Muscarinic M1 and M2 receptor subtypes play opposite roles in LPS-induced septic shock

• Published in: Pharmacological reports Vol. 71; no. 6; pp. 1108 - 1114
• Main Authors: Wang, Zhen, Li, Mingyi, Liu, Lu, Geng, Bin
• Format: Journal Article
• Language: English
• Published: Cham Elsevier B.V 01.12.2019; Springer International Publishing
• Subjects: Animals; Atropine - pharmacology; Cholinergic anti-inflammatory pathway; Cytokines - metabolism; Drug Safety and Pharmacovigilance; Inflammation; Lipopolysaccharides; Liver - pathology; Lung - pathology; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Muscarinic cholinergic receptor; Neutrophil Infiltration - drug effects; Original Article; Pharmacotherapy; Pharmacy; Pirenzepine - analogs & derivatives; Pirenzepine - pharmacology; Receptor, Muscarinic M1 - antagonists & inhibitors; Receptor, Muscarinic M1 - physiology; Receptor, Muscarinic M2 - antagonists & inhibitors; Receptor, Muscarinic M2 - physiology; Sepsis; Shock, Septic - chemically induced; Shock, Septic - drug therapy; Shock, Septic - mortality; Shock, Septic - physiopathology; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - metabolism; Muscarinic cholinergic receptor; Sepsis; Inflammation; Cholinergic anti-inflammatory pathway
• ISSN: 1734-1140; 2299-5684; 2299-5684
• DOI: 10.1016/j.pharep.2019.06.005

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