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Muscarinic M1 and M2 receptor subtypes play opposite roles in LPS-induced septic shock.
Pharmacol Rep 2019; 71(6):1108-1114PR

Abstract

BACKGROUND

To compare pharmacologic effects of pirenzepine and AF-DX116, a selective competitive antagonist for M1 and M2 subtype muscarinic cholinergic receptors (mAChRs), respectively, with atropine, a non-selective competitive antagonist for mAChRs, on Lipopolysaccharide (LPS).

METHODS

Male C57BL/6 mice were used to establish models of LPS-induced experimental endotoxemia. Mice were intraperitoneally injected 10 min prior to LPS injection with control (saline), atropine, pirenzepine and AF-DX116, respectively. Overall survival time was estimated using Kaplan-Meier plots. Inflammatory cytokine tumor necrosis factor-α (TNF-α) was monitored at various intervals after LPS injection and individual reagent administration. Pathological alternations in lungs and liver were analyzed.

RESULTS

Pirenzepine and atropine pretreatment improved survival rate of LPS-induced septic shock; in contrast, AF-DX116 accelerated death from sepsis. Moreover, TNF-α plasma level was decreased in response to pirenzepine or atropine, whereas increased in response to AF-DX116. Pirenzepine and atropine relieved whereas AF-DX116 accelerated LPS-induced pulmonary and hepatic injury. Pirenzepine reduced proportion of M1 subtype of macrophages, while AF-DX116 promoted polarization of macrophages to M1 subtype. Pirenzepine pretreatment reduced while AF-DX116 enhanced expression of SOCS3 at mRNA level.

CONCLUSIONS

The administration of pirenzepine and atropine may have beneficial effects on septic shock.

Authors+Show Affiliations

Department of Emergency Medicine, the 9th Clinical Medical College of Peking University, Beijing Shijitan Hospital, Capital Medical University, Beijng, China. Electronic address: Wangzhen1369@hotmail.com.Department of Emergency Medicine, the 9th Clinical Medical College of Peking University, Beijing Shijitan Hospital, Capital Medical University, Beijng, China.Department of Emergency Medicine, the 9th Clinical Medical College of Peking University, Beijing Shijitan Hospital, Capital Medical University, Beijng, China.Fuwai Hospital, Chinese Academy of Medical Science, Beijng, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31634798

Citation

Wang, Zhen, et al. "Muscarinic M1 and M2 Receptor Subtypes Play Opposite Roles in LPS-induced Septic Shock." Pharmacological Reports : PR, vol. 71, no. 6, 2019, pp. 1108-1114.
Wang Z, Li M, Liu L, et al. Muscarinic M1 and M2 receptor subtypes play opposite roles in LPS-induced septic shock. Pharmacol Rep. 2019;71(6):1108-1114.
Wang, Z., Li, M., Liu, L., & Geng, B. (2019). Muscarinic M1 and M2 receptor subtypes play opposite roles in LPS-induced septic shock. Pharmacological Reports : PR, 71(6), pp. 1108-1114. doi:10.1016/j.pharep.2019.06.005.
Wang Z, et al. Muscarinic M1 and M2 Receptor Subtypes Play Opposite Roles in LPS-induced Septic Shock. Pharmacol Rep. 2019 Jun 13;71(6):1108-1114. PubMed PMID: 31634798.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Muscarinic M1 and M2 receptor subtypes play opposite roles in LPS-induced septic shock. AU - Wang,Zhen, AU - Li,Mingyi, AU - Liu,Lu, AU - Geng,Bin, Y1 - 2019/06/13/ PY - 2018/12/10/received PY - 2019/05/17/revised PY - 2019/06/12/accepted PY - 2019/10/22/pubmed PY - 2019/10/22/medline PY - 2019/10/22/entrez KW - Cholinergic anti-inflammatory pathway KW - Inflammation KW - Muscarinic cholinergic receptor KW - Sepsis SP - 1108 EP - 1114 JF - Pharmacological reports : PR JO - Pharmacol Rep VL - 71 IS - 6 N2 - BACKGROUND: To compare pharmacologic effects of pirenzepine and AF-DX116, a selective competitive antagonist for M1 and M2 subtype muscarinic cholinergic receptors (mAChRs), respectively, with atropine, a non-selective competitive antagonist for mAChRs, on Lipopolysaccharide (LPS). METHODS: Male C57BL/6 mice were used to establish models of LPS-induced experimental endotoxemia. Mice were intraperitoneally injected 10 min prior to LPS injection with control (saline), atropine, pirenzepine and AF-DX116, respectively. Overall survival time was estimated using Kaplan-Meier plots. Inflammatory cytokine tumor necrosis factor-α (TNF-α) was monitored at various intervals after LPS injection and individual reagent administration. Pathological alternations in lungs and liver were analyzed. RESULTS: Pirenzepine and atropine pretreatment improved survival rate of LPS-induced septic shock; in contrast, AF-DX116 accelerated death from sepsis. Moreover, TNF-α plasma level was decreased in response to pirenzepine or atropine, whereas increased in response to AF-DX116. Pirenzepine and atropine relieved whereas AF-DX116 accelerated LPS-induced pulmonary and hepatic injury. Pirenzepine reduced proportion of M1 subtype of macrophages, while AF-DX116 promoted polarization of macrophages to M1 subtype. Pirenzepine pretreatment reduced while AF-DX116 enhanced expression of SOCS3 at mRNA level. CONCLUSIONS: The administration of pirenzepine and atropine may have beneficial effects on septic shock. SN - 1734-1140 UR - https://www.unboundmedicine.com/medline/citation/31634798/Muscarinic_M1_and_M2_receptor_subtypes_play_opposite_roles_in_LPS-induced_septic_shock L2 - https://linkinghub.elsevier.com/retrieve/pii/S1734-1140(18)30744-8 DB - PRIME DP - Unbound Medicine ER -