ACE inhibition and glucose transport in insulinresistant muscle: roles of bradykinin and nitric oxide

Abstract

Acute administration of the angiotensin-converting enzyme (ACE) inhibitor captopril enhances insulin-stimulated glucose transport activity in skeletal muscle of the insulin-resistant obese Zucker rat. The present study was designed to assess whether this effect is mediated by an increase in the nonapeptide bradykinin (BK), by a decrease in action of ANG II, or both. Obese Zucker rats (8–9 wk old) were treated for 2 h with either captopril (50 mg/kg orally), bradykinin (200 μg/kg ip), or the ANG II receptor (AT1 subtype) antagonist eprosartan (20 mg/kg orally). Captopril treatment enhanced in vitro insulin-stimulated (2 mU/ml) 2-deoxyglucose uptake in the epitrochlearis muscle by 22% (251 ± 7 vs. 205 ± 9 pmol ⋅ mg−1 ⋅ 20 min−1; P < 0.05), whereas BK treatment enhanced this variable by 18% (249 ± 15 vs. 215 ± 7 pmol ⋅ mg−1 ⋅ 20 min−1; P < 0.05). Eprosartan did not significantly modify insulin action. The BK-mediated increase in insulin action was completely abolished by pretreatment with either the specific BK-B2 receptor antagonist HOE 140 (200 μg/kg ip) or the nitric oxide synthase inhibitor N ω-nitro-l-arginine methyl ester (50 mg/kg ip). Collectively, these results indicate that the modulation of insulin action by BK likely underlies the metabolic effects of ACE inhibitors in the insulin-resistant obese Zucker rat. Moreover, this modulation of insulin action by BK is likely mediated through B2 receptors and by an increase in nitric oxide production and/or action in skeletal muscle tissue.

Selective Angiotensin II Receptor Antagonism Reduces Insulin Resistance in Obese Zucker Rats

“…We have confirmed our previous observation 19 that acute oral administration of an AT 1 -specific Ang II receptor antagonist does not appreciably enhance insulin action on glucose transport activity in skeletal muscle comprised primarily of less-insulin-responsive type IIb fibers (epitrochlearis) from the obese Zucker rat. However, we report here for the first time that acute administration of an Ang II receptor antagonist increases, in a dosage-dependent fashion, insulin action on glucose transport in skeletal muscle made up of more-insulin-responsive type I fibers from soleus ( Figure 2).…”

“…24 Glucose transport activity, assessed as 2-deoxyglucose (2-DG) uptake, was determined in the absence of presence of insulin (13.3 nmol/L) exactly as described previously. [7][8][9][10]19 Muscle GLUT-4 Protein…”

“…19 In contrast, chronic administration of Ang II receptor antagonists to insulin-resistant fructose-fed 12 or spontaneously hypertensive 20 rats or to human subjects with essential hypertension 21 leads to significant improvements in whole-body insulin sensitivity. Moreover, Rao 22 and Richey et al 23 have reported that acute infusion of Ang II leads to substantial reduction in glucose disposal in normal skeletal muscle, which could not be attributed to hemodynamic alterations.…”

Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome

“…They may increase the percentage of type I fibers in skeletal muscle [141]. They enhance skeletal muscle blood flow, improving insulin delivery and enhancing glucose uptake and metabolism in insulin-sensitive tissues [25,142,143].They also improve insulin-mediated glucose uptake by reducing the degradation of bradykinin and increasing the production of NO through their blockade of kininase II and ACE [133,144]. They enhance vascular sensitivity to insulin and improve endothelial function [145,146].…”

The -9 /+9 Polymorphism of the Bradykinin Receptor Beta 2 Gene and Athlete Status: A Study Involving Two European Cohorts

“…The activation of the BDKRB2 results in increased skeletal muscle glucose uptake during exercise, muscle blood flow and endurance performance (Dietze et al, 1996, Henriksen et al, 1999). Additionally, the production of the vasodilator nitric oxide (NO) from arginine by the enzyme nitric oxide synthase (NOS) has been observed (Rett et al, 1990;Shen et al, 1995;Mayfield et al, 1996).…”