Effects of TAK-637, an NK1 antagonist, on functions of the lower urinary tract (2) Role of the NK1 receptors in the micturition reflex in guinea pigs

• Published in: Japanese Journal of Pharmacology Vol. 79; no. suppl.1; p. 195
• Main Authors: Doi, Takayuki, Kamo, Izumi, Okanishi, Satoshi, Ishimaru, Takenori, Ikeura, Yoshinori, Natsugari, Hideaki
• Format: Journal Article
• Language: English; Japanese
• Published: The Japanese Pharmacological Society 1999
• ISSN: 0021-5198; 1347-3506
• DOI: 10.1016/S0021-5198(19)34795-X

Effects of TAK-637 on the micturition reflex in urethane-anesthetized guinea pigs were studied in comparison with those of clinically used anti-pollakiuria agents. TAK-637 dose-dependently inhibited the distention-induced rhythmic bladder contractions (DIRBCs, MED=1.0 mg/kg, i.v) without affecting their amplitude. TAK-637 inhibited the DIRBCs in spinalized animals at a dose of 1.0 mg/kg, i.v. On the other hand, the enantiomer of TAK-637, which has much lower affinity for the NK1 receptor, did not show any effects on DIRBCs, indicating the effects of TAK-637 can be ascribed to its NK1 antagonism. TAK-637 dose-dependently inhibited the micturition reflex induced by topical application of capsaicin to the surface of the bladder dome (MED=0.3 mg/kg). The anti-pollakiuria agents did not show any effects on the frequency of DIRBCs but dose-dependently reduced their amplitudes, suggesting their sites of action are in the motor component of the micturition reflex pathway. These results suggest that NK1 receptors in the spinal cord are involved in both physiological (distention) and nociceptive sensory transmissions from the bladder. Therefore, TAK-637 may be the first agent in a new class of drug for incontinence.