Sulfaphenazole treatment restores endothelium-dependent vasodilation in diabetic mice.
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.
Elmi
Shahrzad
S
Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
Sallam
Nada A
NA
Rahman
Mohammad M
MM
Teng
Xiaowei
X
Hunter
Arwen L
AL
Moien-Afshari
Farzad
F
Khazaei
Majid
M
Granville
David J
DJ
Laher
Ismail
I
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000032:analysis; D003497:Cyclic N-Oxides / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005215:Fasting / Q000097:blood; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009573:Nitrites / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D013053:Spectrophotometry / Q000379:methods; D013113:Spin Labels; D013426:Sulfaphenazole / Q000008:administration & dosage / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D015415:Biomarkers; D001786:Blood Glucose; D003497:Cyclic N-Oxides; D065607:Cytochrome P-450 Enzyme Inhibitors; D009573:Nitrites; D013113:Spin Labels; C400322:cytochrome P-450 CYP2C subfamily; D013426:Sulfaphenazole; D014810:Vitamin E; D009599:Nitroprusside; C075750:8-epi-prostaglandin F2alpha; D003577:Cytochrome P-450 Enzyme System; D015237:Dinoprost; D000109:Acetylcholine; C001803:tempol