title: Combined treatment with atorvastatin and imipenem improves survival and vascular functions in mouse model of sepsis.
abstract: 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 18h 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 α1D AR, GRK2 and eNOS. Atorvastatin plus imipenem extended the survival time to 56.00±4.62h from 20.00±1.66h observed in CLP mice. The survival time with atorvastatin or imipenem alone was 20.50±1.89h and 27.00±4.09h, respectively. The combined treatment reversed the hyporeactivity to nor-adrenaline through preservation of α1D AR mRNA/protein expression and reversal of α1D AR desensitization mediated by GRK2/Gβγ 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.
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India.
authors: Soumen
authors: S
authors: Choudhury
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India.
authors: Kandasamy
authors: K
authors: Kannan
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India.
authors: M
authors: M
authors: Pule Addison
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India.
authors: Sazad A
authors: SA
authors: Darzi
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India.
authors: Vishakha
authors: V
authors: Singh
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India.
authors: Thakur Uttam
authors: TU
authors: Singh
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India.
authors: Ramasamy
authors: R
authors: Thangamalai
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India.
authors: Jeevan Ranjan
authors: JR
authors: Dash
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India.
authors: Subhashree
authors: S
authors: Parida
authors: Division of Veterinary Pathology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India.
authors: Biplab
authors: B
authors: Debroy
authors: Division of Physiology and Climatology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India.
authors: Avishek
authors: A
authors: Paul
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India. Electronic address: smishraivri@rediffmail.com.
authors: Santosh Kumar
authors: SK
authors: Mishra
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D000069059:Atorvastatin / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D015378:Imipenem / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D009924:Organ Culture Techniques; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate / Q000639:trends
chemical_list: D000900:Anti-Bacterial Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015378:Imipenem; D000069059:Atorvastatin
keywords: Atorvastatin; GRK2; Imipenem; Sepsis; eNOS; α(1D) adrenoceptor