Mechanism of gastrointestinal abnormal motor activity induced by cisplatin in conscious dogs

Figure 1 Interdigestive motor activity observed after intravenous administration of cisplatin (1. 2 mg/kg). A: Interdigestive motor activity was observed in the ND (n = 10); B: From approximately 3 to 4 h after the intravenous administration of cisplatin, the ND exhibited retropropagation of gastrointestinal motor activity from jejunum 2 to the gastric body, accompanied by emesis. ND: Normal intact dog group; i.v.: Intravenous administration.

Figure 2 Changes in concentrations of 5-hydroxytryptamine in plasma and intestinal fluids. A: Changes in the plasma 5-HT concentrations in ND (n = 10). Each symbol represents mean ± SE. The plasma 5-HT concentration obtained at 0 h was significantly higher than those obtained at 4 and 7 h (^aP < 0.05); B: Changes in the 5-HT concentrations in intestinal fluids in ND (n = 10). Each symbol represents mean ± SE. The 5-HT concentration in intestinal fluids at 0 h was significantly higher than those obtained at 3, 4, and 5 h (^aP < 0.05). 5-HT: 5-hydroxytryptamine; ND: Normal intact dog group.

Figure 3 In normal intact dog group, cisplatin (1. 2 mg/kg) was given 1 h after dexamethasone administration (1.0 mg/kg), and interdigestive motor activity was observed.

Figure 4 Blocker study chart. In the ND, dexamethasone (1 mg/kg), phentolamine (regitin; 0.5 mg/kg), propranolol (inderal; 0.5 mg/kg), or granisetron (kytril; 0.05 mg/kg) was given as a single-bolus injection starting 20 min after the spontaneous phase III contractions of the jejunum 2 had terminated. Kytril (0.05 mg/kg) was also given as a single-bolus injection in the ND and NDRVN (n = 4). Cisplatin (1.2 mg/kg) was given 1 h after the administration of each inhibitor. In ND, atropine (0.05 mg/kg + 0.05 mg/kg per hour) was given as a single-bolus injection, followed by a 30-min continuous intravenous infusion starting 20 min after the spontaneous phase III contractions of the jejunum 2 had terminated. In the ND, metoclopramide (0.5 mg/kg + 0.5 mg/kg per hour) was given as a single-bolus injection, followed by a 5-h continuous intravenous infusion starting 20 min after the spontaneous phase III contractions of the jejunum 2 had terminated. Cisplatin (1.2 mg/kg) was given 1 h after the start of the administration of each inhibitor. ND: Normal intact dog group; NDRVN: Normal intact dog group with resection of the vagus nerve; i.v.: Intravenous administration.

Figure 5 In normal intact dog group with resection of the vagus nerve, interdigestive motor activity was observed after the intravenous administration of cisplatin (1. 2 mg/kg). A: Normal intact dog group with resection of the vagus nerve (NDRVN) (n = 4) was given cisplatin (1.2 mg/kg), and interdigestive motor activity was observed; B: In the NDRVN (n = 4), cisplatin (1.2 mg/kg) was given 1 h after granisetron (kytril) administration (0.05 mg/kg), and interdigestive motor activity was observed. i.v.: Intravenous administration.

Figure 6 In the normal intact dog group (n = 6), cisplatin (1. 2 mg/kg) was given 1 h after granisetron (kytril) administration (0.05 mg/kg), and interdigestive motor activity was observed.

Figure 7 Numbers of emetic episodes in dogs receiving cisplatin alone (control, n = 10), kytril (0. 05 mg/kg, intravenous administration, n = 6) alone, and vagotomy (the normal intact dog group with resection of the vagus nerve; n = 4). Each bar represents mean ± SE. Significant differences were detected among the control group, granisetron (kytril) group, and normal intact dog group with resection of the vagus nerve (NDRVN). Control, open bar; i.v., hatched line; RNG, filled bar. ^aP < 0.05 vs control. i.v.: Intravenous administration.

Figure 8 Responses to the intravenous and duodenal administration of 5-hydroxytryptamine in the normal intact dog group. A: Responses to the intravenous administration of 5-hydroxytryptamine (5-HT) (600 μg/kg) in the ND; B: Responses to the duodenal administration of 5-HT (600 μg/kg) in the ND. ND: Normal intact dog group; i.v.: Intravenous administration; i.d.: Intraduodenal administration.

Figure 9 Responses to the intravenous and duodenal administration of 5-hydroxytryptamine in the normal intact dog group with resection of the vagus nerve. A: Responses to the intravenous administration of 5-HT (600 μg/kg) in the NDRVN; B: Responses to the duodenal administration of 5-HT (600 μg/kg) in the NDRVN; C: Responses to the duodenal administration of 5-HT (5400 μg/kg) in the NDRVN. NDRVN: Normal intact dog group with resection of the vagus nerve; 5-HT: 5-hydroxytryptamine, serotonin; i.v.: Intravenous administration; i.d.: Intraduodenal administration.

Figure 10 Motility index during 60 min following 5-hydroxytryptamine administration. A: MI during 60 min following 5-HT administration (600 μg/kg) was calculated in the ND (n = 4); B: MI during 60 min following 5-HT administration (600 μg/kg) was calculated in the NDRVN (n = 4). Open bar, i.d. administration; filled bar, i.v. administration. ^aP < 0.05. NDRVN: Normal intact dog group with resection of the vagus nerve; MI: Motility index; ND: Normal intact dog group; 5-HT: 5-hydroxytryptamine, serotonin; i.v.: Intravenous administration; i.d.: Intraduodenal administration.