RESPONSE HETEROGENEITY OF 5-HT3 RECEPTOR ANTAGONISTS IN A RAT VISCERAL HYPERSENSITIVITY MODEL

Subcutaneous administration of granisetron (BRL 43694, abicyclo[3.3.1] non-3-yl-1H-indazole-3-carboxamide) and zacopride clo[2.2.2.]oct-3-yl) -5-chloro-2-methoxybenzamide), two 5-HT3 receptor antagonists, at dose s ranging from 3 to 1000 mu g/kg, inhibited abdominal contractions ind uced by distension (30 mmHg, 10 min) of irritated colon (0.6% acetic a cid) in conscious rats with a bell-shaped dose-response curve. The ED( 50) of granisetron and zacopride were 17.6 and 8.2 mu g/kg, respective ly, In contrast, both tropisetron (ICS 205-930, (3-a-tropanyl)1-indole -3-carboxylic ester) and ondansetron (GR38032F, -methyl-1H-imidazol-1- yl)methyl]-4H-carbazol-4-one hydrocloride dihydrate) were inactive in this model. These data further support the concept of a heterogeneity in the potency of 5-HT3 receptor antagonists in modulating visceral hy persensitivity in conscious rats. This finding is in agreement with a reported efficacy of granisetron but not of ondansetron in patients wi th irritable bowel syndrome.