The SAFE pathway is involved in the postconditioning mechanism of oxytocin in isolated rat heart.

•Oxytocin triggers anti-infarct, anti-arrhythmia and anti-apoptotic effects through SAFE pathway activation against I/R injury in the early reperfusion phase.•STAT3 and NOS inhibitors and a mitoKATP blocker abrogated the cardioprotective effects of oxytocin.•Oxytocin evokes NO release, mitoKATP opening and JAK/STAT3 activation to provide cardioprotective effects against IR injury.•Oxytocin through SAFE pathway activation protects cardiomyocites against I/R injury and it considered as a clinically useful drug in patients with coronary artery diseases.