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 a cid, on the contractile response and electromechanical coupling activa ted by stimulation of the tachykinin NK1 receptor in the longitudinal muscle of rabbit proximal colon, in the presence of indomethacin (5 mu M). The application of submaximal equieffective concentrations of the tachykinin NK1 receptor-selective agonist [Sar(9)]substance P sulfone (30 nM), of carbachol (300 nM) and KCl (40 mM), produced distinct pha sic and tonic components of contraction. Niflumic acid (10-100 mu M) p referentially and markedly inhibited the tonic component of the respon se to [Sar(9)]substance P sulfone and to carbachol, without affecting the response to KCl. Nifedipine (1 mu M) abolished the response to KCl and greatly reduced the response to [Sar(9)]substance P sulfone and c arbachol. The nifedipine-resistant response to [Sar(9)]substance P sul fone was attenuated by niflumic acid (100 mu M), while that to carbach ol was unaffected. In sucrose gap experiments, superfusion with niflum ic acid (100 mu M), in the presence of nifedipine (3 mu M), produced m embrane hyperpolarization, which was totally blocked by tetraethylammo nium (10 mM). Niflumic acid inhibited both depolarization and contract ion induced by [Sar(9)]substance P sulfone, both in the absence or in the presence of tetraethylammonium. The present findings support the i dea that a niflumic acid-sensitive mechanism, probably an effect on Cl - channels, takes part in the post-receptorial events activated by tac hykinin NK1 receptor stimulation in the longitudinal muscle of rabbit colon, and suggest that this mechanism would be more important for gen erating the sustained tonic than the phasic component of contraction.