1 We examined the gastric mucosal blood¯ow (GMBF) and ulcerogenic responses following barrier disruption induced by sodium taurocholate (TC) in diabetic rats and investigated the role of capsaicinsensitive sensory neurons in these responses. 2 Animals were injected streptozotocin (STZ: 70 mg kg 71 , i.p.) and used after 5, 10 and 15 weeks of diabetes with blood glucose levels of 4350 mg dl 71 . The stomach was mounted on an ex-vivo chamber under urethane anaesthesia and exposed to 20 mM TC plus 50 mM HCl for 30 min in the presence of omeprazole. Gastric transmucosal potential dierence (PD), GMBF, and luminal acid loss (H + backdiusion) were measured before and after exposure to 20 mM TC, and the mucosa was examined for lesions 90 min after TC treatment. 3 Mucosal application of TC caused PD reduction in all groups; the degree of PD reduction was similar between normal and diabetic rats, although basal PD values were lower in diabetic rats. In normal rats, TC treatment caused luminal acid loss, followed by an increase of GMBF, resulting in minimal damage in the mucosa. 4 The increased GMBF responses associated with H + back-diusion were mitigated in STZ-treated rats, depending on the duration of diabetes, and severe haemorrhagic lesions occurred in the stomach after 10 weeks of diabetes. 5 Intragastric application of capsaicin increased GMBF in normal rats, but such responses were mitigated in STZ diabetic rats. The amount of CGRP released in the isolated stomach in response to capsaicin was signi®cantly lower in diabetic rats when compared to controls. 6 The deleterious in¯uences on GMBF and mucosal ulcerogenic responses in STZ-diabetic rats were partially but signi®cantly antagonized by daily insulin (4 units rat 71 ) treatment. 7 These results suggest that the gastric mucosa of diabetic rats is more vulnerable to acid injury following barrier disruption, and this change is insulin-sensitive and may be partly accounted for by the impairment of GMBF response associated with acid back-diusion and mediated by capsaicin-sensitive sensory neurons.

We investigated the relationship between prostaglandin E‐type receptor (EP receptor) subtypes and gastroduodenal HCO3− secretion in rats. Under urethane anaesthesia, a stomach mounted in an ex vivo chamber or a proximal duodenal loop was perfused with saline and the HCO3− secretion was measured at pH 7.0 using a pH‐stat method and by adding 10 mmol/L HCl. Prostaglandin E2 (PGE2, i.v.) increased HCO3− secretion in both the stomach and duodenum; this action was verapamil sensitive and only in the duodenum was potentiated by isobutylmethyl xanthine (IBMX). Duodenal HCO3− secretion was also stimulated by both sulprostone (EP1/EP3 agonist), enprostil (EP1/EP3 agonist), misoprostol (EP2/EP3 agonist), 11‐deoxy PGE1 (EP3/EP4 agonist) and ONO‐NT‐012 (EP3 agonist), but was not affected by either butaprost (EP2 agonist) or 17‐phenyl‐ω‐trinor‐PGE2 (EP1 agonist). In contrast, gastric HCO3− secretion was stimulated by sulprostone, enprostil and 17‐phenyl‐ω‐trinor‐PGE2, but not by misoprostol, butaprost, 11‐deoxy PGE1 or ONO‐NT‐012. The EP1 antagonist SC‐51089 inhibited the HCO3− stimulatory action of sulprostone in the stomach but not in the duodenum. Isobutylmethyl xanthine potentiated the HCO3− response to sulprostone in the duodenum, while verapamil reduced the response in both the stomach and duodenum. These results suggest that PGE2 stimulates HCO3− secretion via different EP receptor subtypes in the stomach and duodenum: in the former the EP1 receptors linked to Ca2+ and in the latter, the EP3 receptors coupled with both cAMP and Ca2+.

Background: We investigated the mechanisms responsible for the increased susceptibility of diabetic rat gastric mucosa to damage inflicted by overnight food deprivation (18 h) and its worsening by the cold restraint stress (4°C, 3 h). Methods: Gastric damage was measured in fasted animals, some of which were rendered diabetic by a single intraperitoneal injection of streptozotocin (STZ; 70 mg/kg) 5 weeks before experiments (STZ 5W). Results: STZ 5W rodents showed a number of hemorrhagic lesions in corpus mucosa (26.8 ± 5.2 mm²) which could be prevented by insulin or nitric oxide synthase (NOS) inhibitors: aminoguanidine or L-NAME (N^ω-nitro-L-arginine methyl ester). Mucosal injury was further aggravated by low temperature (51.1 ± 7.8 mm²), the damage ameliorated by insulin, aminoguanidine, or L-NAME. The salutary actions of L-NAME were L-arginine sensitive. Low temperature and L-NAME did not significantly influence the gastric secretory parameters in normal rats. On the other hand, L-NAME and aminoguanidine counteracted the attenuation of gastric juice acidity and acid output in STZ 5W rodents. Blood plasma nitrite and nitrate levels and outputs in gastric juice were augmented in STZ 5W animals in comparison to controls. The total activities of NOS including inducible NOS but not constitutive NOS were markedly enhanced by fasting and cold restraint in gastric mucosa of STZ 5W animals (2.2- and 3.7- or 2.4- and 17.9-fold respectively). Conclusions: Stressful stimuli, such as food bereavement and cold challenge contribute to the elevated susceptibility of diabetic gastric mucosa to damage, even though the main aggressive factor, i.e., gastric acid secretion, is attenuated. The enhanced production of nitric oxide by inducible NOS during food deprivation and cold exposure seems to play an important role in gastric mucosal integrity disturbances during diabetes.

The role of the cholinergic and peptidergic pathways in the impairment of gastric motility associated with diabetic gastroparesis was assessed at the postsynaptic level using isolated fundus smooth muscle strips. Maximal contractile responses to carbachol and galanin were significantly decreased in fundus strips isolated from rats rendered diabetic by a single intraperitoneal injection of streptozotocin (STZ, 70 mg/kg) 1, 4 and 8 weeks before experiments. We also observed notable decrements in the slopes and Hill’s coefficients without conspicuous changes in the EC₅₀ of the respective galanin concentration-response curves measured in strips obtained from STZ animals after 4 and 8 weeks. L-NAME reversed the above-mentioned alterations in an L-arginine-sensitive manner in STZ rats after 4 weeks but not in STZ rats after 8 weeks. The blood plasma nitrite/nitrate levels in STZ animals after 4 and 8 weeks were increased by 44.6 and 61.9%, respectively. Ca²⁺-independent nitric oxide synthase activity in gastric fundus strips and stomach corpus mucosa from STZ rats after 4 weeks was markedly enhanced by 37.4 and 31.9%, respectively, suggesting an enhanced nitric oxide production. In vivo insulin treatment prevented diabetes-induced alterations in smooth muscle contractility. We conclude that the smooth muscle dysfunction evoked by experimental diabetes causing diminished contractions of fundus strips to carbachol and galanin is at least partly due to the increased nitric oxide synthesis.

We investigated the relationship between prostaglandin E-type receptor (EP receptor) subtypes and gastroduodenal HCO secretion in rats. Under urethane anaesthesia, a stomach mounted in an ex vivo chamber or a proximal duodenal loop was perfused with saline and the HCO secretion was measured at pH 7.0 using a pH-stat method and by adding 10 mmol/L HCl. Prostaglandin E (PGE , i.V.) increased HCO secretion in both the stomach and duodenum; this action was verapamil sensitive and only in the duodenum was potentiated by isobutylmethyl xanthine (IBMX). Duodenal HCO secretion was also stimulated by both sulprostone (EP /EP agonist), enprostil (EP /EP agonist), misoprostol (EP /EP agonist), 11-deoxy PGE (EP /EP agonist) and ONO-NT-012 (EP agonist), but was not affected by either butaprost (EP agonist) or 17-phenyl-ω-trinor-PGE (EP agonist). In contrast, gastric HCO secretion was stimulated by sulprostone, enprostil and 17-phenyl-ω-trinor-PGE , but not by misoprostol, butaprost, 11-deoxy PGE or ONO-NT-012. The EP antagonist SC-51089 inhibited the HCO stimulatory action of sulprostone in the stomach but not in the duodenum. Isobutylmethyl xanthine potentiated the HCO response to sulprostone in the duodenum, while verapamil reduced the response in both the stomach and duodenum. These results suggest that PGE stimulates HCO secretion via different EP receptor subtypes in the stomach and duodenum: in the former the EP receptors linked to Ca and in the latter, the EP receptors coupled with both cAMP and Ca .