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MR activation, in acute myocardial infarction (AMI), worsens cardiac function, and increase NHE activity contributing to the deleterious process. In contrast, effects of GR activation are not fully understood, probably because of the controversial scenario generated by using different doses or potencies of corticosteroids.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aims<\/jats:title><jats:p>We tested the hypothesis that an acute dose of hydrocortisone (HC), a low\u2010potency glucocorticoid, in a murine model of AMI could be cardioprotective by regulating NHE1 activity, leading to a decrease in oxidative stress.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>Isolated hearts from Wistar rats were subjected to regional ischemic protocol. HC (10\u2009nmol\/L) was added to the perfusate during early reperfusion. Infarct size and oxidative stress were determined. Isolated papillary muscles from non\u2010infarcted hearts were used to evaluate HC effect on sodium\u2010proton exchanger 1 (NHE1) by analysing intracellular pH recovery from acute transient acidosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>HC treatment decreased infarct size, improved cardiac mechanics, reduced oxidative stress after AMI, while restoring the decreased level of the pro\u2010fusion mitochondrial protein MFN\u20102. Co\u2010treatment with the GR\u2010blocker Mifepristone avoided these effects. HC reduced NHE1 activity by increasing the NHE1 pro\u2010inhibiting Ser648 phosphorylation site and its upstream kinase AKT. HC restored the decreased AKT phosphorylation and anti\u2010apoptotic BCL\u20102 protein expression detected after AMI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results provide the first evidence that acute HC treatment during early reperfusion induces cardioprotection against AMI, associated with a non\u2010genomic HC\u2010triggered NHE1 inhibition by AKT and antioxidant action that might involves mitochondrial dynamics improvement.<\/jats:p><\/jats:sec>","DOI":"10.1111\/eci.14172","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T09:15:25Z","timestamp":1706692525000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Hydrocortisone cardioprotection in ischaemia\/reperfusion injury involves antioxidant mechanisms"],"prefix":"10.1111","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8561-5239","authenticated-orcid":false,"given":"Daiana S.","family":"Escudero","sequence":"first","affiliation":[{"name":"Centro de Investigaciones Cardiovasculares \u2018Dr. Horacio E. 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