Jiro Matsumoto

Oxygen Free Radicals and Lipid Peroxidation in the Pathogenesis of Gastric Mucosal Lesions Induced by Indomethacin in Rats

The relationship of gastric hypermotility to mucosal hemodynamics, lipid peroxidation and vascular permeability changes was investigated in the pathogenesis of indomethacin-induced gastric lesions in

Role of capsaicin-sensitive afferent neurons in alkaline secretory response to luminal acid in the rat duodenum

The role of capsaicin-sensitive afferent neurons in acid-induced HCO3- secretion was investigated in the duodenum of anesthetized rats. The proximal duodenum was perfused with saline (pH 4.5), the pH of perfusate and the transmucosal potential differences were continuously monitored, and HCO3- output was determined by pH change. Under these conditions, duodenal pH, potential difference, and HCO3- output were significantly increased in response to IV injection of prostaglandin E2 (300 micrograms/kg) and luminal acidification (10 mmol/L HCl, 10 minutes). These responses induced by luminal acid were significantly attenuated by SC pretreatment with indomethacin (5 mg/kg), preexposure of the mucosa to lidocaine (4%, 15 minutes), functional ablation of capsaicin-sensitive afferent neurons, or even prior application of capsaicin (6 mg/mL, 30 minutes) to the duodenum. Although capsaicin application by itself (0.3-6 mg/mL) produced a concentration-dependent increase of HCO3- output, this effect was significantly reduced by lidocaine, indomethacin, or chemical deafferentation and exhibited a tachyphylaxis after repeated application at a high concentration (6 mg/mL). Neither of these treatments significantly affected the HCO3- response induced by prostaglandin E2. It was concluded that stimulation of capsaicin-sensitive afferent neurons increased duodenal HCO3- secretion and that these neurons may be involved in the mechanism of HCO3- response induced by luminal acid in the duodenum.

Role of Capsaicin-Sensitive Afferent Neurons in Mucosal Blood Flow Response of Rat Stomach Induced by Mild Irritants

The role of capsaicin-sensitive sensory nerves in gastric mucosal blood flow (GMBF) responses to mild irritants was investigated in the rat stomach mounted on a lucite chamber using hypertonic NaCl and 0.2 N HCl. Exposure of the mucosa to hypertonic NaCl (0.5, 0.75, 1 M) for 10 min caused a reduction in the transmucosal potential difference (PD) in a concentration-related manner, followed by an increase of luminal pH and GMBF. In contrast, mucosal application of 0.2 N HCl caused no or little change in PD and pH, but increased GMBF significantly. Functional ablation of capsaicin-sensitive sensory nerves significantly inhibited the increase of GMBF after exposure to these irritants, although the PD and pH responses induced by 1 M NaCl remained unaltered by this treatment. Pretreatment with indomethacin (5 mg/kg, subcutaneously) significantly attenuated the GMBF responses to 1 M NaCl and 0.2 N HCl and inhibited the increase of pH caused by 1 M NaCl. Mucosal application of capsaicin (0.1 mg/ml for 10 min) produced an increase of GMBF without being accompanied by change in PH and pH, and this effect was significantly blocked by either indomethacin or chemical deafferentation. These results suggest that capsaicin-sensitive sensory nerves as well as endogenous prostaglandins may be involved in the mechanism of GMBF responses induced by mild irritants, and the latter might sensitize these nerves to mucosal irritation. PD reduction may be obligatory for pH but not GMBF responses.

Role of capsaicin-sensitive sensory nerves in acid-induced bicarbonate secretion in rat stomach

The effect of capsaicin-sensitive afferent nerves on the alkaline secretory response induced by mucosal acidification was investigated in theex vivo stomachs of anesthetized rats. The stomach was mounted on a Lucite chamber and perfused with saline (pH 4.5) in the absence of acid secretion (omeprazole pretreatment: 60 mg/kg, intraperitoneal), and luminal pH and transmucosal potential difference (PD) were monitored simultaneously. Under these conditions the gastric mucosa responded to intravenous infection of prostaglandin E2 (PGE2: 300 μg/kg) and mucosal acidification (0.2 N HCl for 10 min) by a significant increase of pH with a slight decrease of PD; the HCO3− output was 9.2±0.7 μmol and 8.4±0.8 μmol, respectively. The increased pH and HCO3− responses were significantly inhibited by prior administration of indomethacin (5 mg/kg, subcutaneously) or chemical deafferentation following capsaicin injections (total dose: 100 mg/kg, subcutaneously), whereas those induced by PGE2 remained unchanged after either treatment. On the other hand, the mucosal application of capsaicin (0.3–6 mg/ml) increased the luminal pH and HCO3− output in a concentration-related manner, and this action was also significantly attenuated by either indomethacin or chemical deafferentation of capsaicin-sensitive sensory neurons. These results suggest that capsaicin-sensitive sensory nerves may be involved in the mechanism of acid-induced HCO3− secretion in the stomach, in addition to endogenous PGs, and these two pathways may interact somewhere in the stimulatory process.

Regulation of gastroduodenal bicarbonate secretion by capsaicin-sensitive sensory neurons in rats.

We investigated the role of capsaicin-sensitive sensory neurons in regulation of gastroduodenal HCO3- secretion in anesthetized rats. The stomach (under acid inhibition by omeprazole 60 mg/kg i.p.) or the duodenum was perfused with saline (pH 4.5) and HCO3- output was determined by pH change in the perfusate. Both the duodenum and stomach responded to prostaglandin E2 (PGE2; 300 micrograms/kg i.v.) or luminal acid by a significant increase in pH and HCO3- output. These tissues also responded to luminal application of capsaicin (0.3-6 mg/ml for 30 min), resulting in a significant increase of pH and HCO3- output in a concentration-related manner. The HCO3- stimulatory action of capsaicin was markedly attenuated by functional ablation of capsaicin-sensitive sensory neurons, significantly mitigated by indomethacin, and exhibited tachyphylaxis after repeated application at a high concentration. The acid-induced pH and HCO3- responses were also significantly mitigated by sensory deafferentation and by indomethacin, whereas those induced by PGE2 remained unaffected. In addition, defunctionalization of these sensory nerves resulted in macroscopically visible damage in the duodenum when acid secretion was concomitantly stimulated by histamine. We conclude that capsaicin-sensitive sensory neurons may be involved in the regulatory mechanism of gastroduodenal HCO3- secretion and contribute to protection of the mucosa against acid. Endogenous PGs may be involved in the HCO3- stimulatory action mediated by capsaicin-sensitive sensory neurons.

Induction of Duodenal Ulcers in Sensory Deafferented Rats following Histamine Infusion

We used capsaicin as a selective probe for sensory neuronal mechanisms and examined in rats whether defunctionalization of the sensory nerves caused duodenal ulcers in the presence of acid hypersecretion. Chemical deafferentation was performed by subcutaneous injection of capsaicin for 3 days (total dose: 100 mg/kg) 2 weeks before the experiment. This treatment did not cause by itself any damage in the duodenum. However, intravenous infusion of histamine (4, 8 and 16 mg/kg/h) in these animals caused hemorrhagic lesions in the proximal duodenum within 6 h in a dose-dependent manner with an incidence of 100%. Histamine alone in the control animals did not induce macroscopically visible lesions at lower doses and caused only slight damage at the highest dose (16 mg/kg/h), although acid secretion was stimulated to the maximal degree at 8 mg/kg/h. Ablation of capsaicin-sensitive sensory neurons did not have any effect on acid secretion induced by histamine (8 mg/kg/h), but significantly inhibited the increase in duodenal HCO3- secretion in response to mucosal acidification. We conclude that functional ablation of capsaicin-sensitive sensory nerves impairs duodenal HCO3- secretory response to acid and results in duodenal ulcers if acid hypersecretion is present. These sensory nerves may be important in the defense mechanism of the duodenum against luminal acid.