Abstract Body (Do not enter title and authors here): Introduction: Cardiac sympathoexcitation is a major contributor to the pathogenesis of ventricular tachyarrhymias (VTs) during ischemia reperfusion (I/R) and chronic myocardial infarction (MI). Afferent network connections in the spinal cord control sympathetic output to the heart. Our team reported spinal cord stimulation (SCS) decreased cardiac sympathoexcitation and reduced VTs during ischemia. RNAsequencing data revealed that oxytocin (OXT) receptor is significantly upregulated with SCS; however, whether OXT alone can modulate the cardiospinal neural network to reduce sympathoexcitation and VTs is unknown. Hypothesis: Both intranasal (IN) and intrathecal (IT) administration of oxytocin agonist reduce sympathoexcitation, VTs, and cellular activation. Methods: Two models of cardiac ischemia were used in Yorkshire domestic swine. In acute I/R, a suture was placed around the left anterior descending (LAD) coronary artery, after sternotomy. Chronic infarction (MI) was created by polystyrene microspheres (1ml) injected via a 3mm angioplasty balloon catheter to the left circumflex under fluoroscopy guidance. Animals recovered post-MI for 6-8wk. Intrathecally, OXT agonist (TGOTFisher Scientific, 90ug) was delivered via catheter placed at T1-T4 level. Intranasally, OXT Pitocin (20U) was administered. The therapeutic doses were chosen based on dose response curve experiments, determining lowest effective dose based on activation recovery interval (ARI) change. We compared ventricular excitability, and arrhythmic substrate between experimental groups by measuring ARI, a validated marker for action potential duration. ARI changes signify the functional density and regional myocardial responses to interventions. After, T2-T4 spinal cord was collected postmortem for molecular analysis. Fluorescence in situ hybridization protocol for RNAscope Fluorescent v2 Assay (ACD) was followed. Cell counts represented as 3 puncta or more centered around DAPI. Results: We report that both ARI and VTs significantly increased as a result of I/R and MI and returned to baseline with administration of both IN and IT OXT (p<0.05, two-way ANOVA n=6-8 animals) Additionally, FOS, a marker of cellular activation, increased with I/R and MI and decreased as a result of both IT and IN OXT in the spinal cord. Conclusions: By evaluating the role of OXT in reducing cardiac sympathoexcitation at the level of the spinal cord, we provide insights into developing new pharmacologic therapies.