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.
McCullough
J L
JL
Department of Pharmacology, Theravance Inc., 901 Gateway Boulevard, South San Francisco, CA 94080, USA.
Armstrong
S R
SR
Hegde
S S
SS
Beattie
D T
DT
D000818:Animals; D004947:Esophagus / Q000187:drug effects / Q000502:physiology; D005748:Gastric Fundus / Q000187:drug effects / Q000502:physiology; D005765:Gastrointestinal Agents / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058830:Serotonin 5-HT2 Receptor Antagonists; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D005765:Gastrointestinal Agents; D007211:Indoles; D058830:Serotonin 5-HT2 Receptor Antagonists; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists; C105050:tegaserod