Cholinergic regulation of atrial natriuretic peptide in spleen during sepsis

Abstract Introduction: Cardiac atrial natriuretic peptide (ANP) regulates blood volume and pressure. ANP is also produced in spleen and reduces pro-inflammatory cytokine production in macrophages. The cholinergic anti-inflammatory pathway targets spleen to inhibit pro-inflammatory cytokines and organ damage in sepsis. We hypothesized that cholinergic regulation of systemic inflammation requires modulation of splenic ANP. Methods: Male 8-12 wk old BALB/c mice received LPS (15 mg/kg, i.p.), and were euthanized after 60 m. Nicotine (2 mg/kg, i.p.) or vehicle was given 1-2 h before LPS. TNF and ANP were measured using ELISA. Other mice received cecal ligation and puncture +/-splenectomy, and were euthanized at 24 h. One-way ANOVA or the Student’s t test was used to compare experimental groups. P-values < 0.05 are significant. Results: Nicotine significantly reduces systemic and splenic TNF. Nicotine significantly reduces systemic ANP and significantly increases splenic ANP. Nicotine fails to regulate TNF or ANP after splenectomy. Splenectomy significantly reduces systemic TNF and ANP (p < 0.07). Splenectomy significantly improves survival and decreases ANP after CLP. Conclusions: Cholinergic stimulation requires spleen to modulate systemic pro-inflammatory cytokines and ANP. Cholinergic stimulation increases splenic ANP and decreases systemic ANP. The cholinergic anti-inflammatory pathway may regulate systemic inflammation by limiting ANP release and enhancing splenic ANP signaling.