Non-competitive inhibition of GABAA responses by a new class of quinolones and non-steroidal anti-inflammatories in dissociated frog sensory neurones.
1. The interaction of a new class of quinolone antimicrobials (new quinolones) and non-steroidal anti-inflammatory agents (NSAIDs) with the GABAA receptor-Cl- channel complex was investigated in frog sensory neurones by use of the internal perfusion and 'concentration clamp' techniques. 2. The new quinolones and the NSAIDs (both 10(-6)-10(-5) M) had little effect on the GABA-induced chloride current (ICI) when applied separately. At a concentration of 10(-4) M the new quinolones, and to a lesser degree the NSAIDs, produced some suppression of the GABA response. 3. The co-administration of new quinolones and some NSAIDs (10(-6)-10(-14) M) resulted in a marked suppression of the GABA response. The size of this inhibition was dependent on the concentration of either the new quinolone or the NSAID tested. The inhibitory potency of new quinolones in combination with 4-biphenylacetic acid (BPAA) was in rank order norfloxacin (NFLX) much greater than enoxacin (ENX) greater than ciprofloxancin (CPFX) much greater than ofloxacin (OFLX), and that of NSAIDs in combination with ENX was BPAA much greater than indomethacin = ketoprofen greater than naproxen greater than ibuprofen greater than pranoprofen. Diclofenac, piroxicam and acetaminophen did not affect GABA responses in the presence of ENX. 4. In the presence of ENX or BPAA, there was a small shift to the right of the concentration-response curve for GABA without any effect on the maximum response. However, the co-administration of these drugs suppressed the maximum of the GABA concentration-response curve, indicating a non-competitive inhibition, for which no voltage-dependency was observed.5. Simultaneous administration of ENX and BPAA also suppressed pentobarbitone (PB)-gated Icl. On the other hand, both PB and phenobarbitone reversed the inhibition of GABA-induced Ic, by coadministration of ENX and BPAA.6. The effect on GABAA responses of co-administration of new quinolones and NSAIDs was not via an interaction with benzodiazepine receptors coupled to the GABAA receptor, since this effect was not reversed by Rol5-1788 or diazepam.7. It is concluded that the co-administration of new quinolones and some of the NSAIDs inhibit GABAergic transmission, and could result in convulsions.
Yakushiji
T
T
Research Laboratories, Yoshitomi Pharmaceutical Industries Ltd., Japan.
Shirasaki
T
T
Akaike
N
N
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018118:Chloride Channels; D002712:Chlorides; D015365:Enoxacin / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D008565:Membrane Proteins / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects*; D010648:Phenylacetates / Q000494:pharmacology; D011892:Rana catesbeiana
D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018118:Chloride Channels; D002712:Chlorides; D058787:GABA-A Receptor Antagonists; D008565:Membrane Proteins; D010648:Phenylacetates; D015365:Enoxacin; C012776:biphenylylacetic acid