CISPLATIN INCREASES THE RELEASE OF 5-HYDROXYTRYPTAMINE (5-HT) FROM THE ISOLATED VASCULARLY PERFUSED SMALL-INTESTINE OF THE GUINEA-PIG - INVOLVEMENT OF 5-HT3 RECEPTORS

Isolated segments of the guinea-pig small intestine were vascularly perfused and the release of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) into the portal venous effluent determined by high pressure liquid chromatography with electrochemical detection. Release of acetylcholine from isolated superfused intestinal segments was determined as outflow of [H-3]radioactivity from preparations preincubated with [H-3]choline. Cisplatin (3-mu-M) increased the outflow of 5-HT and 5-HIAA by about 90%. At 30 and 100-mu-M cisplatin decreased the outflow of 5-HT and its metabolite by 40%-50%. The stimulatory effect of cisplatin was consistently observed only when the bicarbonate-phosphate buffer of the Tyrode's solution was replaced by HEPES-buffer. The stimulatory effect of cisplatin was abolished in the absence of extracellular calcium or presence of tetrodotoxin (1-mu-M). The stimulatory effect of cisplatin was also prevented by hexamethonium (100-mu-M) or scopolamine (100-nM). The 5-HT3 receptor antagonists ondansetron and ICS 205-930 in concentrations as low as 1 pM also abolished the stimulatory effect of cisplatin. The 5-HT3 receptor antagonist MDL 72222 prevented the stimulatory effect of cisplatin only at a concentration of 1-mu-M. None of the 5-HT3 receptor antagonists alone significantly altered the outflow of 5-HT and 5-HIAA. Cisplatin (3-mu-M) enhanced the outflow of [H-3]radioactivity from intestinal segments and caused longitudinal muscle contractions that were abolished by 100 nM scopolamine. In conclusion, cisplatin, at concentrations which occur during anti-cancer therapy in humans and induce emesis, increases the release of 5-HT from the enterochromaffin cells of the small intestine of the guinea-pig. This effect of cisplatin is mediated by a cascade of events which involves release of acetylcholine and stimulation of 5-HT3 receptors.