STAUROSPORINE, A PROTEIN-KINASE-C INHIBITOR, DECREASES THE GENERAL ANESTHETIC REQUIREMENT IN RANA-PIPIENS TADPOLES

Protein kinase C, the intracellular effector for the inositol phosphate-mediated signal transduction pathway, plays a key role in neurotransmission in the central nervous system. Although the in vitro activity of protein kinase C is inhibited by therapeutic concentrations of volatile anesthetics, the relation of this effect to in vivo obtundation has not been established. If obtundation by volatile anesthetics involves protein kinase C inhibition, then an inhibitor of this enzyme should decrease the anesthetic requirement. To test this hypothesis, we compared the EC50s of halothane and diethylether for loss of the righting reflex in Rana pipiens tadpoles pretreated with staurosporine and in untreated controls. Anesthetic concentrations were confirmed by gas chromatography and staurosporine concentrations by ultraviolet absorbance spectrophotometry Results obtained in more than 1000 animals indicated that pretreatment with staurosporine concentrations in the nanomolar range significantly decreased the EC50 for both halothane (68% of control; P < 0.035) and diethylether (41% of control; P < 0.001). This finding implies that protein kinase C inhibition may play a role in general anesthetic-induced obtundation.