Chong Liu, F. Shen, Y. Le
Feb 1, 2009
Citations
3
Influential Citations
57
Citations
Quality indicators
Journal
Critical Care Medicine
Abstract
Objective:Vagus nerve stimulation inhibits proinflammatory cytokine production by signaling through the α7 nicotinic acetylcholine receptor (α7nAChR). Anisodamine, a muscarinic acetylcholine receptor antagonist, has been used clinically in China for treatment of various shocks, but the mechanism was poorly understood. Here, we tested the hypothesis whether anisodamine attained its antishock effect through activation of α7nAChR. Design:Randomized and controlled in vitro and in vivo study. Settings:Research laboratory and animal facility rooms. Subjects:Sprague-Dawley rats, Kunming mice, α7nAChR-deficient mice, and RAW264.7 cells. Interventions:Sprague-Dawley rats were injected with lipopolysaccharide (LPS) (15 mg/kg, intravenous) to induce septic shock. Methyllycaconitine, a selective α7nAChR antagonist, was administered (10 mg/kg, intraperitoneal) 10 minutes before anisodamine (10 mg/kg, intravenous). Mean arterial pressure was monitored and cytokines were analyzed 2 hours after the onset of LPS. In vagotomized mice and α7nAChR-deficient mice, the antishock effect of anisodamine was appraised, respectively. RAW264.7 cells were stained by fluorescein isothiocyanate- labeled-α-bungarotoxin and the fluorescence intensity was observed. Mice peritoneal macrophages were pretreated and stimulated with LPS, and tumor necrosis factor (TNF)-α in the supernatant was measured by enzyme-linked immunosorbent assay. Measurements and Main Results:Methyllycaconitine significantly antagonized the beneficial effect of anisodamine on mean arterial pressure and TNF-α, interleukin-1β expression in response to LPS. The antishock effects of anisodamine were markedly attenuated in vagotomized mice and α7nAChR-deficient mice. In vitro, anisodamine significantly augmented the effect of acetylcholine on fluorescence intensity stained with fluorescein isothiocyanate-labeled-α-bungarotoxin and TNF-α production stimulated with LPS. Conclusion:These findings demonstrate that the antishock effect of anisodamine is intimately linked to α7nAChR-dependent anti-inflammatory pathway.