Protein kinase C-ε primes the cardiac sarcolemmal adenosine triphosphate-sensitive potassium channel to modulation by isoflurane

Background. Cardioprotection by volatile anesthetic-induced preconditioning is known to involve intracellular signaling pathways. Recent studies have shown that protein kinase C (PKC) plays an important role in anesthetic-induced preconditioning. In this study, the effects of the activation of specific isozymes of PKC, specifically PKG-epsilon and -delta, on the modulation of the sarcolemmal adenosine triphosphate-sensitive potassium (sarcK(ATP)) channel by isoflurane were investigated. Methods: The sarcK(ATP) current was measured in ventricular myocytes isolated from guinea pig hearts using the whole cell configuration of the patch clamp technique. Peptides that induced the translocation of specific PKC isozymes were used to activate PKG-epsilon and PKC-delta. Results: Under whole cell conditions, isoflurane alone was unable to elicit the opening of the sarcKATP channel. Pretreatment with the specific PKG-epsilon activator, PP106, primed the sarcK(ATP) channel to open in the presence of isoflurane. The resulting sarcKATP current densities in the presence of 0.88 mm isoflurane were 6.5 +/- 6.0 pA/pF (n = 7) and 40.4 +/- 18.2 pA/pF (n = 7) after pretreatment with 100 and 200 nm PP106, respectively. The PKG-epsilon antagonist PP93 abolished this effect. A scrambled peptide of the PKC-epsilon activator PP105 did not prime the sarcK(ATP) channel. The PKC-delta activator PP114 was significantly less effective in priming the sarcK(ATP) channel. 5-Hydroxydecanoate significantly attenuated the effect of the PKC-epsilon activator on the sarcK(ATP) channel. In addition, immunohistochemical analysis showed that the PKC-epsilon isoform translocated to both the mitochondria and sarcolemma after anesthetic-induced preconditioning, whereas the PKC-delta isoform translocated to the mitochondria. Conclusion: The PKG-epsilon isozyme primed the sarcK(ATP) channel to open in the presence of isoflurane. The PKC-delta isozyme was significantly less effective in modulating the isoflurane effect on this channel.