Exercise training enhanced myocardial endothelial nitric oxide synthase (eNOS) function in diabetic Goto-Kakizaki (GK) rats

Background: Different mechanisms of diabetic-induced NO dysfunction have been proposed and central to most of them are significant changes in eNOS function as the rate-limiting step in NO bioavailability. eNOS exists in both monomeric and dimeric conformations, with the dimeric form catalyzing the synthesis of nitric oxide, while the monomeric form catalyzes the synthesis of superoxide (O-2-). Diabetic-induced shifts to decrease the dimer: monomer ratio is thought to contribute to the degradation of nitric oxide (NO) bioavailability. Exercise has long been useful in the management of diabetes. Although exercise-induced increases expression of eNOS has been reported, it is unclear if exercise may alter the functional coupling of eNOS. Methods: To investigate this question, Goto-Kakizaki rats ( a model of type II diabetes) were randomly assigned to a 9-week running program ( train) or sedentary ( sed) groups. Results: Exercise training significantly (p < .05) increased plantaris muscle cytochrome oxidase, significantly improved glycosylated hemoglobin ( sed: 7.33 +/- 0.56%; train: 6.1 +/- 0.18%), ad improved insulin sensitivity. Exercise increased both total eNOS expression and the dimer: monomer ratio in the left ventricle LV (sed: 11.7 +/- 3.2%; train: 41.4 +/- 4.7%). Functional analysis of eNOS indicated that exercise induced significant increases in nitric oxide (+28%) production and concomitant decreases in eNOS-dependent superoxide (-12%) production. This effect was observed in the absence of tetrahydrobiopterin (BH4), but not in the presence of exogenous BH4. Exercise training also significantly decreased NADPH-dependent O-2- activity. Conclusion: Exercise-induced increased eNOS dimerization resulted in an increased coupling of the enzyme to facilitate production of NO at the expense of ROS generation. This shift that could serve to decrease diabetic-related oxidative stress, which should serve to lessen diabetic-related complications.