Effects of propofol on sodium channel-dependent sodium influx and glutamate release in rat cerebrocortical synaptosomes.
BACKGROUND
Previous electrophysiologic studies have implicated voltage-dependent Na+ channels as a molecular site of action for propofol. This study considered the effects of propofol on Na+ channel-mediated Na+ influx and neurotransmitter release in rat brain synaptosomes (isolated presynaptic nerve terminals).


METHODS
Purified cerebrocortical synaptosomes from adult rats were used to determine the effects of propofol on Na+ influx through voltage-dependent Na+ channels (measured using 22Na+) and intracellular [Na+] (measured by ion-specific spectrofluorimetry). For comparison, the effects of propofol on synaptosomal glutamate release evoked by 4-aminopyridine (Na+ channel dependent), veratridine (Na+ channel dependent), KCi (Na+ channel independent) were studied using enzyme-coupled fluorimetry.


RESULTS
Propofol inhibited veratridine-evoked 22Na+ influx (inhibitory concentration of 50% [IC50] = 46 microM; 8.9 microM free) and changes in intracellular [Na+] (IC50 = 13 microM; 6.3 microM free) in synaptosomes in a dose-dependent manner. Propofol also inhibited 4-aminopyridine-evoked (IC50 = 39 microM; 19 microM free) and veratridine (20 microM)-evoked (IC50 = 30 microM; 14 microM free), but not KCi-evoked (up to 100 microM) glutamate release from synaptosomes.


CONCLUSIONS
Inhibition of Na+ channel-mediated Na+ influx, increased in intracellular [Na+], and glutamate release occurred in synaptosomes at concentrations of propofol achieved clinically. These results support a role for neuronal voltage-dependent Na+ channels as a molecular target for presynaptic general anesthetic effects.
Ratnakumari
L
L
Department of Anesthesiology, Cornell University Medical College, New York, New York 10021, USA.
Hemmings
H C
HC
D015761:4-Aminopyridine / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D011189:Potassium Chloride / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D014701:Veratridine / Q000494:pharmacology
D018686:Anesthetics, Intravenous; D015220:Calcium Channels; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D018698:Glutamic Acid; D011189:Potassium Chloride; D014701:Veratridine; D012964:Sodium; D015761:4-Aminopyridine; D000254:Sodium-Potassium-Exchanging ATPase; D015742:Propofol