Effects of TAK-637 on NK(1) receptor-mediated mechanisms regulating colonic secretion.

This study investigates the effect of a selective NK(1) receptor antagonist TAK-637 on enteric mechanisms involved in regulation of epithelial secretion in the colon. Mucosal sheets isolated from guinea-pig colon were placed in modified Ussing chambers and the net active transport of electrolytes was measured as short-circuit current (Isc). GR-73632, a selective NK(1) receptor agonist, induced an increase in basal Isc, which was inhibited by TAK-637 (IC(50) of 21 nM). The increase in Isc induced by GR-73632 was significantly attenuated by tetrodotoxin (TTX, 1 microM), indicating that TAK-637 inhibits neuronal NK(1) receptors. Moreover, TAK-637 reduced the TTX-resistant component of the response to GR-73632 suggesting that NK(1) receptors expressed by epithelial cells are inhibited by TAK-637. In separate experiments, TAK-637 partially inhibited the submaximal Isc induced by electrical field stimulation (EFS, 0.5 ms, 15 Hz) of enteric nerves or by activation of primary afferent fibers using capsaicin (50 microM). TAK-637 had no significant effect on the basal Isc or on responses induced by neurokinin A (NKA), senktide, or forskolin. The results imply that inhibition of peripheral NK(1) receptors may reduce autonomic epithelial secretion in response to activation of autonomic secretomotor pathways, while having no significant effect on basal epithelial transport.