1. The role of nitric oxide (NO) in the regulation of acid secretion was examined in the anaesthetized rat. 2. A rat stomach was mounted in an ex vivo chamber, instilled with 2 ml of saline every 15 min, and the recovered sample was titrated at pH 7.0 against 0.1 N NaOH by use of an automatic titrator for acid secretion. Gastric mucosal blood¯ow (GMBF) was measured simultaneously by laser Doppler owmeter. 3. Intragastric application of NO donors such as FK409 (3 and 6 mg ml 71 ) and sodium nitroprusside (SNP; 6 and 12 mg ml 71 ) as well as i.p. administration of cimetidine (60 mg kg 71 ), a histamine H 2 -receptor antagonist, signi®cantly inhibited the increase in acid secretion in response to pentagastrin (60 mg kg 71 h 71 , i.v.), in doses that increased gastric mucosal blood¯ow (GMBF). 4. Intragastric application of FK409 (6 mg ml 71 ) increased both basal and stimulated acid secretion induced by YM-14673 (0.3 mg kg 71 , i.v.), an analogue of thyrotropin-releasing hormone (TRH), but had no e ect on the acid secretory response induced by histamine (4 mg kg 71 h 71 , i.v.). 5. Pretreatment with N G -nitro-L-arginine methyl ester (L-NAME; 10 mg kg 71 , i.v.) did not a ect basal acid secretion, but signi®cantly potentiated the increase in acid secretion induced by YM-14673 and slightly augmented the acid secretory response to pentagastrin. 6. Both pentagastrin and YM-14673 increased the release of nitrite plus nitrate (NO x ), stable NO metabolites, into the gastric lumen, and these changes were completely inhibited by prior administration of L-NAME (10 mg kg 71 , i.v.). 7. Pentagastrin caused an increase in luminal release of histamine and this response was signi®cantly suppressed by intragastric application of FK409 (6 mg ml 71 ). 8. These results suggest that either exogenous or endogenous NO has an inhibitory action on gastric acid secretion through suppression of histamine release from enterochroma n-like (ECL) cells.

The effect of nitric oxide (NO) on HCO^–₃ secretion was examined in vitro using an isolated preparation of bullfrog duodenum. The tissue was bathed in unbuffered Ringer’s solution gassed with 100% O₂ on the mucosal side and HCO^–₃ Ringer’s solution gassed with 95% O₂–5% CO₂ on the serosal side. The HCO^–₃ secretion was measured by the pH-stat method using 2 mmol/l HCl as the titrant to keep the mucosal pH at 7.4. (±)-(E)-Ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamine (NOR3) was used as a NO donor and added to the serosal solution. To analyze the NOR3 action on HCO^–₃ secretion, the effects of dibutyryl adenosine-3′,5′-cyclic monophosphate (dbcAMP), dibutyryl guanosine-3′,5′-cyclic monophosphate (dbcGMP), methylene blue, and indomethacin on the HCO^–₃ response were also examined. NOR3 (1×10^–4 and 3×10^–4 mol/l) caused an increase in HCO^–₃ secretion in a dose-dependent manner, and this effect appeared with an about 30-min time lag, reaching the level of 1.5–2.5 times greater than basal values at 1–2 h later. Both dbcAMP (1×10^–3 mol/l) and dbcGMP (1×10^–3 mol/l) also caused a significant increase in HCO^–₃ secretion in bullfrog duodenums in vitro, although the onset of the HCO^–₃ response to dbcGMP was delayed as compared to the former. The stimulatory action of NOR3 on duodenal HCO^–₃ secretion was significantly attenuated by methylene blue (5×10^–5 mol/l) and indomethacin (1×10^–5 mol/l), the latter also inhibiting the HCO^–₃ response to dbcGMP. The release of prostaglandin E₂ in the serosal solution was significantly increased after addition of NOR3 (3×10^–4 mol/l) and dbcGMP (1×10^–3 mol/l) in an indomethacin-sensitive manner. These results suggest that the NO donor increases duodenal HCO^–₃ secretion in vitro, and this action of NO donor is cGMP-dependent and mediated by endogenous prostaglandins. Duodenal HCO^–₃ secretion may be regulated locally by NO/cGMP in addition to prostaglandin/cAMP.

No abstract

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+.

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 .