Background/Objectives: Treatment of patients with myocardial ischemic diseases crucially involves cardiac reperfusion (CR). However, oxidative stress and tissue lesions caused by CR may also lead to lethal complications, such as arrythmias and vasoplegic syndrome (VS). Although methylene blue (MB) has long been used to treat VS due to cardiac ischemia and reperfusion (CIR) and/or surgery because of its vascular effects, MB’s effects on the heart are unclear. Therefore, we investigated the potential cardioprotective or arrhythmogenic effects of MB in an animal model of CIR. To this end, 12–16-week-old male Wistar rats were divided into four experimental groups: (a) rats subjected to SHAM surgery with no ischemia; (b) rats subjected to CIR and treated with a vehicle (SS + CIR); and (c) rats subjected to CIR and treated with 2 mg/kg i.v. MB before ischemia (MB + ISQ) or (d) after ischemia but before reperfusion (ISQ + MB). An ECG analysis was used to evaluate the incidence of ventricular arrhythmias (VAs), atrioventricular blocks (AVBs), and lethality (LET) resulting from CIR. After CIR, rat hearts were removed for histopathological analysis and lipid hydroperoxide (LH) measurements. Results: The incidence of VA, AVB, and LET was significantly increased in the MB + ISQ group (VA = 100%; AVB = 100%; LET = 100%) but significantly reduced in the ISQ + MB group (VA = 42.8%; AVB = 28.5%; LET = 21.4%) compared with the SS + CIR group (VA = 85.7%; AVB = 71.4%; LET = 64.2%). LH concentration was significantly reduced in both MB-treated groups, but myocardial injuries were increased only in the MB + ISQ group when compared with the SS + CIR group. Conclusions: These results indicate that MB produces a biphasic effect on CIR, with cardiotoxic effects when administered before cardiac ischemia and cardioprotective effects when administered after ischemia but before cardiac reperfusion.

Proton pump inhibitors (PPIs) are widely prescribed for acid-related disorders and are generally considered safe for short-term use. However, increasing experimental and clinical evidence suggests potential cardiovascular effects associated with chronic exposure, possibly related to endothelial dysfunction and impaired nitric oxide bioavailability. Therefore, we decided to investigate whether the cardiovascular effects of omeprazole are dependent on the timing of administration in a model of cardiac ischemia–reperfusion (CIR) in normotensive Wistar rats (NWR) and spontaneously hypertensive rats (SHR). Twelve- to sixteen-week-old male NWR and SHR were allocated into four groups: (1) SHAM: NWR and SHR were submitted to surgery with no ischemia; (2) (SS + CIR): NWR and SHR were treated with a 0.9% saline solution and submitted to CIR; and (3) (OME + ISQ): NWR and SHR were treated with 10 mg/kg i.v. omeprazole (OME) before cardiac ischemia and submitted to CIR or (4) after cardiac ischemia but before cardiac reperfusion (ISQ + OME). Electrocardiograms were monitored to assess ventricular arrhythmias (VA), atrioventricular block (AVB), and lethality (LET). Serum creatine kinase-MB (CK-MB) levels were quantified, and histopathological analyses were performed to evaluate the degree of myocardial injury in the different study groups. Administration of OME prior to cardiac ischemia increased the incidence of VA, AVB, LET, and serum CK-MB levels in both NWR and SHR. In contrast, administration before cardiac reperfusion did not exacerbate cardiac injury and was associated with the attenuation of electrophysiological instability. Histopathological findings corroborated the biochemical and functional outcomes. OME, when administered prior to cardiac ischemia, worsens both cardiac arrhythmias and myocardial injury; however, administration immediately prior to cardiac reperfusion does not increase cardiac arrhythmias and decreases myocardial injury in both NWR and SHR.