ACTIVATION OF THE CA2-RETICULUM BY VOLATILE ANESTHETICS( RELEASE CHANNEL OF CARDIAC SARCOPLASMIC)

Background: Depression of myocardial contractility associated with the volatile anesthetics is well established clinically and experimentall y. The molecular mechanisms underlying this effect, however, have not been completely characterized. Whereas the Ca2+ release channel of car diac sarcoplasmic reticulum (SR) has been implicated as a potential ta rget contributing to anesthetic-induced myocardial depression, the eff ect of the volatile anesthetics on this protein have not been characte rized at the isolated, single-channel level. The authors sought to ide ntify changes in channel gating and conductance resulting from exposur e to halothane, enflurane, and; isoflurane that would contribute to th e associated negative inotropy, as well as to explain the observation that isoflurane causes less contractile depression than either halotha ne or ennurane. Methods: Vesicles enriched in SR were prepared from po rcine left ventricular tissue. Fusion of these vesicles with artificia l lipid bilayers under the experimental conditions provided Single-cha nnel recordings of the SR Ca2+ release channel. The gating properties and the conductance of these channels were determined in the presence and absence of clinical concentrations of halothane, enflurane, and is oflurane. Results: Halothane (1.2 vol%) and enflurane (1.6 vol%) activ ated the Ca2+ release channel by increasing the open probability (frac tion of time that the channel is open) without altering the channel co nductance. These agents altered channel gating by increasing the durat ion of open events, rather than the number of open events. Isoflurane (1.4 vol%) had no effect on channel gating or conductance. Halothane c aused dose-dependent channel activation (0.2-1.5 vol%), and channel ac tivation was found to be reversible upon washout of halothane from the solutions bathing the lipid bilayer. Conclusions: Halothane and enflu rane gate the Ca2+ release channel into the open state without alterin g the channel conductance. An increase in the duration of open events results from halothane and enflurane, but does not occur in the presen ce of isoflurane. Activation of the SR Ca2+ release channel would lead to loss of SR stores of Ca2+ into the cytoplasm, which is rapidly mob ilized to the extracellular space. A net depletion of Ca2+ available f or excitation-contraction coupling would result. The observation that isoflurane does not alter gating of this channel contributes to the un derstanding of the molecular mechanisms by which isoflurane depresses myocardial contractility less than halothane and enflurane.