Inhibition by propofol of [~3H]-batrachotoxinin-A 20-α-benzoate binding to voltage-dependent sodium channels in rat cortical synaptosomes

摘要

1 Propofol (2,6 di-isopropylphenol), an intravenous general anaesthetic, blocks voltage-dependent Na~+ channels (Na~+ channels). In this study the interaction between propofol and Na~+ channels was analysed by examining its effects on neurotoxin binding to various receptor sites of the Na~+ channel in rat cerebrocortical synaptosomes. 2 Propofol (10-200 μM) exhibited concentration-dependent inhibition of equilibrium binding of [~3H]-batrachotoxinin-A 20-α-benzoate ([~3H]-BTX-B) to receptor site 2 of the Na~+ channel (mean IC_(50) = 26 μM); 6.5 μM) free). Scatchard analysis revealed that propofol significantly increased the K_D without affecting the B_(max) for [~3H]-BTX-B binding. 3 Kinetic studies of [~3H]-BTX-B binding in the presence of various concentrations (25-200 μM) of propofol showed no significant changes in the association rate of [~3H]-BTX-B. However, propofol at 200 μM significantly increased the rate of dissociation of [~3H]-BTX-B, consistent with an indirect allosteric competitive mechanism of inhibition. 4 [~3H]-saxitoxin binding to receptor site 1 and [~3H]-brevetoxin-3 binding to receptor site 5 of the Na~+ channel were not inhibited by propofol (10-200 μM). 5 Propofol (10-100 μM) exhibited concentration-dependent inhibition of veratridine-evoked Na~+ influx either in the absence or presence of scorpion toxin with IC_(50) values of 46 μM (8.8 μM free) and 44 μM (8.5 μM free), respectively. 6 These results suggest that propofol inhibits voltage-dependent Na~+ channels due to a preferential interaction with the inactivated state of the channel. Blockade of Na~+ channels by propofol, which is known to inhibit glutamate release from synaptosomes, may contribute to its anaesthetic, anticonvulsant and neuroprotective properties.