Effects of a Long-Term Treatment with an Antioxidant Pyridoindole on Vascular Responsiveness in Diabetes-Induced Aging Rats

Impaired vascular reactivity is a hallmark of cardiovascular diseases induced by diabetes, which is also an accelerated aging model. This study was designed to investigate the effect of chronic treatment of stobadine, a pyridoindole antioxidant, on vascular responsiveness in diabetic animals. Age- (13-week old) and gender-matched Wistar rats were randomly divided into control and diabetic groups. Streptozotocin (55mg/kg, i.p.) was used to induce experimental diabetes. After induction of diabetes, rats were randomly assigned for receving stobadine (24.7 mg/kg/day, p.o.) or vehicle for 8-10 months. Stobadine treatment significantly reduced the severity of hyperglycemia, heart and kidney weights, systolic blood pressure, and attenuated diabetes-induced loss in body weight gain. Increased vasoconstriction responses to phenylephrine (PE; 10(-8)-10(-5) M) and BayK-8644 (3x10(-7)-3x10(-5) M) were significantly decreased by stobadine treatment in diabetes. Although stobadine treatment increased acetylcholine (ACh; 10(-9)-10(-5) M)-induced relaxation responses, sodium nitroprusside (10(-11)-10(-6) M)-induced relaxations were not affected by the treatment or diabetes. Stobadine treatment markedly reduced A23187 (10(-9)-3x10(-6) M)-induced relaxation responses while it remained unchanged in diabetics compared to controls. The transient vasoconstriction to PE was reduced by cyclopiazonic acid (10(-6) M) or thapsigargin (TH; 10(-6) M) in all groups. TH also inhibited the relaxation to ACh (3x10(-6) M) in control and stobadine-treated diabetic groups. These results suggest that antioxidative and Ca(2+) current regulatory effects of stobadine, contribute to the mechanisms responsible for its beneficial effects in aged diabetic rats.