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. 1999 Feb;44(2):174–179. doi: 10.1136/gut.44.2.174

Cisplatin impairs fluid and electrolyte absorption in rat small intestine: a role for 5-hydroxytryptamine

C Bearcroft 1, P Domizio 1, F Mourad 1, E Andre 1, M Farthing 1
PMCID: PMC1727387  PMID: 9895375

Abstract

Background—The antineoplastic drug cisplatin has been widely used for the treatment of cancer in humans but its use has been limited by vomiting and diarrhoea. Cisplatin releases 5-hydroxytryptamine into the gut which is thought to be the major mediator of cisplatin induced vomiting. 
Aim—To determine whether cisplatin affects fluid and electrolyte transport in rat jejunum and whether this change can be modulated by the 5-hydroxytryptamine3 receptor antagonist, ondansetron. 
Methods—Jejunal perfusion in rats in vivo was performed one hour after intraperitoneal cisplatin (5 and 10 mg/kg) administration. The effect of pretreatment with subcutaneous ondansetron 300 µg/kg was investigated. 
Results—Median net fluid absorption after cisplatin 10 mg/kg (67 µl/min/g dry intestinal weight (interquartile range 46 to 100); n = 15) was reduced compared with controls (120 (107to 151) µl/min/g; n = 13; p<0.001). Ondansetron reversed the impairment of jejunal fluid absorption produced by cisplatin to normal (161(130 to 176) µl/min/g; n = 11; p<0.001). Electrolyte movement paralleled fluid movement. Jejunal histological examination of sections from cisplatin treated animals showed villus damage, which was not prevented by pretreatment with ondansetron. 
Conclusion—These findings suggest that diarrhoea during cisplatin therapy may be due to altered fluid transport in the small bowel. The reversal of fluid transport to normal in the presence of a 5-hydroxytryptamine3 receptor antagonist suggests that 5-hydroxytryptamine is a local mediator in the small intestine. 



Keywords: cisplatin; 5-hydroxytryptamine; rat; ondansetron; small intestine; fluid transport

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Figure 1 .

Figure 1

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Net fluid movement (µl/min/g) in controls and animals treated with cisplatin or cisplatin and ondansetron. Values are expressed as median (horizontal line) and interquartile range (bar). ***p<0.001 compared with controls; †††p<0.001 compared with cisplatin 10mg/kg alone but no different from controls. 


Figure 2 .

Figure 2

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Net sodium movement (µmol/min/g) in controls and animals treated with cisplatin or cisplatin and ondansetron. Values are expressed as median (horizontal line) and interquartile range (bar). ***p<0.001 compared with controls; †††p<0.001 compared with cisplatin 10 mg/kg alone but no different from controls. 


Figure 3 .

Figure 3

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Net potassium movement (µmol/min/g) in controls and animals treated with cisplatin or cisplatin and ondansetron. Values are expressed as median (horizontal line) and interquartile range (bar). *p<0.05 compared with controls; †p<0.05 compared with cisplatin 10 mg/kg alone but no different from controls. 


Figure 4 .

Figure 4

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Net chloride movement (µmol/min/g) in controls and animals treated with cisplatin or cisplatin and ondansetron. Values are expressed as median (horizontal line) and interquartile range (bar). **p<0.01 compared with controls; †††p<0.001 compared with cisplatin 10 mg/kg alone but no different from controls. 


Figure 5 .

Figure 5

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Histological sections from (A) controls, (B) cisplatin (10 mg/kg) treated animals and (C) animals treated with cisplatin 10 mg/kg and ondansetron 300 µg/kg showing degeneration of the tips of the villi and enterocyte damage (arrows). These sections were selected to be representative of the histological appearance for each of the groups. An example of more serious damage after treatment with cisplatin 10 mg/kg is shown in (D), with denudation of the distal third of some of the villi which occurred in 23% of villi in one out of nine animals and was not present in all sections. All sections were examined in a blinded fashion but were `selected' to be representative of the histology in each of the treatment groups. Bar = 100 µm. 


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