Capsaicin-sensitive sensory neurons in healing gastric lesions induced by HCl in rats

The role of capsaicin-sensitive sensory neurons in the healing of HCl-induced gastric lesions was investigated in rats. Rats fasted for 18 hr were given 0.6 N HCl orally for induction of gastric lesions, and they were fed normally from 1 hr later. On various days after HCl treatment, area of lesions, acid secretion, mucosal H⁺ permeability, and blood flow responses were measured. Functional ablation of capsaicin-sensitive sensory neurons was performed two weeks before the experiment by subcutaneous injections of high-dose capsaicin. Sensory deafferentation did not affect the development of gastric damage in response to HCl but significantly delayed the healing of these lesions. The mucosa damaged by HCl secreted less acid but showed significant rise in H⁺ permeability, resulting in acid back-diffusion accompanied by an increase of mucosal blood flow. Sensory deafferentation had no effect on acid secretion and mucosal permeability changes in the damaged stomach but completely blocked the hyperemic response caused by acid back-diffusion. Capsaicin-sensitive sensory neurons may contribute to healing of gastric lesions, probably by mediating the mucosal hyperemic responses associated with acid back-diffusion and by facilitating acid disposal in the mucosa.     

Increased susceptibility of rat gastric mucosa to ulcerogenic stimulation with aging

We examined the influences of aging on gastric damage and gastric mucosal blood flow (GMBF) responses induced by acid back-diffusion, following the barrier disruption, and investigated the relation of capsaicin-sensitive sensory nerves to these changes. Male Fischer rats 3, 13, and 24 months old were used. Under urethane anesthesia, a rat stomach was mounted on a chamber, and gastric potential difference (PD), luminal H⁺ loss, and GMBF were measured before, during, and after exposure to 20 mM sodium taurocholate (TC) for 30 min, in the presence of 50 mM HCl. Mucosal exposure to TC caused surface cell damage, PD reduction, and acid back-diffusion (luminal H⁺ loss) in all groups of rats; PD reduction and the amount of H⁺ loss were not significantly different between young and aged rats. In young rats, a marked increase of GMBF was observed with luminal acid loss following TC treatment, yet it resulted in less damage in the gastric mucosa. In aged rats, however, such GMBF responses were apparently mitigated, leading to a significant worsening of gastric mucosal lesions induced by TC. Mucosal application of capsaicin (0.1 mg/ml) caused an increase of GMBF in young rats, but this response was significantly attenuated in aged rats. In addition, the amount of calcitonin gene-related peptide (CGRP) released in the isolated stomach in response to capsaicin (1 × 10^–5 M) was significantly lower in aged animals when compared to young rats. These findings suggest that the gastric mucosa of aged rats is more vulnerable to acid back-diffusion following the barrier disruption, partly because of dysfunction of GMBF responses mediated by capsaicin-sensitive sensory neurons in the acidic conditions.     

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 dorsal motor nucleus of vagus in gastric function and mucosal damage induced by ethanol in rats

Experimental evidence indicates that the autonomic nervous system, especially the cholinergic pathway, modulates the mucosal defensive mechanism and affects mucosal damage in the stomach. The present study investigated the role of the dorsal motor nucleus of vagus (DMV) in gastric function and its influences on ethanol-induced mucosal damage in pentobarbitone-anesthetized rats. Electrolytic lesion of the DMV as compared with sham operation and lesions of other brain areas, eg, nucleus reticular gigantocellularis and cuneate nucleus, reduced the basal gastric mucosal blood flow (GMBF) and also the blood flow after ethanol administration. The same operation did not affect the acid secretion either in the basal state or during the ethanol treatment period. Lesions at the caudal half of the DMV produced a bigger depression of GMBF when compared with lesion at the rostral half. In the sham-operated rats, ethanol induced severe hemorrhagic lesions in the gastric glandular mucosa, and this was significantly potentiated by lesions at the DMV, especially in the caudal half. The present findings indicate that acute DMV damage at the caudal half markedly affects the GMBF but not the acid secretion. The action on GMBF may contribute to the aggravation of ethanol-induced gastric damage in rats. These data reinforce the idea that the central vagal pathway, especially the caudal half of the DMV, plays a significant role in the modulation of GMBF, which in turn affects the integrity of gastric mucosal barrier.     

The role of the vagus nerve in the protective action of acid inhibitors on ethanol-induced gastric mucosal damage in rats

The role of vagus in the actions of different acid inhibitors on ethanol-induced gastric damage and mucosal blood flow (GMBF) changes was studied in anaesthetized rats, using an ex vivo stomach chamber preparation. Subdiaphragmatic bilateral vagotomy decreased the basal gastric acid secretion and GMBF; it also intensified ethanol-evoked lesions in the glandular mucosa. Misoprostol, omeprazole and cimetidine produced a similar degree of reduction in acid output. Misoprostol given subcutaneously (s.c.) (50 micrograms/kg), or added to the incubation solution (12.5 micrograms) for 15 min, markedly prevented ethanol-induced lesion formation and reduction in GMBF. The reversing effect of s.c. injection of misoprostol on either lesion formation or on GMBF reduction was attenuated by vagotomy. Omeprazole protected against lesion formation only when present in the incubation solution (12.5 mg) of ex vivo chamber preparations of both vagus-intact and vagotomized animals, but the effect was significantly less in the latter group. The drug also prevented the depressive action of ethanol in vagus-intact animals. Cimetidine pretreatment (50 mg s.c. or 12.5 mg in incubation solution), however, did not modify the effects of ethanol on lesion formation and the GMBF. The findings indicate that the three different types of acid inhibitors exert different actions on ethanol-induced gastric mucosal damage, although they produced similar inhibition of acid output. Vagotomy lowers the GMBF and attenuates the antiulcer action of misoprostol and omeprazole, especially when the drugs are given by the parenteral route.     

Mechanism of intragastric nicotine protection against ethanol-induced gastric injury

To elucidate the mechanism of intragastric nicotine protection against ethanol-induced gastric mucosal injury seen in a previous report and in our preliminary study, the following studies were performed. Rats were pretreated with naloxone (8 mg/kg intraperitoneal, 0.5 hr prior to study) to block opiate receptors; or capsaicin (125 mg/kg subcutaneous 10 days prior to study) to denervate the afferent sensory fibers; or indomethacin (2.5 mg/kg intragastric or 5 mg/kg subcutaneous, 1 hr prior to study) to inhibit endogenous prostaglandin synthesis. At 1-hr intervals, nicotine (4 mg/kg) or vehicle and 40% ethanol were then given intragastrically. Total gastric corpus mucosal lesion length was measured unbiasedly. In separate studies, gastric mucosal blood flow (GMBF) was assessed by hydrogen gas clearance before and after intragastric nicotine or vehicle; luminal mucus volume, gastric juice volume, and acid output were measured 1 hr after either intragastric nicotine or vehicle administration. The results showed that the acute protective effect of intragastric nicotine was associated with a significantly larger luminal mucus volume. It was not blocked by naloxone, capsaicin, or indomethacin. There was no increase in GMBF. The larger gastric residual volume did not account for the protection. We conclude that the mechanism mediating nicotine protection is unique and is independent of opiate receptors, capsaicin-sensitife afferent sensory nerve fibers, endogenous prostaglandin generation, or dilution of the injurious agent. The increase in luminal gastric mucus volume may contribute to the protective effect of intragastric nicotine against gastric mucosal injury produced by 40% ethanol.     

Effect of lafutidine, a novel histamine H2-receptor antagonist, on monochloramine-induced gastric lesions in rats: Role of capsaicin-sensitive sensory neurons

BACKGROUND: Lafutidine ((+/-)-2-(furfurylsulfinyl)-N-(4-(4-(piperidinomethyl)-2-pyr idyl)oxy-(Z)-2-butenyl)acetamide) is a novel histamine H2-receptor antagonist and has been shown to exhibit a potent gastroprotective activity in addition to its antisecretory action. In the present study, we examined the effects of lafutidine on the mucosal ulcerogenic and potential difference (PD) responses induced by monochloramine (NH2Cl) in rat stomachs. METHODS: Oral administration of NH2Cl at 120 mmol/L produced haemorrhagic lesions in the stomach in unanaesthetized rats. RESULTS: Lafutidine (3-30mg/kg), given p.o., showed a dose-dependent and significant inhibition against damage caused by NH2Cl: the effect was significant at 10 mg/kg or greater but disappeared almost totally in the sensory deafferented animals following capsaicin pretreatment. Likewise, capsaicin (10 mg/kg, p.o.), but not cimetidine (100 mg/kg, p.o.) exhibited a potent protection against NH2Cl-induced gastric lesions. Topical application of NH2Cl (10 mmol/L) reduced transmucosal PD in ex-vivo stomachs of anaesthetized rats, but this PD response was also prevented by pre-exposure to lafutidine, in a dose-dependent and sensory neuron-sensitive manner. Mucosal exposure to NH4OH (60 mmol/L) also caused PD reduction in ex-vivo stomachs made ischaemic by bleeding from the carotid artery (1 mL/100 g bodyweight), resulting in severe gastric lesions. These ulcerogenic and PD responses caused by NH4OH plus ischaemia were attenuated by prior application of lafutidine as well as taurine, a scavenger of NH2Cl. The former effect was, again, dependent on the sensory neurons. Intraluminal capsaicin but not cimetidine was also effective in preventing a PD response to NH2Cl. CONCLUSIONS: These results suggest that lafutidine, but not cimetidine, protects the stomach against NH2Cl, whether occurring endogenously or administered exogenously and that this action may be mediated by capsaicin-sensitive sensory neurons.     

左旋精氨酸甲酯及左旋精氨酸对应激状态下胃黏膜耐受性细胞保护作用的影响

目的：探讨内源性一氧化氮（NO）在应激状态下胃黏膜耐受性细胞保护中的作用及其可能的机制。方法：以重复浸水束缚应激（WRS）制作动物模型,以左旋精氨酸甲酯（L－NAME）或左旋精氨酸（L－Arg）抑制或促进内源性NO的合成,动态检测胃黏膜血流量（GMBF）、溃疡指数（UI）、黏膜一化氮含量的变化。结果：重复应激后,实验对照组大鼠UI明显下降,同时GMBF上升,黏膜内NO含量增高;L－NAME使WWRS引起的胃黏膜损伤加重,消除了GMBF的递增趋势,黏膜NO含量下降;而L－Arg可减轻WRS造成的黏膜损伤,GMBF、黏膜NO含量增相应增加;GMBF、UI、黏膜NO含量变化之间有相关关系。结论：内源性NO通过调节GMBF而介导耐受性细胞保护作用,L－NAME抑制其合成,延缓这一作用,L－Arg增加其合成,促进该作用。     

Influence of NG‐nitro‐L‐arginine methyl ester and L‐arginine on gastric mucosal tolerant cytoprotection under stress

OBJECTIVE : To determine the role of endogenous nitric oxide (NO) in gastric mucosal tolerant cytoprotection under stress and its possible mechanism. METHODS : Sprague–Dawley rats were exposed to repeated water immersion and restraint stress (WRS), during which N^G‐nitro‐L ‐arginine methyl ester (L ‐NAME), a non‐selective NO synthase inhibitor, and L ‐arginine (L ‐Arg), a substrate for NO synthesis, were administered to inhibit or promote the synthesis of endogenous NO, respectively. Gastric mucosal blood flow (GMBF) was measured with an LDF‐3 Flowmeter (Electronic Instrument Factory of Nankai University, Tianjin, China), the NO level in the gastric mucosa was monitored by the Griess reaction and gastric mucosal lesions were evaluated using the ulcer index (UI). The relationships between changes in GMBF, UI and NO content in the gastric mucosa were analyzed by linear correlation analysis. RESULTS : Repeated WRS induced gastric mucosal tolerant cytoprotection and this was accompanied by increased GMBF and NO levels in the gastric mucosa. Inhibition of endogenous NO synthesis by L ‐NAME worsened mucosal lesions induced by single WRS and, after repeated WRS, the adaptive incremence in GMBF was abolished and the NO content in the gastric mucosa was significantly reduced. In contrast, enhancement of endogenous NO synthesis by L ‐Arg attenuated mucosal erosions caused by single WRS. After repeated WRS, GMBF and the NO content in the mucosa increased gradually. Mucosal lesions were negligible after rats were exposed to the fourth WRS. CONCLUSIONS : During the tolerant cytoprotection, GMBF, UI and the NO content showed regular changes and there were good relationships between them. L ‐NAME and L ‐Arg changed the levels of endogenous NO, which, accordingly, affected GMBF and the gastric tolerance. By regulating GMBF, endogenous NO may play an important role in the gastric mucosal tolerant cytoprotection under stress. Inhibition of the synthesis of NO delayed the induction of tolerant cytoprotection, whereas increased NO synthesis promoted cytoprotection.     

Protective effect of Irsogladine on monochloramineinduced gastric mucosallesions in rats:a comparative study with rebamipide

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The influence of acute or chronic nicotine treatment on ethanol-induced gastric mucosal damage in rats

The influences of acute or chronic nicotine pretreatment on ethanol-induced changes on gastric secretion, mucosal blood flow (GMBF), and glandular mucosal damage were studied in anesthetized rats. Ethanol administration decreased gastric acid secretion and GMBF, which were accompanied by a marked increase in gastric mucosal damage. Acute nicotine incubation 2 or 4 mg dose-dependently elevated both the titratable acid in the luminal solution and the gastric secretory volume; it also prevented the depressive action on GMBF and gastric mucosal damage in ethanol-treated animals. Chronic nicotine treatment for 10 days reduced the inhibitory action of ethanol on gastric acid secretion; the higher dose (25 micrograms/ml drinking water) potentiated the decrease of GMBF and the ulcerogenic property of ethanol. However, chronic treatment with the lower dose (5 micrograms/ml drinking water) had the opposite effects; it also markedly increased the gastric secretory volume. It is concluded that acute nicotine pretreatment elevates, whereas chronic nicotine pretreatment differentially affects GMBF. These effects could account for their protective or preventive actions on ethanol ulceration. The increase in nonacid gastric secretory volume by nicotine could partially explain its antiulcer effect. Furthermore, the acid secretory state of the stomach appears unrelated to the ulcerogenic property of ethanol.     

Impairment by 5-Fluorouracil of the Healing of Gastric Lesions in Rats: Effect of Lafutidine, a Histamine H2 Receptor Antagonist, Mediated by Capsaicin-Sensitive Afferent Neurons

We investigated the influence of 5-fluorouracil (5-FU), an anti-tumor agent, on the healing of gastric lesions generated by 0.6 M HCl in rats and the effect of lafutidine, a histamine H₂ receptor antagonist, on the impaired healing. Animals fasted for 18 h were given 1 ml of 0.6 M HCl p.o., fed normally from 1 h later, and killed 1–96 h thereafter. 5-FU was given i.v. twice, 1 h and 24 h after the HCl. The gastric lesions healed spontaneously within 96 h. Although it decreased acid secretion, 5-FU markedly delayed the healing. Lafutidine, but not cimetidine, given p.o. immediately after each dosing of 5-FU significantly reversed the delay in healing by 5-FU, and this effect was attenuated by the chemical ablation of capsaicin-sensitive afferent neurons. Capsaicin also significantly reversed the delay in healing. The mucosal application of 50 mM HCl did not affect gastric mucosal blood flow (GMBF) in the normal stomach, but significantly increased it in the stomach damaged by 0.6 M HCl. The increases in GMBF were attenuated by 5-FU; however, the co-administration of lafutidine significantly restored the response. In addition, 5-FU inhibited both cell proliferation and migration in rat gastric epithelial cells (RGM1) in vitro. These results suggest that 5-FU delayed the healing of gastric lesions generated by 0.6 M HCl, probably through the inhibition of cell migration and proliferation, as well as the impairment of GMBF, and lafutidine reversed the delay in healing, mainly through the amelioration of the GMBF response mediated by capsaicin-sensitive afferent neurons.     

Nitric oxide in gastroprotection by sucralfate,mild irritant,and nocloprost

Pretreatment with sucralfate is known to protect gastric mucosa against the damaging effect of strong irritants, and this protection is accompanied by an increase in mucosal blood flow but the mechanisms underlying these effects have not been elucidated. Similar gastroprotective and hyperemic effects can be obtained with exogenous prostaglandins (PG), mild irritants such as dilute ethanol, and by capsaicin. In this study we investigated the role of nitric oxide (NO) in the prevention of ethanol-induced gastric damage and gastric blood flow by sucralfate, mild irritant such as 20% ethanol, capsaicin, and nocloprost, a stable PGE₂ analog. Pretreatment withN ^G-nitro-l-arginine (l-NNA), an inhibitor of NO synthase, enhanced ethanol-induced mucosal damage and reduced dose-dependently the gastroprotective and hyperemic effects of sucralfate, dilute ethanol, and capsaicin. The doses ofl-NNA attenuating significantly the protective effects of sucralfate or 20% ethanol were 25–50 mg/kg, while those reducing the protection by capsaicin were 6.2–12.5 mg/kg. The attenuating effect ofl-NNA on gastroprotection was reversed byl-arginine but notd-arginine. For comparison, the gastroprotective (but not hyperemic) effect of nocloprost was not affected by the pretreatment withl-NNA and/or arginine. We conclude that sucralfate, mild irritant, and capsaicin activate the NO system that may contribute to their gastroprotective effect through enhancing mucosal circulation but that NO is not essential for the mucosal protection by PGE₂ analog.     

Protective action of omeprazole, a benzimidazole derivative, on gastric mucosal damage by aspirin and ethanol in rats

This study was designed to compare the influence of omeprazole, a potent inhibitor of H+/K+-ATP-ase involved in the final step of H+ secretion and prostaglandin (PG) I2 on the formation of gastric mucosal lesions induced by absolute ethanol or acidified aspirin (ASA). Omeprazole given intragastrically in both inhibitory (20 or 200 mumol/kg) and noninhibitory doses (2 mumol/kg) prevented dose dependently ASA- and ethanol-induced gastric lesions. The protective effect of omeprazole against ASA-induced lesions occurred when mucosal generation of PGs was completely suppressed and that against ethanol lesions when PG generation was increased above normal values. Pretreatment with PGI2 given intragastrically or subcutaneously both in inhibitory and noninhibitory doses prevented almost completely the formation of gastric mucosal lesions caused by both absolute ethanol and acidified ASA. This study indicates that omeprazole is capable of protecting gastric mucosa against ASA- and ethanol-induced injury and that this protection is unrelated to gastric inhibition or the biosynthesis of mucosal PGs.     

Portal hypertension

The time-course effects of portal hypertension on gastric secretory function, mucosal blood flow, vascular permeability, and ethanol-induced gastric mucosal damage were examined in anesthetized rats. Partial ligation of the portal vein effectively produced portal hypertension one to three days later but the raised pressure returned to normal on the sixth day after ligation. This time-course effect coincided with reduced pepsin secretion and mucosal blood flow and also with potentiated ethanol-induced mucosal damage during the first to third days. These effects started to tail off on the sixth day. However, gastric acid output was significantly reduced on the third day, and this was strongest on the sixth day after operation. Portal vein ligation also reduced basal vascular permeability, which was markedly potentiated after ethanol treatment. It is concluded that: (1) portal vein blood pressure changes are a time-dependent process following ligation; (2) changes in gastric mucosal blood flow (GMBF) and lesion formation are closely related to portal hypertension; (3) gastric mucosal injury is associated with vascular damage, as evidenced by increased in vascular permeability; and (4) pepsin but not acid secretion is closely related to the state of the GMBF.     

Laparotomy-induced gastric protection against ethanol injury is mediated by capsaicin-sensitive sensory neurons

Laparotomy significantly attenuates ethanol-induced gastric mucosal lesions in the rat. The effects of sensory denervation by capsaicin, indomethacin, atropine, guanethidine, and hexamethonium on laparotomy-induced protection were studied in the rat. Gastric mucosal injury was induced by the intragastric instillation of 1 mL of 75% ethanol. The laparotomy-induced protection against ethanol injury was abolished by sensory denervation by capsaicin (total dose, 125 mg/kg, SC) and also by pretreatment with indomethacin (5 mg/kg, SC). In contrast, pretreatment with atropine (0.5 mg/kg, IP), guanethidine (total dose, 20 mg/kg, SC), or hexamethonium (20 mg/kg, IP) had no significant effect on laparotomy-induced protection. These data indicate that capsaicin-sensitive sensory afferent neurons, but not cholinergic or adrenergic autonomic neurons, mediate laparotomy-induced protection against ethanol injury. The hypothesis is put forward that the protective response to laparotomy arises from a somatovisceral and/or viscerovisceral axon reflex of capsaicin-sensitive afferent neurons. Prostaglandins might play a mediator role in the activation by laparotomy of somatic and/or visceral branches of the afferent neurons.     

电针足阳明经穴对胃粘膜损伤大鼠胃粘膜血流量及生长抑素的影响

目的 :观察电针足阳明经“四白”、“天枢”、“足三里”穴对胃粘膜损伤大鼠胃窦和延髓内生长抑素(SS)含量的影响及与胃粘膜损伤、胃粘膜血流量的关系 ,以探讨经脉 -脏腑相关的物质基础。方法 :健康 SD大鼠 6 0只 ,随机分为正常对照组 (对照组 ) ,模型组 ,针刺四白组、天枢组及非穴点组共 6组 ,以乙醇灌胃造成胃粘膜损伤大鼠模型 ,观察电针大鼠足三里、天枢、四白穴对胃粘膜血流量 (氢气清除法 )的影响 ,用放免分析法检测大鼠胃窦及延髓 SS含量。结果 :胃粘膜血流量在胃粘膜损伤后明显降低 ,针刺四白、天枢、足三里及非穴点后 ,均有不同程度升高 ,尤以足三里和四白组升高明显 (P<0 .0 1) ;胃窦及延髓 SS模型组较对照组升高 (P<0 .0 5 ,<0 .0 1) ,而针刺四白、足三里组升高不明显 (P>0 .0 5 )。结论 :胃窦、延髓 SS含量变化与胃粘膜血流量的改变有一定关系 ,电针足阳明经四白、足三里穴可能通过对胃窦及延髓 SS含量的改变来影响胃粘膜血流量 ,促进胃粘膜损伤的修复。     

Characterization of spontaneous and ethanol-induced gastric damage in cirrhotic rats.

Cirrhosis was induced in Sprague-Dawley rats via ligation of the common bile duct. Changes in gastric blood flow and mucosal architecture were examined. Using an ex vivo gastric chamber preparation, the susceptibility of the cirrhotic gastric mucosa to injury by 20% ethanol was also examined. The gastric mucosa of cirrhotic animals was abnormal, even before ethanol administration. The macroscopically visible damage in these animals ranged from superficial hyperemia to epithelial sloughing. These gastric lesions were similar in appearance to the gastropathy described in cirrhotic patients, including "cherry-red spots" and areas of generalized erythema. Cirrhotic rats had a lower resting gastric transmucosal potential difference than control rats, and their gastric mucosa was also significantly more susceptible to damage by topical ethanol application. Ethanol administration caused a significant increase in gastric blood flow in control rats, whereas it significantly decreased gastric blood flow in cirrhotic rats. This lack of a reactive hyperemic response in cirrhotic rats may be responsible for the increased susceptibility of the gastric mucosa to ethanol-induced damage.     

Effect of lafutidine,a histamine H2-receptor antagonist,on gastric mucosal blood flow and duodenal HCO3- secretion in rats: relation to capsaicin-sensitive afferent neurons

Lafutidine is a new type of antiulcer drug, possessing both an antisecretory effect, exerted via a blockade of the histamine H₂ receptor, and gastroprotective activity, mediated by capsaicin-sensitive afferent nerves (CSN). In the present study, we examined the effect of lafutidine on gastric mucosal blood flow (GMBF) and duodenal HCO₃ ^– secretion (DAS) under basal and acid-stimulated conditions in rats. Under urethane anesthesia, GMBF was measured using a laser Doppler flowmeter in a chambered stomach before and after exposure to 20 mM taurocholate (TC) plus 50 mM HCl, while DAS was measured in a proximal duodenal loop before and after mucosal acidification (10 mM HCl for 10 min) by titrating the perfusate at pH 7.0 using a pH-stat method and by adding 10 mM HCl. Lafutidine given intraperitoneally affected neither GMBF nor DAS under basal conditions, but augmented an increase in both GMBF and DAS induced by mucosal acidification. Although the acid-induced GMBF and DAS responses were significantly mitigated by both indomethacin and sensory deafferentation but not by ruthenium red (RT), the vanilloid receptor (VR)-1 antagonist, the responses were preserved in lafutidine-treated animals, even in the presence of indomethacin. Both GMBF and DAS were significantly increased by local application of capsaicin, the responses being attenuated by indomethacin and RT as well as sensory deafferentation. Lafutidine augmented the GMBF and DAS responses to capsaicin and preserved the responses, even in the presence of indomethacin. Capsaicin evoked an increase in [Ca²⁺]_i in rat VR1-transfected HEK293 cells, while lafutidine had no effect by itself on [Ca²⁺]_i in these cells and did not affect the increase in [Ca²⁺]_i evoked by capsaicin. In conclusion, these results suggest that lafutidine mimics endogenous effects of prostaglandins to augment the GMBF and DAS responses to acid or capsaicin, probably by sensitizing CSN through an unknown site other than VR1. The luminal H⁺ itself is not a ligand for the RT-sensitive site of VR1 but plays a modulator role in the CSN-mediated physiological responses.     

铝碳酸镁对胃粘膜保护的实验研究

研究铝碳酸镁对幽门结扎及乙醇诱发大鼠胃粘膜损伤的保护作用及其机制。方法：通过结扎幽门和灌服乙醇制备大鼠胃牯膜损伤模型，测定胃酸分泌、胃蛋白酶活性、胃粘膜中前列腺素、血流、丙二醛(MDA)、氨基己糖含量和一些酶的活性。结果：口服铝碳酸镁500mg／kg连续3天，能显著防止幽门结扎和乙醇诱发的胃粘膜损伤，并中和胃酸及抑制胃蛋白酶活性。铝碳酸镁有促进前列腺素分泌和粘膜血流的作用。此外，铝碳酸镁能降低乙醇所致MDA含量的增加，并阻止乙醇引起的醌还原酶，谷胱甘肽转移酶、谷胱甘肽还原酶和谷胱甘肽过氧化物酶活性的降低。结论：铝碳酸镁对幽门结扎和乙醇诱发的大鼠胃粘膜损伤具有保护作用，其作用机制与粘膜保护和抗脂质过氧化作用有关。