BACKGROUND - Pretreatment with the volatile anesthetic sevoflurane protects cardiomyocytes against subsequent ischemic episodes caused by a protein kinase C (PKC)-δ mediated preconditioning effect. Sevoflurane directly modulates cardiac Ca handling, and because Ca also serves as a mediator in other cardioprotective signaling pathways, possible involvement of the Na/Ca exchanger (NCX) in relation with PKC-δ in sevoflurane-induced cardioprotection was investigated. METHODS AND RESULTS - Isolated right ventricular rat trabeculae were subjected to simulated ischemia and reperfusion (SI/R), consisting of superfusion with hypoxic glucose-free buffer for 40 minutes after rigor development, followed by reperfusion with normoxic glucose containing buffer. Preconditioning with sevoflurane before SI/R improved isometric force development during contractile recovery at 60 minutes after the end of hypoxic superfusion (83±7% [sevo] versus 57±2% [SI/R];n=8; P<0.01). Inhibition of the reverse mode of the NCX by KB-R7943 (10 μmol/L) or SEA0400 (1 μmol/L) during preconditioning attenuated the protective effect of sevoflurane. KB-R7943 and SEA0400 did not have intrinsic effects on the contractile recovery. Furthermore, inhibition of the NCX in trabeculae exposed to sevoflurane reduced sevoflurane-induced PKC-δ translocation toward the sarcolemma, as demonstrated by digital imaging fluorescent microscopy. The degree of PKC-δ phosphorylation at serine as determined by western blot analysis was not affected by sevoflurane. CONCLUSIONS - Sevoflurane-induced cardioprotection depends on the NCX preceding PKC-δ translocation presumably via increased NCX-mediated Ca influx. This may suggest that increased myocardial Ca load triggers the cardioprotective signaling cascade elicited by volatile anesthetic agents similar to other modes of preconditioning.