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Introduction: Vasoplegic syndrome (VS), defined as systemic hypotension induced by severe vasodilation as a result of low systemic vascular resistance, is linked to increased morbidity and mortality after cardiac surgery. Although the firstchoice medications for treating VS are vasopressors like norepinephrine and vasopressin, some additional medications, including methylene blue (MB), are utilized as adjuvant therapy, including rescue therapy. The main mechanisms of action of MB responsible for the cardiovascular effects in the treatment of VS consist of the inhibition of the nitric oxide (NO) pathway. Recently, omeprazole (OME) has been suggested as effective in inhibiting the NO pathway. Objective: To evaluate the effects caused by OME and MB in an animal model of cardiac ischemia and reperfusion (CIR), and to identify new pharmacological strategies to prevent and/or attenuate the VS occurrence. Methods: Rats were treated intravenously (IV) with MB at 2 mg/kg and OME at 10 mg/kg before CIR. The rates of ventricular arrhythmias (VA), atrioventricular block (AVB), and lethality (LET) were recorded. The animals employed in this investigation were divided into the following experimental groups: (1) SS+CIR group (n=20): rats treated with a saline solution and submitted to CIR; (2) MB+CIR (n=12): rats treated with MB and submitted to CIR; (3) OME+CIR group (n=12): rats treated with OME and submitted to CIR. The Prism 8.0 program (GraphPad, Boston, MA, USA) was used for this analysis. Fisher's exact test was used to statistically assess the incidence rates of VA, AVB, and LET and analysis of variance (ANOVA) test, and then Tukey's post-test statistically assesses the serum concentrations of the cardiac lesion biomarkers CK-MB and TnI. When P < 0.05, the results were deemed statistically significant. Results: When comparing the MB+CIR (100%) and OME+CIR (100%) groups to the SS+CIR group (60%), there was a statistically significant difference in the incidence rates of AVB and LET, but not VA, suggesting that the administration of MB and OME before CIR elevated the AVB and LET incidence rates brought on by CIR. Rats submitted to CIR had higher serum levels of CK-MB in MB+CIR and OME+CIR groups than in the SS+CIR group, which suggests that MB or OME treatment before CIR elevated blood CK-MB levels but not TnI. Conclusion: Treating animals who underwent CIR with OME had the same effects as treating them with MB. This finding raises the prospect of employing OME alone or in conjunction with MB in treating VS. [ABSTRACT FROM AUTHOR]