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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.

Rheumatoid arthritis (RA) is a complicated and treatment refractory autoimmune disease that is characterized by a chronic inflammatory infiltration of immune cells 1. The central nervous system plays an important role in limiting inflammatory responses via an inflammatory reflex of the vagus nerve termed as “the cholinergic antiinflammatory pathway” 2. Acetylcholine, the principal neurotransmitter of the vagus nerve, interacts with α7 nicotinic acetylcholine receptor (α7nAChR) expressed on macrophages and other cells and could inhibit the production of proinflammatory cytokines such as TNFα, interleukin (IL)-1β, and IL-6. Decreased level of vagus nerve activity is correlated with increased serum concentration of late-phase inflammation cytokine high-mobility group box chromosomal protein 1 in patients with RA. Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis (CIA) in mice. Lack of α7nAChR aggravates the development of CIA 3.