Choice of Anesthetic Combination Determines Ca2+Leak after Ischemia-Reperfusion Injury in the Working Rat Heart

BACKGROUND: There is a lack of studies investigating cardioprotection by common combinations of anesthetics. However, because a general anesthetic consists of a mixture of drugs with potentially interfering effects on signaling and cytoprotection, the most favorable combination should be used. METHODS: Working rat hearts were exposed to 20 min of ischemia and 30 min of reperfusion. Periischemic sevoflurane (2 vol-%), propofol (10 μM), or remifentanil (3 nM) (single treatments) and the three combinations thereof (combination treatments) were assessed for their ability to improve postischemic left ventricular work and to prevent intracellular Ca leak and overload. Beat-to-beat oscillations in intracellular [Ca] were measured using indo-1 AM. Phosphorylation of calcium/calmodulin-dependent protein kinase IIδ, ryanodine receptor-2, and phospholamban was determined. RESULTS: The single treatments with sevoflurane or remifentanil were highly protective with respect to functional recovery and Ca overload, but propofol, even at high concentrations, did not show similar protection. Sevoflurane combined with propofol completely lost its protection in the presence of low sedative propofol concentrations (≥1 μM), whereas remifentanil combined with propofol (10 μM) retained its protection. Propofol antagonism of sevoflurane protection was concentration-dependent and mimicked by the reactive oxygen species scavenger N-2-mercaptopropionyl-glycine. Addition of propofol to sevoflurane activated calcium/calmodulin-dependent protein kinase type IIδ and hyperphosphorylated the ryanodine receptor-2, consistent with causing a postischemic Ca leak from the sarcoplasmic reticulum. Remifentanil did not enhance sevoflurane protection. CONCLUSIONS: The choice of anesthetic combination determines the postischemic Ca leak and intracellular overload. The results from these experiments will help to design studies for optimizing perioperative cardioprotection in high-risk surgical patients.