Nebivolol improves insulin sensitivity in the TGR(Ren2)27 rat

Abstract

Objective Hypertension is often associated with increased oxidative stress and systemic insulin resistance. Use of β adrenergic receptor blockers in hypertension is limited due to potential negative influence on insulin sensitivity and glucose homeostasis. We sought to determine the impact of nebivolol, a selective vasodilatory β1adrenergic blocker, on whole-body insulin sensitivity, skeletal muscle oxidative stress, insulin signaling and glucose transport in the transgenic TG(mRen2)27rat (Ren2). This rodent model manifests increased tissue renin angiotensin expression, excess oxidative stress, and whole-body insulin resistance. Research design and methods Young (age 6-9 wks) Ren2 and age-matched Sprague-Dawley control rats were treated with nebivolol 10 mg/kg/day or placebo for 21 days. Basal measurements were obtained for glucose and insulin to calculate the Homeostasis Model Assessment (HOMA–IR). Additionally, insulin metabolic signaling, NADPH oxidase activity, reactive oxygen species (ROS), and ultrastructural changes as evaluated by transmission electron microscopy were examined ex vivo in skeletal muscle tissue. Results The Ren2 rat demonstrated systemic insulin resistance as examined by HOMA-IR, along with impaired insulin metabolic signaling in skeletal muscle. This was associated with increased oxidative stress and mitochondrial remodeling. Treatment with nebivolol was associated with improvement in insulin resistance and decreased NADPH oxidase activity/levels ROS in skeletal muscle tissue. Conclusions Nebivolol treatment for 3 weeks reduces NADPH oxidase activity and improves systemic insulin resistance, in concert with reduced oxidative stress in skeletal muscle in a young rodent model of hypertension, insulin resistance and enhanced tissue RAS expression.

Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the transgenic (mRen2) rat

“…As previously described (25,51), SBP was elevated in the Ren2-C group compared with the SD-C group (207 Ϯ 8 vs.…”

“…Nebivolol is a highly cardiac-selective ␤ 1 -adrenergic receptor blocker that contributes to vasodilation by increasing bioavailable NO through its coupling to the ␤ 3 -receptor subtype (13). It has been reported that nebivolol treatment leads to reductions in NADPH oxidase activity in the heart and vascular tissue (13,32,41,43), and recent work has highlighted improvements in insulin metabolic signaling and enhancement in bioavailable NO in skeletal muscle (25) and kidney tissue (51) in a transgenic (TG) (mRen2)27 (Ren2) rat model. This Ren2 rat manifests tissue overexpression of the mouse renin gene and tissue ANG II with elevations in SBP, insulin resistance, and increases in myocardial oxidative stress and diastolic dysfunction (14,50).…”

Identification of Bona Fide Alternative Renin Transcripts Expressed Along Cortical Tubules and Potential Roles in Promoting Insulin Resistance In Vivo Without Significant Plasma Renin Activity Elevation

“…In earlier days, it was demonstrated that enhanced kinetics of the reaction between mouse renin and rat angiotensinogen are one of pathophysiological mechanism for this model. 39,40 Recently, this animal model was reported to have various pathophysiological features such as insulin resistance, [41][42][43] left ventricular dysfunction, 44,45 nonalcoholic fatty liver disease-like significant hepatic steatosis with increased hepatic reactive oxygen species, lipid peroxidation, steatohepatitis, and fibrosis 46 as a result of tissue RAS overactivation. We generated transgenic ARen2 overexpression mice with a C57BL/6J background, which endogenously have only the Ren1C renin gene.…”

Combination antihypertensive therapy in patients with arterial hypertension and coronary heart disease

“…Высокая клиническая эффективность небиво-лола при различных сердечно-сосудистых заболе-ваниях -АГ, ИБС, в том числе у больных с СД на сегодняшний день имеет большую доказатель-ную базу -более 70 исследований [30][31][32][33][34][35].…”