Hydrogen peroxide-induced inhibition of vasomotor activity: evaluation of single and combined treatments with vitamin A and insulin in streptozotocin-diabetic rats.
A positive correlation has been established between increased oxidative stress and cardiovascular diseases in diabetes mellitus. We evaluated the effects of single or combined treatments with vitamin A (retinol acetate, 30 mg/kg/day, for 12-weeks) and insulin (8-10 IU/rat/day for the final 6-week) on vasomotor activity, oxidative stress and retinol metabolism in 12-week streptozotocin diabetic rats. The vasomotor activity was determined by measuring in vitro responsiveness of aorta rings to phenylephrine (PE) and acetylcholine (ACh) in the absence or in the presence of hydrogen peroxide (H2O2). Preincubation with H2O2 (10 microM) produced a significant decrease in PE (1 mM)-induced contraction in untreated-diabetic but not in control rats. Single treatment with insulin counteracted this effect of H2O2 and also reversed the increased contractile response of diabetic aorta to PE, while vitamin A was found to be ineffective. H2O2 (10 microM) also inhibited ACh (1 mM)-stimulated endothelium-dependent relaxation two fold more in diabetic than in control aorta. In the prevention of H2O2-induced inhibition of vascular relaxation to ACh, vitamin A alone was markedly effective while insulin alone was not. The combination of vitamin A plus insulin removed the inhibitory action of H2O2 in diabetic aorta. Diabetic animals displayed an increased level of aorta thiobarbituric acid reactive substance (TBARS) in association with decreased levels of plasma retinol and retinol-binding protein (RBP). Single treatment with insulin, in spite of allowing recovery of normal growth rate and improved glucose and retinol metabolism in diabetic rats, was unable to control TBARS production to the same extent as vitamin A alone. Our findings suggest that the maintenance of ACh-stimulated endothelium-dependent vasorelaxant tone in normal physiological levels depends largely on the prevention and/or inhibition of peroxidative stress, which is achieved by combined treatment with vitamin A plus insulin. The use of vitamin A together with insulin provides a better metabolic control and more benefits than use of insulin alone in the reduction of diabetes-induced vascular complications.
Zobali
Fulya
F
Department of Pharmacology, Faculty of Pharmacy, Ankara University, Tandogan, Turkey
Besler
Tanju
T
Ari
Nuray
N
Karasu
Cimen
C
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000503:physiopathology; D004224:Diterpenes; D004327:Drinking Behavior / Q000187:drug effects; D004359:Drug Therapy, Combination; D005247:Feeding Behavior / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000084562:Retinyl Esters; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014666:Vasomotor System / Q000187:drug effects / Q000503:physiopathology*; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000494:pharmacology*
D001786:Blood Glucose; D004224:Diterpenes; D007004:Hypoglycemic Agents; D007328:Insulin; D000084562:Retinyl Esters; D017392:Thiobarbituric Acid Reactive Substances; D014801:Vitamin A; D010656:Phenylephrine; C009166:retinol acetate; D006861:Hydrogen Peroxide