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 Ca2+ current regulatory effects of stobadine, contribute to the mechanisms responsible for its beneficial effects in aged diabetic rats.