls received daily intraperitoneal injections of either the CYP 2C inhibitor sulfaphenazole (5.13 mg/kg) or saline (vehicle control) for 8 weeks. Although sulfaphenazole did not change endothelium-dependent vasodilation in control mice, it restored endothelium-mediated relaxation in db/db mice. We report for the first time that CYP 2C inhibition reduces oxidative stress (measured as plasma levels of 8-isoprostane), increases NO bioavailability (measured as NO(2)(-)) 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 450 monooxygenase enzymes restores endothelium-dependent vasodilation to acetylcholine. In addition, it reduces oxidative stress and increases NO bioavailability.

• Authors: Shahrzad Elmi, Nada A Sallam, Mohammad M Rahman, Xiaowei Teng, Arwen L Hunter, Farzad Moien-Afshari, Majid Khazaei, David J Granville, Ismail Laher
• Journal: Vascular pharmacology (Vascul Pharmacol) Vol. 48 Issue 1 Pg. 1-8 (Jan 2008) ISSN: 1537-1891 [Print] United States
• PMID: 17974492 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Biomarkers
• Blood Glucose
• Cyclic N-Oxides
• Cytochrome P-450 Enzyme Inhibitors
• Nitrites
• Spin Labels
• cytochrome P-450 CYP2C subfamily
• Sulfaphenazole
• Vitamin E
• Nitroprusside
• 8-epi-prostaglandin F2alpha
• Cytochrome P-450 Enzyme System
• Dinoprost
• Acetylcholine
• tempol

Topics

• Acetylcholine (pharmacology)
• Animals
• Antioxidants (pharmacology)
• Aorta, Thoracic (drug effects, metabolism, physiopathology)
• Biomarkers (blood)
• Blood Glucose (analysis)
• Cyclic N-Oxides (pharmacology)
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Enzyme System
• Diabetes Mellitus, Type 2 (genetics, physiopathology)
• Dinoprost (analogs & derivatives, blood)
• Dose-Response Relationship, Drug
• Endothelium, Vascular (physiopathology)
• Fasting (blood)
• In Vitro Techniques
• Injections, Intraperitoneal
• Male
• Mice
• Mice, Mutant Strains
• Nitrites (metabolism)
• Nitroprusside (pharmacology)
• Spectrophotometry (methods)
• Spin Labels
• Sulfaphenazole (administration & dosage, pharmacology)
• Vasodilation (drug effects)
• Vitamin E (pharmacology)