Activation of the Ca2+ release channel of cardiac sarcoplasmic reticulum by volatile anesthetics.

BACKGROUND

Depression of myocardial contractility associated with the volatile anesthetics is well established clinically and experimentally. The molecular mechanisms underlying this effect, however, have not been completely characterized. Whereas the Ca2+ release channel of cardiac sarcoplasmic reticulum (SR) has been implicated as a potential target contributing to anesthetic-induced myocardial depression, the effect of the volatile anesthetics on this protein have not been characterized at the isolated, single-channel level. The authors sought to identify changes in channel gating and conductance resulting from exposure to halothane, enflurane, and isoflurane that would contribute to the associated negative inotropy, as well as to explain the observation that isoflurane causes less contractile depression than either halothane or enflurane.

METHODS

Vesicles enriched in SR were prepared from porcine left ventricular tissue. Fusion of these vesicles with artificial lipid bilayers under the experimental conditions provided single-channel 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 isoflurane.

RESULTS

Halothane (1.2 vol%) and enflurane (1.6 vol%) activated the Ca2+ release channel by increasing the open probability (fraction of time that the channel is open) without altering the channel conductance. These agents altered channel gating by increasing the duration of open events, rather than the number of open events. Isoflurane (1.4 vol%) had no effect on channel gating or conductance. Halothane caused dose-dependent channel activation (0.2-1.5 vol%), and channel activation was found to be reversible upon washout of halothane from the solutions bathing the lipid bilayer.

CONCLUSIONS

Halothane and enflurane gate the Ca2+ release channel into the open state without altering the channel conductance. An increase in the duration of open events results from halothane and enflurane, but does not occur in the presence of isoflurane. Activation of the SR Ca2+ release channel would lead to loss of SR stores of Ca2+ into the cytoplasm, which is rapidly mobilized to the extracellular space. A net depletion of Ca2+ available for excitation-contraction coupling would result. The observation that isoflurane does not alter gating of this channel contributes to the understanding of the molecular mechanisms by which isoflurane depresses myocardial contractility less than halothane and enflurane.