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 possibility that general anesthetics produce their effect on BK channels by disrupting the phospholipase A(2) (PLA(2))-arachidonic acid signal transduction 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 halothane (0.6 mM), ketamine (100 mu M), or etomidate (10 mu M) that would 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 quinacrine (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 anesthetics inhibition. Aristolochic acid and ketamine significantly inhibit the PLA(2)-mediated production of arachidonic acid in GH(3) cells.