Enhancement of muscle glucose uptake by the vasopeptidase inhibitor, omapatrilat, is independent of insulin signaling and the AMP kinase pathway

Abstract

Omapatrilat (OMA), a vasopeptidase inhibitor (VPI), presently being tested in clinical trials for its antihypertensive properties, inhibits both angiotensin-converting enzyme and neutral endopeptidase, and raises tissue bradykinin levels. Recent studies from our laboratory and those of others have demonstrated that VPIs enhance muscle glucose uptake in animal models, and this effect is mediated by the bradykinin-nitric oxide pathway. The mechanism of the effect of OMA on muscle glucose uptake, however, is presently unknown. To investigate the effect of OMA on insulin signaling, soleus muscle was isolated 2 or 5 min after an i.v. bolus of insulin or saline from male Zucker fatty rats (8-10 weeks of age), following a 5-day treatment period of oral OMA (15 mg/kg per day) or drug vehicle (placebo). OMA resulted in significantly lower systolic blood pressure compared with the placebo-treated group (84$4G 7$52 mmHg in OMA vs 112G2$18 mmHg in controls, P!0$01). Immunoprecipitation and Western blot analysis of insulin receptor substrate 1 (IRS-1) revealed no changes in protein mass with OMA treatment. OMA did not enhance basal or insulin-stimulated IRS-1 tyrosine phosphorylation or its subsequent association with the p85 regulatory subunit of phosphatidylinositol 3-kinase. Under basal and insulinstimulated conditions, OMA treatment did not alter the protein mass or the phosphorylation of Akt/protein kinase B, p42/44 extracellular signal-regulated kinase or adenosine monophosphate-activated protein kinase, or GLUT4 protein expression. We conclude that the ability of OMA to enhance whole body and specifically muscle glucose uptake in Zucker fatty rats is not mediated by enhancing insulin or AMPK signaling. Future studies should examine whether hemodynamic effects of the drug, independent of insulin signaling, enhance glucose uptake in insulin-resistant skeletal muscle.

Effect of inhibition of angiotensin converting enzyme and/or neutral endopeptidase on vascular and neural complications in high fat fed/low dose streptozotocin-diabetic rats

“…In a similar independent study it was found that Omapatrilat, a vasopeptidase inhibitor, induced insulin sensitization and increased myocardial glucose uptake in obese Zucker rats and that the effect of Omapatrilat was greater than Ramipril in part due to stimulation of the B 2 receptor (Wang, et al 2003). Later this group reported that treatment of obese Zucker rats with a vasopeptidase inhibitor increased muscle glucose uptake independent of insulin signaling (Wong, et al 2006). In two of these studies protection of bradykinin from degradation by neutral endopeptidase was found to improve insulin action (Arbin, et al 2001; Wang, et al 2003).…”

Effect of Inhibition of Angiotensin-Converting Enzyme and/or Neutral Endopeptidase on Neuropathy in High-Fat-Fed C57Bl/6J Mice

“…In a similar independent study it was found that Omapatrilat, a vasopeptidase inhibitor, induced insulin sensitization and increased myocardial glucose uptake in obese Zucker rats and that the effect of Omapatrilat was greater than Ramipril in part due to stimulation of the B 2 receptor [33]. Later this group reported that treatment of obese Zucker rats with a vasopeptidase inhibitor increased muscle glucose uptake independent of insulin signaling [34]. In two of these studies protection of bradykinin from degradation by NEP was found to improve insulin action [32, 33].…”

“…The natriuretic peptides are also degraded by NEP [36]. Because NEP is expressed in skeletal muscle in relatively large amounts and being located on the cell surface, NEP is able to hydrolyze peptides in the vicinity of their receptors thereby neutralizing their bioactivity [34, 36]. However, inhibition of ACE may also lead to protection of bradykinin levels by inhibiting kininase-II-mediated degradation of this nonapeptide [37].…”

“…They attributed the improvement to modulation of insulin action by bradykinin mediated through B 2 receptors and by an increase in nitric oxide production. Since bradykinin and natriuretic peptides may have a role in enhancing insulin action and regulating glucose and fatty acid metabolism by muscle protecting their bioactive function by preventing degradation through inhibition of ACE and/or NEP may be a therapeutic approach for treatment of obesity and insulin resistance [34, 36, 38]. …”

Salicylate prevents hepatic insulin resistance caused by short-term elevation of free fatty acids in vivo

“…The results showed that the index of purity of both fractions were O90%. Homogenization of muscle (Wong et al 2006) and fat (Beard et al 2006) samples was performed as described previously. The protein concentration in all samples was determined by the detergent-compatible modified Lowry microassay, using a standardized assay kit.…”