Activation of ATP-sensitive Potassium Channels by the Predominant Metabolite of Isoflurane in Rabbit Ventricular Myocytes

Background: Recent in vivo experimental evidence suggests that isoflurane-induced cardioprotection may involve $K_{ATP}$ channel activation. However, it was demonstrated that isoflurane inhibited $K_{ATP}$ channel activities in the inside-out patch mode. To explain this discrepancy, the present investigation tested the hypothesis that a metabolite of isoflurane, trifluoroacetic acid (TFA), contributes to isoflurnae-induced cardioprotection via $K_{ATP}$ channel activation during myocardial ischemia and reperfusion. Methods: Single ventricular myocytes were isolated from rabbit hearts by an enzymatic dissociation procedure. Patch-clamp techniques were used to record single-channel currents. $K_{ATP}$ channel activities were assessed before and after the application of TFA with the inside-out patch mode. Results: TFA enhanced channel activity in a concentration-dependent fashion. The concentration of TFA for half-maximal activation and the Hill coefficient were 0.03 mM and 1.2, respectively. TFA did not affect the single channel conductance of $K_{ATP}$ channels. Analysis of open and closed time distributions showed that TFA increased burst duration and decreased the interburst interval without changes in open and closed time distributions shorter than 5 ms. TFA diminished ATP sensitivity of $K_{ATP}$ channels in a concentration-response relationship for ATP. Conclusions: TFA, a metabolite of isoflurane, enhanced $K_{ATP}$ channel activity in a concentration-dependent fashion. These results imply that TFA could mediate isoflurane-induced cardioprotection via $K_{ATP}$ channel activation during myocardial ischemia and reperfusion.