The effects of general anesthetics on norepinephrine release from isolated rat cortical nerve terminals.
Intravenous and volatile general anesthetics inhibit norepinephrine (NE) release from sympathetic neurons and other neurosecretory cells. However, the actions of general anesthetics on NE release from central nervous system (CNS) neurons are unclear. We investigated the effects of representative IV and volatile anesthetics on [(3)H]NE release from isolated rat cortical nerve terminals (synaptosomes). Purified synaptosomes prepared from rat cerebral cortex were preloaded with [(3)H]NE and superfused with buffer containing pargyline (a monoamine oxidase inhibitor) and ascorbic acid (an antioxidant). Basal (spontaneous) and stimulus-evoked [(3)H]NE release was evaluated in the superfusate in the absence or presence of various anesthetics. Depolarization with increased concentrations of KCl (15-20 mM) or 4-aminopyridine (0.5-1.0 mM) evoked concentration- and Ca(2+)-dependent increases in [(3)H]NE release from rat cortical synaptosomes. The IV anesthetics etomidate (5-40 microM), ketamine (5-30 microM), or pentobarbital (25-100 microM) did not affect basal or stimulus-evoked [(3)H]NE release. Propofol (5-40 microM) increased basal [(3)H]NE release and, at larger concentrations, reduced stimulus-evoked release. The volatile anesthetic halothane (0.15-0.70 mM) increased basal [(3)H]NE release, but did not affect stimulus-evoked release. These findings demonstrate drug-specific stimulation of basal NE release. Noradrenergic transmission may represent a presynaptic target for selected general anesthetics in the CNS. Given the contrasting effects of general anesthetics on the release of other CNS transmitters, the presynaptic actions of general anesthetics are both drug- and transmitter-specific.


CONCLUSIONS
General anesthetics affect synaptic transmission both by altering neurotransmitter release and by modulating postsynaptic responses to transmitter. Anesthetics exert both drug-specific and transmitter-specific effects on transmitter release: therapeutic concentrations of some anesthetics stimulate basal, but not evoked, norepinephrine release, in contrast to evoked glutamate release, which is inhibited.
Pashkov
Victor N
VN
Departments of Anesthesiology and Pharmacology, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021, USA.
Hemmings
Hugh C
HC
D000759:Adjuvants, Anesthesia / Q000494:pharmacology; D000778:Anesthetics, Dissociative / Q000494:pharmacology; D018681:Anesthetics, General / Q000494:pharmacology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005045:Etomidate / Q000494:pharmacology; D006221:Halothane / Q000494:pharmacology; D066298:In Vitro Techniques; D007649:Ketamine / Q000494:pharmacology; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D010424:Pentobarbital / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology; D051381:Rats; D017661:Receptors, Presynaptic / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D000759:Adjuvants, Anesthesia; D000778:Anesthetics, Dissociative; D018681:Anesthetics, General; D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D017661:Receptors, Presynaptic; D004533:Egtazic Acid; D011189:Potassium Chloride; D007649:Ketamine; D010424:Pentobarbital; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D006221:Halothane; D009638:Norepinephrine; D015742:Propofol; D005045:Etomidate