title: The protective action of ketanserin against lipopolysaccharide-induced shock in mice is mediated by inhibiting inducible NO synthase expression via the MEK/ERK pathway.
abstract: Nitric oxide (NO) plays an important role in the pathogenesis of endotoxic shock. This work tested the hypothesis that ketanserin could attenuate endotoxic shock by inhibiting the expression of inducible NO synthase (iNOS). The results demonstrated that ketanserin could inhibit iNOS expression in the heart, lungs, liver, and kidneys and nitrate production in the serum upon endotoxic shock in mice. In RAW264.7 cells, ketanserin significantly inhibited the expression of iNOS and decreased the production of NO, TNFα, IL-6, and reactive oxygen species upon lipopolysaccharide (LPS) challenge. Ketanserin also increased the level of ATP and mitochondrial membrane potential in RAW264.7 cells upon LPS exposure. LPS-induced iNOS expression was inhibited by the 5-HT2A receptor antagonist ritanserin and not the α1 receptor antagonist prazosin. Knockdown of 5-HT2A receptor by siRNA abolished the inhibitory effect of ketanserin on the expression of iNOS. These results indicated that the inhibitory effect of ketanserin on the expression of iNOS is mediated by blocking the 5-HT2A receptor. Furthermore, ketanserin significantly inhibited the activation of ERK1/2 and NF-κB signal. Pretreatment with PD184352, a specific inhibitor of ERK1/2, blocked the inhibitory effect of ketanserin on the expression of iNOS and NO production, indicating a critical role for the MEK/ERK1/2 signaling pathway. Collectively, our findings indicate that inhibition of the expression of iNOS via the MEK/ERK pathway mediates the protective effects of ketanserin against LPS-induced shock in mice.
authors: Department of Pharmacology, Second Military Medical University, Shanghai 200433, China. Electronic address: wanlc2004@aliyun.com.
authors: Chong
authors: C
authors: Liu
authors: Department of Pharmacology, Second Military Medical University, Shanghai 200433, China.
authors: Xin
authors: X
authors: Zhang
authors: Department of Pharmacology, Second Military Medical University, Shanghai 200433, China.
authors: Jv-Xiang
authors: JX
authors: Zhou
authors: Department of Pharmacology, Second Military Medical University, Shanghai 200433, China.
authors: Wei
authors: W
authors: Wei
authors: Department of Pharmacology, Second Military Medical University, Shanghai 200433, China.
authors: Dian-Hua
authors: DH
authors: Liu
authors: Department of Pharmacology, Second Military Medical University, Shanghai 200433, China.
authors: Ping
authors: P
authors: Ke
authors: Department of Pharmacology, Second Military Medical University, Shanghai 200433, China.
authors: Gu-Fang
authors: GF
authors: Zhang
authors: Department of Pharmacology, Second Military Medical University, Shanghai 200433, China. Electronic address: 13386277625@163.com.
authors: Guo-Jun
authors: GJ
authors: Cai
authors: Department of Pharmacology, Second Military Medical University, Shanghai 200433, China. Electronic address: dfsu2008@gmail.com.
authors: Ding-Feng
authors: DF
authors: Su
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007650:Ketanserin / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D034741:RNA, Small Interfering; D012772:Shock, Septic / Q000378:metabolism*; D014162:Transfection
chemical_list: D000959:Antihypertensive Agents; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D007650:Ketanserin; D052247:Nitric Oxide Synthase Type II
keywords: Endotoxic shock; Free radicals; Inducible nitric oxide synthase; Ketanserin; Nitric oxide