Sodium bicarbonate attenuates myocardial ischemia-reperfusion injury via activation of the splenic cholinergic anti-inflammatory pathway.

OBJECTIVE: The spleen plays a central role in mediating inflammatory responses during myocardial ischemia-reperfusion injury (IRI) via a neuroimmune axis involving vagal signaling and cholinergic modulation. Sodium bicarbonate (NaHCO3) has been implicated in the activation of a splenic cholinergic anti-inflammatory pathway, but its role in myocardial IRI remains incompletely defined. The present study aims to determine whether NaHCO3 administration before reperfusion attenuates myocardial injury by modulating splenic inflammatory signaling. METHODS: C57BL/6 mice underwent 40 minutes of left coronary artery occlusion, followed by 60 minutes of reperfusion. Ten minutes before reperfusion, mice received either intravenous phosphate-buffered saline, NaHCO3 (1 mEq/mL), or osmolality-matched hypertonic saline (5.8% NaCl). Additional groups received intraperitoneal NaHCO3 and a topical splenic or liver NaHCO3 rinse (1mEq/mL, 1 μL/g). Infarct size was quantified by triphenyltetrazolium chloride-phthalo blue staining as a percentage of risk region. Cytokines, acetylcholine levels, splenic signaling pathways, and monocyte polarization were assessed. RESULTS: Assessed risk region was comparable across groups. Intravenous NaHCO3 administration significantly reduced infarct size compared with phosphate-buffered saline and hypertonic saline controls (25 ± 3% vs 51 ± 4% and 46 ± 3%; P < .05). Intraperitoneal and topical splenic NaHCO3 produced similar infarct-sparing effects (P < .05), whereas topical hepatic rinse had no impact. NaHCO3 reduced inflammatory cytokines, reduced circulating plasma citrate synthase, increased plasma acetylcholine, and promoted M2 polarization of splenic monocytes. Arterial blood gas analysis demonstrated increased bicarbonate without significant changes in systemic pH. CONCLUSIONS: Acute NaHCO3 administration attenuates myocardial IRI through modulation of the splenic cholinergic anti-inflammatory pathway. These findings identify bicarbonate as a potential neuroimmune-targeting strategy for limiting reperfusion injury.