Background. Sevoflurane protects the myocardium against ischaemic injury through protein kinase C (PKC) activation, mitochondrial KATP +-channel (mitoKATP +) opening and production of reactive oxygen species (ROS). However, it is unclear whether the type of ischaemia determines the involvement of these signalling molecules. We therefore investigated whether hypoxia (HYP) or metabolic inhibition (MI), which differentially inhibit the mitochondrial electron transport chain (ETC), are comparable concerning the relative contribution of PKC, mitoKATP + and ROS in sevoflurane-induced cardioprotection. Methods. Rat right ventricular trabeculae were isolated and isometric contractile force (Fdev) was measured. Trabeculae were subjected to HYP (hypoxic glucose-free buffer; 40 min) or MI (glucose-free buffer, 2 mM cyanide; 30 min), followed by 60 min recovery (60 min). Contractile recovery (Fdev,rec) was determined at the end of the recovery period and expressed as a percentage of Fdev before hypoxia or MI, respectively. Chelerythrine (CHEL; 6 μM), 5-hydroxydecanoic acid sodium (100 μM) and n-(2-mercaptopropionyl)-glycine (MGP; 300 μM) were used to inhibit PKC, mitoKATP + and ROS, respectively. Results. Fdev,rec after HYP was reduced to 47 (3)% (P & lt;0.001 vs control; n=5) whereas MI reduced Fdev,rec to 28 (5)% (P<0.001 vs control; n=5). A 15 min period of preconditioning with sevoflurane (3.8%) equally increased contractile recovery after HYP [76 (9)%; P <0.05 vs HYP] and MI [67 (8)%; P <0.01 vs MI]. Chelerythrine, 5-hydroxydecanoate and n-(2-mercaptopropionyl)-glycine abolished the protective effect of sevoflurane in both ischaemic models. Trabeculae subjected to HYP or MI did not demonstrate any increased apoptotic or necrotic markers. Conclusions. mitoKATP + and ROS are involved in sevoflurane-induced cardioprotection after HYP or MI, suggesting that the means of mitochondrial ETC inhibition does not determine the signal transduction pathway for cardioprotection by anaesthetics.