The 5-HT2B antagonist and 5-HT4 agonist activities of tegaserod in the anaesthetized rat

The 5-HT4 receptor agonist and gastroprokinetic, tegaserod, possesses 5-HT2B receptor antagonist activity. However, the relevance of such activity is unclear. In this study, the 5-HT2B receptor antagonist and 5-HT4 agonist activities of tegaserod were investigated. Two piezoelectric crystals were implanted on the stomach fundus or oesophagus of anaesthetized Sprague-Dawley rats. Measurement of the transmission time of ultrasonic pulses between the implanted crystals provided a continuous record of inter-crystal distance, and thus of muscle length. In the stomach fundus, tegaserod (1 and 3 mg kg(-1)), administered subcutaneously (s.c.), inhibited the contractile response evoked by the 5-HT2B receptor agonist, BW 723C86 (0.01-1 mg kg(-1) intravenously (i.v.)). SB 206553 (1 mg kg(-1) s.c.), a selective 5-HT2B/2C receptor antagonist, also inhibited the BW 723C86-mediated responses. In the rat oesophagus, tegaserod (0.001-0.3 mg kg(-1) i.v. or 0.003-3 mg kg(-1) s.c.) increased inter-crystal distance, consistent with smooth muscle relaxation; the responses were inhibited by the 5-HT4 antagonist, piboserod (0.1 mg kg(-1) s.c.). Data from this in vivo rat study are consistent with tegaserod-induced 5-HT4 receptor-mediated oesophageal relaxation, and antagonism of 5-HT2B receptor-mediated stomach fundus contraction. The clinical relevance of the 5-HT2B receptor antagonism of tegaserod remains to be determined.