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J Pharm Pharmacol. 1994 Aug;46(8):666-70.

Constipation evoked by 5-HT3-receptor antagonism: evidence for heterogeneous efficacy among different antagonists in guinea-pigs.

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  • 1SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.


The abilities of selective 5-HT3-receptor antagonists to evoke constipation were examined in conscious guinea-pigs and in preparations of guinea-pig isolated colon. Compared with vehicle-treated guinea-pigs, acute doses of granisetron (0.1, 1 and 10 mg kg-1, i.p.) and tropisetron (10 mg kg-1, i.p., but not 1 and 0.1 mg kg-1, i.p.) significantly (P < 0.05) reduced the total number of faecal pellets excreted during a 12-h observation period. By contrast, BRL 46470 (0.1-10 mg kg-1, i.p.) had no significant effect on the incidence of defecation. Mid-to-distal lengths of guinea-pig isolated colon spontaneously expelled faecal pellets. Granisetron (0.1 and 1 microM) and tropisetron (1 microM) reduced or prevented the rate at which they were spontaneously expelled. Morphine (0.1 microM) and clonidine (10 nM) also showed faecal pellet transit time. Naloxone (0.1 microM) had no effects alone, but reversed the actions of granisetron, morphine and clonidine. BRL 46470 (1 microM) had no significant effect on the transit of faecal pellets in guinea-pig isolated colon. In segments of guinea-pig isolated colon which did not contain faecal pellets, granisetron, tropisetron and BRL 46470 antagonized the ability of 5-HT to evoke cholinergically-mediated contractions of the longitudinal muscle. The respective pA2 values and slopes of the Schild plots were 8.5 +/- 0.05, slope 1.06 +/- 0.03; 8.5 +/- 0.1, slope 0.91 +/- 0.04; and 7.9 +/- 0.1, slope 0.93 +/- 0.05. Our experiments suggest that not all 5-HT3-receptor antagonists are the same.(ABSTRACT TRUNCATED AT 250 WORDS)

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