A POSSIBLE ROLE FOR PHOSPHOLIPASE A(2) IN THE ACTION OF GENERAL-ANESTHETICS

General anesthetics inhibit Ca2+-activated potassium (BK) channels at clinically relevant concentrations. This study examined the possibilit y that general anesthetics produce their effect on BK channels by disr upting the phospholipase A(2) (PLA(2))-arachidonic acid signal transdu ction pathway. Treatment of excised patches with exogenous arachidonic acid (2.5 mu M) resulted in a 3.6 +/- 1.3-fold increase in BK channel activity. Subsequent exposure of these patches to concentrations of h alothane (0.6 mM), ketamine (100 mu M), or etomidate (10 mu M) that wo uld normally block the channel by similar to 60-80% in the absence of arachidonic acid did not reduce the channel activity. Arachidonic acid resulted in a significant increase in the 50% effective concentration for the ketamine dose-response curve from 3.4 +/- 0.4 to 693 +/- 379 mu M (P < 0.001) as well as a significant decrease in slope from 1.40 +/- 0.21 to 0.59 +/- 0.05 (P < 0.001). The PLA(2) inhibitors quinacrin e (1 mu M), aristolochic acid (250 mu M), and octadecylbenzoylacrylic acid (7 mu M) inhibited BK channels by 61 +/- 6, 47 +/- 2, and 30 +/- 9%, respectively, and in a manner indistinguishable from general anest hetics inhibition. Aristolochic acid and ketamine significantly inhibi t the PLA(2)-mediated production of arachidonic acid in GH(3) cells.