title: Reserpine: interactions with batrachotoxin and brevetoxin sites on voltage-dependent sodium channels.
abstract: Reserpine inhibited batrachotoxin-elicited sodium influx in guinea pig brain synaptoneurosomes with an IC50 of about 1 microM. In the presence of brevetoxin the IC50 increased to about 80 microM. Reserpine inhibited binding of batrachotoxinin-A [3H]benzoate ([3H]BTX-B) binding in a complex manner causing a partial inhibition from 0.001 to 0.08 microM, then a rebound stimulation from 0.1 to 0.8 microM, followed by complete inhibition by 80 microM. The stimulation was prevented by the presence of brevetoxin; reserpine then smoothly inhibited binding with an IC50 of about 1 microM. Reserpine at 1 microM slightly reduced the off-rate of [3H]BTX-B binding measured in the presence of veratridine, while at a concentration of 50 microM it enhanced the off-rate, presumably by an allosteric mechanism. Reserpine at 0.3-10 microM elicited a partial inhibition of the binding of [3H]brevetoxin-3. The local anesthetic dibucaine had effects similar to reserpine: It partially inhibited binding of [3H]brevetoxin. The presence of brevetoxin reduced the potency of dibucaine as an inhibitor of batrachotoxin-elicited sodium influx from an IC50 of about 2 microM to an IC50 of about 50 microM. The results suggest that reserpine binds at both a local anesthetic site to cause allosteric inhibition of batrachotoxin-binding and action, but that it also binds to another site causing, like brevetoxin, an enhancement of batrachotoxin-binding and action. Local anesthetics also may bind to the brevetoxin site.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Flowers
authors.forename: Kenolisa
authors.initials: K
authors.lastname: Onwueme
authors.forename: Cyrus R
authors.initials: CR
authors.lastname: Creveling
authors.forename: John W
authors.initials: JW
authors.lastname: Daly
mesh_terms: D000818:Animals; D000992:Antitoxins / Q000494:pharmacology; D001496:Batrachotoxins / Q000493:pharmacokinetics / Q000633:toxicity*; D001665:Binding Sites; D002540:Cerebral Cortex / Q000502:physiology; D003992:Dibucaine / Q000494:pharmacology; D006168:Guinea Pigs; D007700:Kinetics; D008387:Marine Toxins / Q000493:pharmacokinetics / Q000633:toxicity*; D009498:Neurotoxins / Q000633:toxicity*; D035964:Oxocins / Q000493:pharmacokinetics / Q000633:toxicity*; D012110:Reserpine / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D000095702:Polyether Toxins
chemical_list: D000992:Antitoxins; D001496:Batrachotoxins; D003992:Dibucaine; D008387:Marine Toxins; D009498:Neurotoxins; D035964:Oxocins; D012110:Reserpine; D015222:Sodium Channels; C053342:brevetoxin; D000095702:Polyether Toxins