Fluoroquinolone-induced motor changes in the guinea-pig isolated ileum

The effects of norfloxacin and enoxacin were examined on spontaneous motor activity in the guinea-pig isolated ileum. Micromolar concentrations of bot h compounds caused a biphasic response consisting of relaxation followed by transient contraction. Relaxation to norfloxacin, which was unaffected by phentolamine, propranolol and hyoscine (each at 1 mu M), was partially sens itive to tetrodotoxin (1 mu M). This indicates that the response is partly mediated by nonadrenergic non-cholinergic (NANC) inhibitory nerves, and par tly related to a direct action on the smooth muscle. Apamin (0.1 mu M) and suramin (300 mu M) inhibited norfloxacin-induced relaxations to an extent s imilar to that of tetrodotoxin. Conversely, N-G-nitro-L-arginine (300 mu M) was ineffective. In the presence of theophylline (100 mu M) and 3-isobutyl -1-methylxanthine (10 mu M), norfloxacin caused relaxation less effective t han when added alone. Based on this observation, the NANC component of the relaxation apparently depends on ATP release, whereas the direct component might be due, at least in part, to phosphodiesterase inhibition. Norfloxaci n-induced contractions were neurogenic and cholinergic in nature. They were reduced by indomethacin or S-ketoprofen (both at 0.01-1 mu M) and suramin (300 mu M), suggesting involvement of local prostaglandin production probab ly induced by ATP release. Previous findings revealed that norfloxacin acte d as a non-competitive antagonist at enteric GABA, receptors. In this study the same property was shared by enoxacin against the contractile response to 3-aminopropane sulphonic acid (3-APS), a GABA(A) receptor agonist. In co nclusion, fluoroquinolones exert inhibitory and excitatory effects in the g uinea-pig ileum. These are mediated by ATP, prostaglandin and acetylcholine release that might underlie, at least in part, the alterations of gastroin testinal motility observed after fluoroquinolone administration. Furthermor e, isolated intestinal preparations might be useful to predict the GABA(A)- antagonist potential of this class of compounds.