Combined treatment with atorvastatin and imipenem improves survival and vascular functions in mouse model of sepsis
| Autor: | Avishek Paul, Santosh K. Mishra, Sazad A. Darzi, Ramasamy Thangamalai, Soumen Choudhury, Subhashree Parida, Kandasamy Kannan, M. Pule Addison, Jeevan Ranjan Dash, Thakur Uttam Singh, Biplab Debroy, Vishakha Singh |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Imipenem Physiology Atorvastatin Hemodynamics Pharmacology Placebo Sepsis Mice Organ Culture Techniques Enos medicine Animals biology business.industry Beta adrenergic receptor kinase biology.organism_classification medicine.disease Anti-Bacterial Agents Survival Rate Disease Models Animal Anesthesia biology.protein Molecular Medicine Drug Therapy Combination Endothelium Vascular Hydroxymethylglutaryl-CoA Reductase Inhibitors business Ex vivo medicine.drug |
| Zdroj: | Vascular Pharmacology. 71:139-150 |
| ISSN: | 1537-1891 |
| DOI: | 10.1016/j.vph.2015.03.012 |
| Popis: | 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 α 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 nor-adrenaline through preservation of α 1D AR mRNA/protein expression and reversal of α 1D AR desensitization mediated by GRK2/G βγ 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. |
| Databáze: | OpenAIRE |
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