The effects of ecdysterone and enalapril on nitric oxide synthesis and the markers of oxidative stress in streptozotocin-induced diabetes in rats: a comparative study

Cardiovascular functions in diabetes greatly depend on constitutive NOS (cNOS) activity. A comparative study of the effects of a steroid hormone ecdysterone and enalapril, an ACE inhibitor widely used to treat cardiac disorders on cNOS, inducible NOS (iNOS), xanthine oxidoreductase (XOR) activity, RNS, ROS, and lipid peroxidation in heart tissue in experimental diabetes was conducted. The rat model of diabetes was established by streptozotocin injection. NOS activity, NO 2 − , NO 3 − , uric acid, nitrosothiols, hydroperoxide, superoxide, and diene conjugate formation were studied spectrophotomerically. In diabetes, cNOS downregulation correlated with a dramatic fall of NO 2 − production and ~4.5-fold elevation of nitrosothiols, which agreed with a steep rise of iNOS activity, while NO 3 − remained close to control. Dramatic activation of XOR was observed, which correlated with the elevation of both superoxide production and nitrate reductase activity and resulted in strong lipid peroxidation. Ecdysterone and enalapril differently affected RNS metabolism. Ecdysterone moderately restored cNOS but strongly suppressed iNOS, which resulted in the reduction of NO 3 − , but full restoration of NO 2 − production. Enalapril better restored cNOS but less effectively suppressed iNOS, which promoted NO 3 − formation. Both drugs similarly inhibited XOR, which equally alleviated oxidative stress and lipid peroxidation. The synergistic action of iNOS and XOR was a plausible explanation for strong lipid peroxidation, abolished by the inhibition of iNOS and XOR by ecdysterone or enalapril. Complementary effects of ecdysterone and enalapril on cNOS, iNOS, and RNS are a promising basis for their combined use in the treatment of cardiovascular disorders caused by cNOS dysfunction in diabetes.