Selective antagonism of the GABA sub(A) receptor by ciprofloxacin and biphenylacetic acid

• Published in: British journal of pharmacology 1997-10, Vol.122 (3), p.584-590
• Main Authors: Green, MA, Halliwell, R F
• Format: Article
• Language: English
• ISSN: 0007-1188

1 Previous studies have shown that ciprofloxacin and biphenylacetic acid (BPAA) synergistically inhibit gamma -aminobutyric acid (GABA) sub(A) receptors. In the present study, we have investigated the actions of these two drugs on other neuronal ligand-gated ion channels. 2 Agonist-evoked depolarizations were recorded from rat vagus and optic nerves in vitro by use of an extracellular recording technique. 3 GABA (50 mu M)-evoked responses, in the vagus nerve in vitro, were inhibited by bicuculline (0.3-10 mu M) and picrotoxin (0.3-10 mu M), with IC sub(50) values and 95% confidence intervals (CI) of 1.2 mu M (1.1-1.4) and 3.6 mu M (3.0-4.3), respectively, and were potentiated by sodium pentobarbitone (30 mu M) and diazepam (1 mu M) to (mean plus or minus s.e.mean) 168 plus or minus 18% and 117 plus or minus 4% of control, respectively. 5-Hydroxytryptamine (5-HT; 0.5 mu M)-evoked responses were inhibited by MDL 72222 (1 mu M) to 10 plus or minus 4% of control; DMPP (10 mu M)-evoked responses were inhibited by hexamethonium (100 mu M) to 12 plus or minus 5% of control, and alpha beta MeATP (30 mu M)-evoked responses were inhibited by PPADS (10 mu M) to 21 plus or minus 5% of control. Together, these data are consistent with activation of GABA sub(A), 5-HT sub(3), nicotinic ACh and P2 sub(x) receptors, respectively. 4 Ciprofloxacin (10-3000 mu M) inhibited GABA sub(A)-mediated responses in the vagus nerve with an IC sub(50) (and 95% CI) of 202 mu M (148-275). BPAA (1-1000 mu M) had little or no effect on the GABA sub(A)-mediated response but concentration-dependently potentiated the effects of ciprofloxacin by up to 33,000 times. 5 Responses mediated by 5-HT sub(3), nicotinic ACh and P2 sub(x) receptors in the vagus nerve and strychnine-sensitive glycine receptors in the optic nerve were little or unaffected by ciprofloxacin (100 mu M), BPAA (100 mu M) or the combination of these drugs (both at 100 mu M). 6 GABA (1 mM)-evoked responses in the optic nerve were inhibited by bicuculline with an IC sub(50) of 3.6 mu M (2.8-4.5), a value not significantly different from that determined in the vagus nerve. Ciprofloxacin also inhibited the GABA-evoked response with an IC sub(50) of 334 mu M (256-437) and BPAA (100 mu M) potentiated these antagonist effects. However, the magnitude of the synergy was 48 times less than that seen in the vagus nerve. 7 These data indicate that ciprofloxacin and BPAA are selective antagonists of GABA sub(A) receptors, an action that may