Combined treatment with atorvastatin and imipenem improves survival and vascular functions in mouse model of sepsis

We have recently reported that pre-treatment, but not the post-treatment with atorvastatin showed survival benefit and improved hemodynamic functions in cecal ligation and puncture (CLP) model of sepsis in mice. Here we examined whether combined treatment with atorvastatin and imipenem after onset of sepsis can prolong survival and improve vascular functions. At 6 and 18 h after sepsis induction, treatment with atorvastatin plus imipenem, atorvastatin or imipenem alone or placebo was initiated. Ex vivo experiments were done on mouse aorta to examine the vascular reactivity to nor-adrenaline and acetylcholine and mRNA expressions of alpha(1D) AR, GRK2 and eNOS. Atorvastatin plus imipenem extended the survival time to 56.00 +/- 4.62 h from 20.00 +/- 1.66 h observed in CLP mice. The survival time with atorvastatin or imipenem alone was 20.50 +/- 1.89 h and 27.00 +/- 4.09 h, respectively. The combined treatment reversed the hyporeactivity to noradrenaline through preservation of am AR mRNA/protein expression and reversal of alpha(1D) AR desensitization mediated by GRK2/G(beta gamma), pathway. The treatment also restored endothelium-dependent relaxation to ACh through restoration of aortic eNOS mRNA expression and NO availability. In conclusion, combined treatment with atorvastatin and imipenem exhibited survival benefit and improved vascular functions in septic mice. (C) 2015 Elsevier Inc. All rights reserved.