Selective Inhibitory Effects of Niflumic Acid on 5-HT-induced Contraction of the Rat Isolated Stomach Fundus

The effects of niflumic acid (NFA), an inhibitor of calcium-activated chloride currents I(Cl(Ca)), were compared with the actions of the voltage-dependent calcium channel (VDCC) blocker nifedipine on 5-hydroxtryptamine (5-HT)- and acetylcholine (ACh)-induced contractions of the rat isolated fundus. NFA (1 - 30 microM) elicited a concentration-dependent inhibition of contractions induced by 5-HT (10 microM) with a reduction to 15. 5+/-6.0% of the control value at 30 microM. 1 microM nifedipine reduced 5-HT-induced contraction to 15.2+/-4.9% of the control, an effect not greater in the additional presence of 30 microM NFA. In contrast, the contractile response to ACh (10 microM) was not inhibited by NFA in concentrations </=100 microM, although this response was partly inhibited by nifedipine (1 microM) to 67.6+/-11. 8% of the control value. NFA (1 - 30 microM) did not affect contraction induced by either 20 mM or 60 mM KCl, suggesting that this drug was not acting via blockade of VDCCs or activation of potassium channels. In contrast, 3, 5-dichlorophenylamine-2-carboxylic acid and 4, 4'-diisothiocyanatostilbene-2,2'-disulphonic acid were less selective in their inhibitory effects, inducing reductions of 60 mM KCl-induced contraction at concentrations >/=10 microM. Our results show that NFA can exert selective inhibitory effects on the chloride-dependent 5-HT-induced contractions of the rat fundus. The data support the hypothesis that activation of Cl((Ca)) channels leading to calcium entry via VDCCs is a mechanism utilized by 5-HT, but not by ACh, to elicit contraction of the rat fundus.