Effect of granisetron on radiation‐induced alterations of colonic motility and fluid absorption in rats

Abstract

It is well accepted that the prophylactic administration of 5-hydroxytryptamine type-3 (5-HT 3 ) receptor antagonists, such as granisetron and ondansetron, has provided a de®nite clinical advance in the treatment of early vomiting induced by either chemo-or radiotherapy. 1 Indeed, physicians and nurses have noted that treatment with 5-HT 3 antagonists contributes to an increased quality of life and to patient compliance with the often distressing anticancer treatment protocols. 2 Ondansetron and granisetron are well tolerated, have a good oral bioavailability 3 and the pharmacodynamic effects appear to last longer than the pharmacokinetic data suggest. 4,5 One notable sideeffect often reported following treatment with these 5-HT 3 antagonists is constipation. 2 This is perhaps of clinical relevance as diarrhoea is also a frequent sequel to radiotherapy of the abdominal region, which may occur acutely during treatment and be related to the release of mediators such as 5-HT as well as to epithelial injury. 6 Indeed, Henriksson et al. have suggested that SUMMARY Background: Radiation-induced diarrhoea is attributed to both mucosal injury and alterations of intestinal motility. Previous reports have indicated that 5-hydroxytryptamine is released following irradiation, which may contribute to these changes. Aims: To investigate the effects of granisetron (5-hydroxytryptamine type-3 receptor antagonist) on colonic motility,¯uid absorption and 5-hydroxytryptamine colonic content following abdominal irradiation (10 Gy) in rats. Methods: In vivo measurements of motility and¯uid absorption in the proximal and distal colon, respectively, diarrhoea score and 5-hydroxytryptamine tissue levels were performed 3 and 7 days after abdominal irradiation. The effects of post-irradiation granisetron (0.3 mg/kg subcutaneously) were also evaluated.

Luminal glucose sensing in the rat intestine has characteristics of a sodium-glucose cotransporter

“…In the present study we measured effects of luminal glucose on fluid secretion in the terminal ileum. In this model, intestinal fluid flux is stimulated by agonists of 5-HT 3 R (Raybould and Freeman, unpublished observations), and secretion stimulated by mechanical stimulation of the mucosa or by abdominal irradiation is reduced by 5-HT 3 R antagonist (20). In the present study, the terminal ileum was absorptive under basal conditions and glucose produced a decrease in intestinal fluid absorption, the magnitude of which was dependent on the amount of glucose administered.…”

“…Activation of a cholinergic reflex pathway in the intestine by 5-HT and 5-HT 3 Rs has been shown to stimulate fluid secretion (20). Therefore, we determined the effect of glucose, given by oral gavage, on fluid flux in the distal ileum.…”

“…Net ileal fluid absorption or secretion was measured in anesthetised rats (pentobarbital sodium, 60 mg/kg ip) using modifications of a previously described method (20). After a midline abdominal incision, a small incision was made into the terminal ileum ϳ2 cm rostral to the ileocecal junction.…”

Syndrome aigu d'irradiation : les atteintes du système gastro-intestinal

“…Ainsi, nous avons montré chez le rat qu'un traitement de granisétron après une irradiation abdominale de 10 Gy réduisait la diminution radio-induite de la motricité et améliorait l'absorption d'eau dans le côlon. Toutes ces mesures étaient en accord avec le profil clinique, puisque les animaux traités au granisétron n'avaient pas de diarrhée (Picard et al, 2002). Néanmoins, il reste i prouver leur efficacité sur la diarrhée réflexe précoce.…”

Effects of radiation upon gastrointestinal motility

“…Serotonin (5-hydroxytryptamine, 5-HT) is known to be released following irradiation and this may contribute to motility changes [36,37] . In a rat high dose model, colonic motility and fluid absorption were reduced after irradiation, producing diarrhea and increased colonic mucosal 5-HT levels.…”