The influence of diabetic hyperglycemia on solid gastric emptying in rats was examined. Diabetes was produced by streptozotocin (STZ, 40 mg/kg i.v.), and diabetic hyperglycemia was observed from 1 day after the STZ injection. The gastric emptying of glass beads in the diabetic rats was significantly delayed compared with that in age-matched control rats at 1, 3 and 7 days after diabetes induction. A slight decrease in gastric emptying was observed in the diabetic rats from 2 to 52 weeks after the diabetes induction. We also investigated the influence of gastroprokinetic agents on STZ-induced diabetic gastroparesis and subdiaphragmatic vagotomy-induced gastroparesis in rats. The selective 5-HT3 receptor antagonists ramosetron (YM060), YM114 (KAE-393), granisetron and ondansetron, and the substituted benzamides (5-HT4 receptor agonist/5-HT3 receptor antagonists) cisapride mosapride and SC-53116 dose-dependently enhanced gastric emptying in normal rats. These compounds also reversed the impairment of diabetic gastroparesis rats at 7 days after the STZ injection, but higher doses were required. The solid gastric emptying in subdiaphragmatic vagotomized rats was also delayed. Ramosetron and the substituted benzamides cisapride and zacopride partially reversed the gastroparesis in the vagotomized rats. These results suggest that acute hyperglycemia is important mechanism for the delay of solid gastric emptying in diabetic rats. It is also suggested that selective 5-HT3 receptor antagonists and substituted benzamides enhance gastric emptying not only in normal rats but also in diabetic and vagotomized rats.
pg/kg) on the von Bezold-Jarisch reflex lasted for 3-6 hr, whereas ondansetron (700 pg/kg, p.o.) an tagonized 5-HT3 receptors for only 1 hr. In isolated guinea pig colon, the inhibitory effect of YM-com pounds on 5-HT-induced contraction persisted significantly longer than those of ondansetron and granisetron after washout of the bath containing compounds. These results suggest that YM-compounds are highly potent 5-HT3-receptor antagonists. Furthermore, non-competitive 5-HT3-receptor antagonism of YM-compounds against the von Bezold-Jarisch reflex at higher doses may be reflected in their slow dissocia tion from the 5-HT3 receptor, and that of granisetron may be reflected in its slow metabolism in anesthetiz ed rats.
We examined the effects of exogenous 5-hydroxytryptamine (5-HT) and selective 5-HT receptor agonists and antagonists on proximal, middle and distal colonic motility in conscious fasted dogs with extraluminal force transducers implanted chronically. 5-HT (0.003-0.1 mg/kg i.v.) dose-dependently enhanced motility along the entire length of the colon. The 5-HT (0.03 mg/kg i.v.)-induced response was inhibited by 0.1-1.0 mg/kg i.v. methysergide, a 5-HT1/2 antagonist, at all recording sites and by 0.1-1.0 mg/kg i.v. ketanserin, a 5-HT2A antagonist, at the middle and distal sites only. At 1 mg/kg i.v., YM060, a 5-HT3 antagonist, reduced the amplitude of the initial transient high-amplitude contractions induced by 5-HT, but did not affect the tonic contraction induced by 5-HT. At doses up to 3 mg/kg i.v., 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino) ethyl ester (SDZ205-557), a 5-HT4 antagonist, and hexamethonium (up to 10 mg/kg i.v.) did not affect 5-HT-induced responses at any recording site. Renzapride, a 5-HT4 agonist, also stimulated motility along the entire length of the colon at 0.3 mg/kg i.v.. The renzapride-induced response was inhibited by 1 mg/kg i.v. SDZ205-557 or 3 mg/kg i.v. hexamethonium. m-Chlorophenylbiguanide (m-CPBG), a 5-HT3 agonist, (1 mg/kg i.v.) produced a transient high-amplitude contraction at all recording sites and this contraction was eliminated by pretreatment with 0.03 mg/kg i.v. YM060. The contraction produced by m-CPBG declined rapidly, so the increase in the motility index by m-CPBG was not significant at any recording site. Of the antagonists tested, 0.1-1 mg/kg i.v. methysergide produced a delayed and prolonged contractile response at the middle and distal sites. The onset of the response was delayed about 20 min after application and the response was maintained over the subsequent 60-min observation period. The methysergide (1 mg/kg i.v.)-induced response was inhibited by 3 mg/kg i.v. hexamethonium. The other antagonists, ketanserin, YM060 and SDZ205-557, had no contractile effect at any recording site. These results indicate that exogenous 5-HT stimulates motility along the entire length of the fasted canine colon and that 5-HT-induced responses in the proximal colon are mediated mainly by 5-HT1, whereas those in the middle and distal colon are mediated by both 5-HT1 and 5-HT2 receptors. Renzapride and methysergide also stimulate colonic motility via additional mechanisms. The activation of 5-HT4 receptors and the blockade of endogenous 5-HT inhibitory regulation via 5-HT1 receptors may be involved in the action of renzapride and methysergide respectively.
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