Previous studies suggest that a link exists between increased oxidative stress and diabetic neuropathy. Moreover, antioxidants may protect neurones from the degenerative effects of reactive oxygen species. In our study, we used streptozotocin (STZ)-diabetic rats in a 8-month chronic diabetes model to study the effects of in vivo treatment with stobadine (ST), a pyridoindole antioxidant, and vitamin E. STZ-diabetic rats were treated with ST (24.7 mg/kg/day), vitamin E (D,L-alpha-tocopheryl acetate, 400-500 IU/kg/day) or ST plus vitamin E through an intra-oral catheter for a 8-month period beginning 10 days after STZ injection. Blood glucose and HbA1c levels were increased in diabetic rats by about 400 and 100%, respectively. Antioxidant treatment significantly decreased haemoglobin glycosylation (P < 0.05). We also determined the effects of chronic diabetes on sympathetic neurotransmission by measuring the contractility of isolated vas deferens. Furthermore, we investigated contractions elicited by electrical field stimulation (EFS) (1-64 Hz) which were significantly decreased in diabetic rats when compared with control rats. Treatment with ST or vitamin E alone partly enhanced the amplitude of the contractions induced by EFS, but a combination of ST and vitamin E treatment showed no additional effects. Contractile response of the vas deferens to exogenous noradrenaline, was increased in diabetic rats when compared with control rats. While the addition of vitamin E alone had no effect, ST completely returned noradrenaline-induced contractions to basal levels. The tension induced by 120 mm KCl was not statistically different among the experimental groups. In normal rats, EFS-induced contractions were significantly inhibited by pyrogallol (10(-4) m), a free-radical generator. Percentage inhibition of pyrogallol on EFS (32 Hz)-induced contractions in ring sections was 48 +/- 5.8 in control, 75 +/- 5.5 in untreated-diabetic, 54 +/- 2.7 in ST-treated diabetic, and 58 +/- 4.7 in vitamin E-treated diabetic rats. Combining both ST and vitamin E treatment had the same effects as each antioxidant alone with a percent inhibition of 48 +/- 6.8. These results are consistent with the degenerative changes seen in sympathetic nerves and the abnormal function observed in chronically diabetic rats, leading to a decrease in EFS response and an increase in response to adrenergic agonists in the vas deferens. Furthermore, we demonstrated that reactive oxygen species are responsible for impaired sympathetic neurotransmission and abnormal function of diabetic vas deferens, and that a combination of antioxidants may be better for the therapy of reproductive system disabilities in male diabetics.

The impairment of endothelium-dependent and nerve-mediated relaxation by diabetes appears to involve an alteration in nitric oxide/cyclic GMP pathway. Administration of oral L-arginine increased endothelium-dependent relaxation, probably through activating nitric oxide synthase. Additionally, decreasing elevated blood glucose concentration and advanced glycosylation products by insulin treatment protected endothelium-dependent relaxation, whereas neither L-arginine nor insulin treatment restored impaired neurogenic relaxation.

It is known that diabetes mellitus alters the vascular responsiveness to several vasoconstrictors and vasodilators. Endothelium-derived nitric oxide is a potent endogenous nitrovasodilator, and endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor substance. They play a major role in the modulation of vascular tone. Selective impairment of endothelium-dependent relaxation and impaired vasoconstriction in response to ET-1 could result in vascular disorders. The purpose of our study was to determine whether vascular responses to ET-1 and endothelium-dependent relaxing substances are impaired in rats with streptozotocin-induced diabetes of 2 weeks duration. Endothelium-dependent relaxations produced by carbachol and ATP in aortic rings precontracted with phenylephrine were significantly attenuated in rings from diabetic rats, but the endothelium-independent relaxations produced by sodium nitroprusside and adenosine in diabetic preparations were not changed when compared to the corresponding controls. The ET-1-induced contractions were significantly attenuated with no change in agonist potency (pD₂ value) in aortae with and without endothelium obtained from diabetic rats when compared to those from controls. Mechanical removal of the endothelium did not significantly change ET-1 responses of aortae from either diabetic or control rats compared with responses of aortae with intact endothelium. These results suggest that, in this diabetic model, the contractile responsiveness of thoracic aortic muscles and the endothelial functions are significantly altered during 2 weeks of diabetes.

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