Effect of niflumic acid on electromechanical coupling by tachykinin NK1 receptor activation in rabbit colon

We have investigated the effect of the Cl- channel blocker, niflumic acid, on the contractile response and electromechanical coupling activated by stimulation of the tachykinin NK1 receptor in the longitudinal muscle of rabbit proximal colon, in the presence of indomethacin (5 microM). The application of submaximal equieffective concentrations of the tachykinin NK1 receptor-selective agonist [Sar9]substance P sulfone (30 nM), of carbachol (300 nM) and KCl (40 mM), produced distinct phasic and tonic components of contraction. Niflumic acid (10-100 microM) preferentially and markedly inhibited the tonic component of the response to [Sar9]substance P sulfone and to carbachol, without affecting the response to KCl. Nifedipine (1 microM) abolished the response to KCl and greatly reduced the response to [Sar9]substance P sulfone and carbachol. The nifedipine-resistant response to [Sar9]substance P sulfone was attenuated by niflumic acid (100 microM), while that to carbachol was unaffected. In sucrose gap experiments, superfusion with niflumic acid (100 microM), in the presence of nifedipine (3 microM), produced membrane hyperpolarization, which was totally blocked by tetraethylammonium (10 mM). Niflumic acid inhibited both depolarization and contraction induced by [Sar9]substance P sulfone, both in the absence or in the presence of tetraethylammonium. The present findings support the idea that a niflumic acid-sensitive mechanism, probably an effect on Cl- channels, takes part in the post-receptorial events activated by tachykinin NK1 receptor stimulation in the longitudinal muscle of rabbit colon, and suggest that this mechanism would be more important for generating the sustained tonic than the phasic component of contraction.