A possible role for phospholipase a2 in the action of general
anesthetics.
Denson, D. D., R. T. Worrell, and D. C. Eaton.
Departments of Anesthesiolgy and Physiology and The Center for
Cellular and Molecular Signaling, Emory University School of
Medicine, Atlanta, Georgia, 30322
APStracts 2:0308C, 1995.
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-A2 (PLA2)-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) which would normally block the channel by
approximately 60-80% in the absence of arachidonic acid did not
reduce the channel activity . Arachidonic acid resulted in a
significant increase in the EC50 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 PLA2 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 PLA2 mediated production of arachidonic acid in GH3
cells.
Received 13 February 1995; accepted in final form 21 August 1995.
APS Manuscript Number C79-5.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 15 September 1995.