Objective: The increase of reactive oxygen species (ROS) in diabetes potentiates the vascular effects of phenylephrine through nitric oxide (NO) impairment, facilitating the development of diabetic nephropathy. We propose that the combination of an antioxidant and L-arginine as diet supplements could prevent the increased vascular response to phenylephrine in diabetic animals.
Design: Changes in the adrenergic system play an important role in the development of vascular complications in the prediabetic condition. The vasoconstrictor effects of phenylephrine are regulated by NO, and the impairment of endothelium-dependent vasodilation in diabetes is associated with ROS.
Setting: Diabetes was induced with a low dose (55 mg/kg body weight) of streptozotocin in 7-week-old rats. Diabetic rats were fed with a diet supplement containing a combination of vitamin E, vitamin C, eicosapentaenoic acid, docosahexaenoic acid, and L-arginine, and the effects on phenylephrine-induced renal vascular responses were evaluated.
Results: Phenylephrine increased the renal perfusion pressure of isolated perfused kidneys from diabetic rats compared with nondiabetic rats. This effect was associated with reduced nitrite release as well as reduced plasma tetrahydrobiopterin and increased superoxide anions in the renal tissue. Diet supplementation with a combination of L-arginine and vitamins in diabetic rats partially prevented the generation of superoxide associated with recovery of the renal release of NO and decreased phenylephrine-induced vasoconstrictor effects, compared with untreated diabetic rats. However, the administration of L-arginine or vitamins alone did not affect phenylephrine-induced vasoconstriction. Vitamin treatment alone did decrease superoxide generation.
Conclusion: The protective mechanism of NO on the vasoconstrictor effects of phenylephrine in the kidney is lost during the development of diabetes, probably via the actions of ROS through a decrease in tetrahydrobiopterin, thus contributing to the pathogenesis of diabetic nephropathy. Restoration of this protective NO mechanism can be achieved by simultaneously stimulating NO synthesis and preventing the effects of ROS through the use of L-arginine and a combination of vitamins E and C as diet supplementation.