b3 adrenergic stimulation restores nitric oxide/redox balance and enhances endothelial function in hyperglycemia

Background--perturbed balance between no and o2 .-. (ie,no/redox imbalance) is central in the pathobiology of diabetesinduced vascular dysfunction. we examined whether stimulation of β3 adrenergic receptors (β3 ars),coupled to endothelial nitric oxide synthase (enos) activation,would re-establish no/redox balance,relieve oxidative inhibition of the membrane proteins enos and na+-k+ (nk) pump,and improve vascular function in a new animal model of hyperglycemia. methods and results--we established hyperglycemia in male white new zealand rabbits by infusion of s961,a competitive highaffinity peptide inhibitor of the insulin receptor. hyperglycemia impaired endothelium-dependent vasorelaxation by uncoupling of enos via glutathionylation (enos-gss) that was dependent on nadph oxidase activity. accordingly,no levels were lower while o2 .- levels were higher in hyperglycemic rabbits. infusion of the β3 ar agonist cl316243 (cl) decreased enos-gss,reduced o2 .-,restored no levels,and improved endothelium-dependent relaxation. cl decreased hyperglycemia-induced nadph oxidase activation as suggested by co-immunoprecipitation experiments,and it increased enos co-immunoprecipitation with glutaredoxin-1,which may reflect promotion of enos de-glutathionylation by cl. moreover,cl reversed hyperglycemia-induced glutathionylation of the β1 nk pump subunit that causes nk pump inhibition,and improved k+-induced vasorelaxation that reflects enhancement in nk pump activity. lastly,enos-gss was higher in vessels of diabetic patients and was reduced by cl,suggesting potential significance of the experimental findings in human diabetes. conclusions-β3 ar activation restored no/redox balance and improved endothelial function in hyperglycemia. β3 ar agonists may confer protection against diabetes-induced vascular dysfunction. © 2016 the authors.