A pharmacologic approach to vagal nerve stimulation prevents mesenteric lymph toxicity after hemorrhagic shock.

BACKGROUND

Electrical stimulation of the vagus nerve (VN) prevents gut and lung inflammation and mesenteric lymph (ML) toxicity in animal models of injury. We have previously shown that treatment with CPSI-121, a guanylhydrazone-derived compound, prevents gut barrier failure after burn injury. While the structure of CPSI-121 predicts that it will activate parasympathetic signaling, its ability to stimulate the VN is unknown. The aims of this study were to (1) measure the ability of CPSI-121 to induce VN activity, (2) determine whether CPSI-121 causes significant hemodynamic effects, and (3) further define the potential for CPSI-121 to limit the systemic inflammatory response to injury.

METHODS

Male Sprague-Dawley rats were given 1-mg/kg CPSI-121 intravenously while blood pressure, heart rate, and efferent VN electrical activity were recorded. Rats were also assigned to sham or trauma/hemorrhagic shock (T/HS). T/HS was induced by laparotomy and 60 minutes of HS (mean arterial pressure, 35 mm Hg) followed by fluid resuscitation. A separate cohort of animals received CPSI-121 after the HS phase. Gut and lung tissues were harvested for histologic analysis. Lung wet-dry ratios were also evaluated. The ability of ML to prime neutrophils was assessed by measuring in vitro oxidative burst using flow cytometry.

RESULTS

Blood pressure was not altered after treatment with CPSI-121, while heart rate decreased only slightly. Recording of efferent VN electrical activity revealed an increase in discharge rate after administration of CPSI-121. T/HS caused gut and lung injury, which were prevented in animals treated with CPSI-121 (p < 0.05). Treatment with CPSI-121 following T/HS attenuated neutrophil priming after exposure to ML (p < 0.05).

CONCLUSION

CPSI-121 causes efferent VN output and limits shock-induced gut and lung injury as well as ML toxicity. CPSI-121 is a candidate pharmacologic approach to VN stimulation aimed at limiting the inflammatory response in patients following T/HS.