Gj. Sanger et Ka. Wardle, CONSTIPATION EVOKED BY 5-HT3-RECEPTOR ANTAGONISM - EVIDENCE FOR HETEROGENEOUS EFFICACY AMONG DIFFERENT ANTAGONISTS IN GUINEA-PIGS, Journal of Pharmacy and Pharmacology, 46(8), 1994, pp. 666-670
The abilities of selective 5-HT3-receptor antagonists to evoke constip
ation were examined in conscious guinea-pigs and in preparations of gu
inea-pig isolated colon. Compared with vehicle-treated guinea-pigs, ac
ute doses of granisetron (0.1, 1 and 10 mg kg(-1), i.p.) and tropisetr
on (10 mg kg(-1), i.p., but not 1 and 0.1 mg kg(-1), i.p.) significant
ly (P < 0.05) reduced the total number of faecal pellets excreted duri
ng 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 mu M) and tropisetron (1 mu M)
reduced or prevented the rate at which they were spontaneously expelle
d. Morphine (0.1 mu M) and clonidine (10 nM) also slowed faecal pellet
transit time. Naloxone (0.1 mu M) had no effects alone, but reversed
the actions of granisetron, morphine and clonidine. BRL 46470 (1 mu M)
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 an
tagonized the ability of 5-HT to evoke cholinergically-mediated contra
ctions of the longitudinal muscle. The respective pA(2) values and slo
pes 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 sa
me. In particular, BRL 46470 does not prevent defecation or faecal pel
let expulsion in guinea-pig colon, even though this compound is an eff
ective 5-HT3-receptor antagonist in the same tissue. For the 5-HT3-rec
eptor antagonists which did cause constipation, the effects can be at
least partly attributed to an indirect opioid-dependent action within
the colonic enteric nervous system.