Acute effect of the dual angiotensin-converting enzyme and neutral endopeptidase 24-11 inhibitor mixanpril on insulin sensitivity in obese Zucker rat

1 The aim of this study was to determine whether acute dual angiotensin-con verting enzyme (ACE)/neutral endopeptidase 24-11 (NEP) inhibition could imp rove whole body insulin-mediated glucose disposal (IMGD) more than ACE inhi bition alone and whether this effect was mediated by the kinin-nitric oxide (NO) pathway activation. 2 We therefore compared in anaesthetized obese (fa/fa) Zucker rats (ZOs) th e effects of captopril (2 mg kg(-1), i.v. + 2 mg kg(-1) h(-1)), retrothiorp han (25 mg kg(-1), i.v. + 25 mg kg(-1) h (1)), a selective NEP inhibitor, a nd mixanpril (25 mg kg(-1), i.v. + 25 mg kg(-1) h(-1)), a dual ACE/NEP inhi bitor, on IMGD using hyperinsulinaemic euglycaemic clamp technique. The rol e of the kinin-NO pathway in the effects of mixanpril was tested using a br adykinin B2 receptor antagonist (Hoe-140, 300 mug kg(-1)) and a NO-synthase inhibitor (N-omega-nitro-L-arginine methyl ester, L-NAME, 10 mg kg ' i.v. + 10 mg kg (1) h (1)) as pretreatments. 3 Insulin sensitivity index (ISI) was lower in ZO controls than in lean lit termates. Increases in ISI were observed in captopril- and retrothiorphan-t reated ZOs. In mixanpril-treated ZOs, TSI was further increased, compared t o captopril- and retrothiorphan-treated ZOs. 4 In ZOs, Hoe-140 and L-NAME alone did not significantly alter and slightly reduced the ISI respectively. Hoe-140 and L-NAME markedly inhibited the IS I improvement induced by mixanpril. 5 These results show that in obese insulin-resistant Zucker rats, under acu te conditions, NEP or ACE inhibition can improve IMGD and that dual ACE/NEP inhibition improves IMGD more effectively than does either single inhibiti on. This effect is linked to an increased activation of the kinin-NO pathwa y.