Interactions of benztropine, atropine and ketamine with veratridine-activated sodium channels: effects on membrane depolarization, K+-efflux and neurotransmitter amino acid release.
1. The effect of benztropine, atropine and ketamine on veratridine-induced efflux of K+, membrane depolarization and release of amino acid neurotransmitters was investigated in the preparation of rat brain synaptosomes. 2. All three drugs inhibited in a concentration-dependent manner the processes measured: the most effective compound was benztropine which exhibited an approximate Kd of 2 microM. The inhibition was not competitive in nature. 3. The veratridine titration curves in the presence of drugs were sigmoid with Hill coefficients of about 1.4. 4. At higher concentrations, benztropine, atropine and ketamine blocked uptake of amino acid neurotransmitters into synaptosomes. 5. It is postulated that benztropine, atropine and ketamine interfere with the veratridine-activated influx of sodium into synaptosomes through voltage-dependent channels by acting at the same site as local anaesthetics. Interactions at this site alter allosterically binding and action of veratridine. In addition, at higher concentrations the drugs interact with the carrier proteins for amino acid neurotransmitters and block their transport.
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology*; D001590:Benztropine / Q000494:pharmacology*; D001834:Body Water / Q000378:metabolism; D066298:In Vitro Techniques; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D015222:Sodium Channels / Q000187:drug effects*; D013574:Synaptosomes / Q000187:drug effects; D014326:Tropanes / Q000494:pharmacology*; D014701:Veratridine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014702:Veratrine / Q000031:analogs & derivatives*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000596:Amino Acids; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D015222:Sodium Channels; D014326:Tropanes; D001590:Benztropine; D005680:gamma-Aminobutyric Acid; D007649:Ketamine; D014701:Veratridine; D001285:Atropine; D014702:Veratrine; D011188:Potassium