Effect of lafutidine on CGRP release from cultured rat dorsal root ganglion cells

Lafutidine increased capsaicin-stimulated CGRP release from isolated rat stomach without changing basal CGRP levels. In order to clarify the mechanism of this effect, we used cultured rat DRG cells and measured CGRP release. (1) DRG cells were treated with each drug, and the CGRP content of the supernatant was determined by EIA. (2) RGM-1 cells were co-cultured with DRG cells through a cell culture insert, and capsaicin-evoked CGRP release from the DRG cells was determined when lafutidine or PGE₂ was added to the RGM-1 cells. (3) The supernatant of isolated rat stomach incubated with lafutidine was added to cultured DRG cells, and capsaicin-evoked CGRP release was determined. PGE2, but not lafutidine, augmented capsaicin-evoked CGRP release from DRG cells. Lafutidine did not modulate CGRP release from DRG cells, even though it sensitized CGRP-containing afferent nerves in the rat stomach. Lafutidne and PGE₂ may have different mechanisms of sensitization.     

Lafutidine facilitates calcitonin gene-related peptide (CGRP) nerve-mediated vasodilation via vanilloid-1 receptors in rat mesenteric resistance arteries

Lafutidine is a histamine H(2)-receptor antagonist with gastric antisecretory and gastroprotective activity associated with activation of capsaicin-sensitive nerves. The present study examined the effect of lafutidine on neurotransmission of capsaicin-sensitive calcitonin gene-related peptide (CGRP)-containing vasodilator nerves (CGRPergic nerves) in rat mesenteric resistance arteries. Rat mesenteric vascular beds were perfused with Krebs solution and vascular endothelium was removed by 30-s perfusion with sodium deoxycholate. In preparations preconstricted by continuous perfusion of methoxamine (alpha(1) adrenoceptor agonist), perfusion of lafutidine (0.1 - 10 microM) concentration-dependently augmented vasodilation induced by the periarterial nerve stimulation (PNS, 1 Hz) without affecting vasodilation induced by exogenous CGRP (10 pmol) injection. Perfusion of famotidine (H(2)-receptor antagonist, 1 - 100 microM) had no effect on either PNS-induced or CGRP-induced vasodilation. Perfusion of lafutidine concentration-dependently augmented vasodilation induced by a bolus injection of capsaicin (vanilloid-1 receptor agonist, 30 pmol). The presence of a vanilloid-1 receptor antagonist, ruthenium red (10 microM) or capsazepine (5 microM), abolished capsaicin-induced vasodilation and significantly decreased the PNS-induced vasodilation. The decreased PNS-induced vasodilation by ruthenium red or capsazepine was not affected by perfusion of lafutidine. These results suggest that lafutidine facilitates CGRP nerve-mediated vasodilation by modulating the function of presynaptic vanilloid-1 receptors located in CGRPergic nerves.     

Pharmacological and therapeutic properties of lafutidine (stogar and protecadin), a novel histamine H2 receptor antagonist with gastroprotective activity]

Potent antisecretory agents, such as histamine H2-receptor antagonists and proton pump inhibitors, have achieved great improvement in peptic ulcer therapy. It has, however, been reported that incidence of ulcer relapse is high after discontinuation of these drugs. Insufficient efficacy against NSAID-induced ulcers is also critical. Lafutidine is a novel histamine H2 antagonist with gastroprotective activity. Lafutidine exhibited potent and long-lasting H2 antagonism and prolonged antisecretion. In addition, lafutidine showed a gastroprotective effect against noxious agents-induced gastric mucosal damage through capsaicin-sensitive afferent nerves. Lafutidine showed antiulcer activities against acute ulcer models, prevented gastric ulcer relapse of acetic ulcer, and accelerated the healing of indomethacin-induced antral ulcers in rats. These results suggest the advantage of the combined antisecretory and gastroprotective activities. In clinical studies, lafutidine showed prolonged antisecretion, healing effect against gastric and duodenal ulcers and gastritis, and its potency was equal or superior to that of conventional H2 antagonists. Additionally, lafutidine induced a high transition rate to the E0 stage determined by endoscopical ultrasonography, suggesting the high quality of ulcer healing. Furthermore, effectiveness of lafutidine against NSAIDs-induced ulcer was high. From these results, lafutidine is equal or superior to conventional H2 antagonists in antiulcer potency, and it may be useful for the prevention of ulcer relapse and or treatment of NSAIDs-induced gastroduodenal damage.     

新型消化性溃疡治疗药拉呋替丁

拉呋替丁是一种新型非竞争性组胺H2 受体拮抗药 ,通过阻断组胺H2 受体和辣椒素感受神经减少胃酸分泌、促进胃粘膜再生、增加胃粘膜血流量以及增加胃粘液等机制发挥抗消化性溃疡作用。同其他组胺H2 受体拮抗药相比 ,本品具有疗效显著、不良反应少和治愈后不易复发等优点     

Gastroprotective mechanism of lafutidine, a novel anti-ulcer drug with histamine H2-receptor antagonistic activity.

Lafutidine (CAS 118288-08-7, FRG-8813) is a novel histamine H2-receptor antagonist with gastroprotective activity. The aim of this study was to investigate the property of the gastro-protective activity of lafutidine by examining the effect on ammonia-induced change in transmucosal potential difference (PD), basal gastric mucosal blood flow (GMBF) and noxious agent-induced cell damage. Intragastrical application of lafutidine accelerated the recovery of the PD reduction after exposure of the mucosa to 0.25% ammonia solution and the accelerating effect was abolished by chemical deafferentation, but not with indometacin, a cyclooxygenase inhibitor. The application of capsaicin, as a reference compound, significantly promoted the recovery of the ammonia-induced PD reduction and this effect was not altered with indometacin. Lafutidine given intragastrically caused a sustained increase in GMBF in a dose-dependent fashion, which was also completely inhibited in the deafferentated rats. In vitro studies revealed that, in contrast to 16,16-dimethyl prostaglandin E2, lafutidine did not protect isolated gastric superficial epithelial cells from ethanol- or ammonia-induced damage. In conclusion, the gastroprotection of lafutidine is induced by promoting the restitution of the damaged mucosa after a noxious agent, not by directly protecting the epithelial cells and this effect may be caused through the mechanism of capsaicin-sensitive afferent nerves.     

Antiulcer effect of lafutidine on indomethacin-induced gastric antral ulcers in refed rats.

Lafutidine is a new type antiulcer agent with antisecretory and gastroprotective activities. We investigated the effect of lafutidine on indomethacin-induced antral ulcer in refed rats. Subcutaneous indomethacin injection resulted in the formation of gastric antral ulcer. Lafutidine (1-10 mg/kg, p.o.) reduced the area of ulcer in a dose-dependent manner when administered immediately after the indomethacin injection. Capsaicin at 3 mg/kg, p.o. and 16,16-dimethyl prostaglandin E2 at 3 microg/kg, p.o. also reduced the ulcer area. Chemical deafferentation of capsaicin-sensitive neurons or N(G)-nitro-L-arginine treatment aggravated the ulcer formation and abolished the preventive effect of lafutidine and capsaicin. After the induction of gastric ulcer, lafutidine given twice daily for 2.5 days reduced the area of ulcer in a dose-dependent manner with a significant effect at 10 mg/kg, p.o., as compared with that of the control group. In chemically-deafferentated rats, lafutidine did not show any healing effect. Cimetidine (30 mg/kg, p.o.) and famotidine (1 mg/kg, p.o.) had no significant effect on indomethacin-induced antral ulcer. These results may suggest that lafutidine, unlike cimetidine and famotidine, can prevent the indomethacin-induced antral ulcer formation and accelerate the healing of the ulcer in refed rats through mechanisms involving the capsaicin-sensitive afferent neurons and nitric oxide.     

Protective effect of lafutidine, a novel H2-receptor antagonist, on reflux esophagitis in rats through capsaicin-sensitive afferent neurons

We examined the effect of lafutidine, a novel histamine H(2)-receptor antagonist, on acid reflux esophagitis in rats in relation to capsaicin-sensitive afferent neurons. The esophagitis was induced in rats by ligating both the pylorus and forestomach for 4 h. Lafutidine (1 - 30 mg/kg) and cimetidine (100 mg/kg) were administered either intragastrically or intraduodenally, while capsaicin (1 - 30 mg/kg) was administered intragastrically after the dual ligation. Intragastrical administered lafutidine at >3 mg/kg significantly prevented the hemorrhagic esophageal damage induced by the dual ligation, and this effect was mimicked by neither capsaicin nor cimetidine given intragastrically, but totally abolished by sensory deafferentation. In contrast, lafutidine and cimetidine given intraduodenally were both protective against the esophageal damage in a sensory deafferentation-resistant manner. The acid secretion in pylorus-ligated stomachs was significantly inhibited by these agents given intraduodenally, but not intragastrically. Vanilloid receptor subtype 1 (VR1) was expressed abundantly in the stomach, but very weakly expressed in the esophagus as assessed by Western blotting. These results suggest that lafutidine is effective against the esophageal lesions induced by acid reflux through inhibition of acid secretion and capsaicin-sensitive afferent neurons. The latter mechanism, not shared by cimetidine, may be due to the interaction of lafutidine with unidentified sites on sensory neurons other than VR1.     

Cetraxate raises levels of calcitonin gene-related peptide and substance P in human plasma

Cetraxate hydrochloride (cetraxate), an anti-ulcer drug, produces a dose-related increase in mucosal blood flow. Recently, it was found that capsaicin-sensitive afferent nerves play an important role in gastric mucosal defence. Capsaicin stimulates afferent nerves and enhances the release of calcitonin gene-related peptide (CGRP) and substance P in the stomach. We studied the effect of cetraxate on human plasma CGRP and substance P in healthy subjects. Cetraxate (800 mg) or placebo were orally administered to five healthy males. Blood samples were taken before, and at 20, 40, 60, 90, 120, 180 and 240 min after administration, followed by the extracting procedure, and submitted to a highly sensitive enzyme immunoassay system for CGRP and substance P. Single administration of cetraxate caused significant increases in plasma CGRP concentration at 60-120 min compared with placebo. Cetraxate significantly increased plasma substance P levels at 40-90 min compared with placebo. In this study, we hypothesized that cetraxate might indirectly stimulate capsaicin-sensitive afferent nerves and increase mucosal blood flow, and that this may be a key mechanism underlying its gastroprotective action.     

Lafutidine-induced increase in intracellular ca(2+) concentrations in PC12 and endothelial cells

Lafutidine, a histamine H(2) receptor antagonist, exerts gastroprotective effects in addition to gastric antisecretory activity. The gastrointestinal protective effects of lafutidine are mediated by capsaicin-sensitive neurons, where capsaicin excites neurons by opening a member of the transient receptor potential channel family (TRPV1). Since the effect of lafutidine on the intracellular Ca(2+) concentration ([Ca(2+)](i)) in cells has not been elucidated, we investigated the lafutidine response to [Ca(2+)](i) in rat pheochromocytoma PC12 and human endothelial cells. Lafutidine at pharmacological concentrations greater than 1 mM induced a sustained increase in [Ca(2+)](i) in the presence of extracellular CaCl(2) in PC12 cells, while capsaicin showed dual effects on [Ca(2+)](i) in PC12 cells, where it activated TRPV1 and inhibited store-operated Ca(2+) entry. The thapsigargin (an activator of store-operated Ca(2+) entry)-induced increase in [Ca(2+)](i) in PC12 cells was inhibited by capsaicin and SKF96365, an inhibitor of store-operated Ca(2+) entry, and the lafutidine response was inhibited by capsaicin but not by SKF96365. In endothelial cells, lafutidine induced an increase in [Ca(2+)](i) in a SKF96365-insensitive manner. These results suggest that lafutidine stimulates Ca(2+) entry via the capsaicin-sensitive pathway but not the SKF96365-sensitive pathway. The possible role of store-operated Ca(2+) entry induced by lafutidine on gastrointestinal function is also discussed.     

Electrophysiological effects of activating the peptidergic primary afferent innervation of rat mesenteric arteries

1. Intracellular recording was used to investigate the electrophysiological effects of activating peptidergic primary afferent axons with capsaicin in the smooth muscle of rat mesenteric arteries in vitro. In addition, continuous amperometry was used to monitor the effects of capsaicin on noradrenaline release from the sympathetic nerves. 2. Capsaicin (1 microm) produced a hyperpolarization (-11+/-2 mV) and a reduction in the time constant of decay of excitatory junction potentials (e.j.p.'s) evoked by electrical stimulation of the perivascular sympathetic nerves. These effects of capsaicin were mimicked by calcitonin gene-related peptide (CGRP; 1 and 10 nm) but not by substance P (50 nm), which produced a small hyperpolarization (maximum -3+/-1 mV) but did not change excitatory junction potential (e.j.p.) time course. 3. The hyperpolarization produced by capsaicin and CGRP was blocked by glibenclamide (10 microm) but was not changed by the CGRP antagonist, CGRP8-37 (0.5 microm). Mechanical denudation of the endothelium also did not reduce the effect of capsaicin on membrane potential. 4. Capsaicin (1 microm) increased the amplitude of e.j.p.'s. This effect was not mimicked by CGRP or substance P nor blocked by glibenclamide or CGRP8-37. 5. All effects of capsaicin desensitized. 6. Capsaicin (1 microm) had no effect on noradrenaline-induced oxidation currents evoked by electrical stimulation, indicating that noradrenaline release was unchanged. 7. These results suggest that CGRP released from primary afferent axons hyperpolarizes vascular smooth muscle by activating glibenclamide-sensitive K+ channels. The findings also indicate that an unknown factor released by the primary afferent axons increases e.j.p. amplitude.     

Capsaicin research as a new tool to approach of the human gastrointestinal physiology,pathology and pharmacology

Background: Capsaicin has been found to act on the capsaicin sensitive afferent nerves in animal experiments. Aim: The specific action of capsaicin on sensory afferent nerves affecting gastrointestinal (GI) functions was investigated in human GI physiology and pathology using pharmacological approaches. Materials and Methods: Observations were carried out in 98 normal healthy human subjects and in 178 patients with different gastrointestinal diseases (gastritis, erosions, ulcer, polyps, cancer, inflammatory bowel diseases, colorectal polyps, cancers). The gastric secretory responses and their chemical composition, gastric emptying, sugar loading test, gastric transmucosal potential difference (GTPD) were investigated following with administration of (a) capsaicin alone, (b) ethanol alone or with capsaicin, and (c) indomethacin-induced gastric mucosal microbleeding with or without capsaicin, both before and after 2 weeks capsaicin treatment. Immunohistochemical investigations were performed to establish the presence of the capsaicin (vanillinoid) receptor (TRVP1), CGRP and SP in the whole GI tract. Conventional molecular pharmacological methods were applied to study the effects of capsaicin and other drugs for their inhibitory effects on the gastric basal acid output. Results: Capsaicin decreased the gastric basal output, enhanced the “non parietal” (buffering) component of gastric secretory responses, gastric emptying, release of glucagon. Capsaicin prevents the indomethacin- and ethanol-induced gastric mucosal injury, while capsaicin itself enhanced the gastric transmucosal potential difference (GTPD). The capsaicin reactive receptors, TRVP1, CGRP, SP were detected in the GI mucosa in patients with different GI disorders, but their presence varied in acute and chronic GI disorders. Conclusion: Application of capsaicin offers a new research tool for understanding the vanilloid-related events of human GI functions in relation to normal physiology and in disease states and the use of pharmacological agents affecting these receptor mediated changes. This paper was part of the Proceedings of the International Mini-Symposium on Gastrointestinal Pharmacology – Tissue Injury, Protection and Healing (10^th July 2006) Kyoto Received 2 September 2006; accepted (after revision) 22 December 2006     

Modifications of capsaicin-sensitive neurons in isolated guinea pig ileum by [6]-gingerol and lafutidine

A segment of guinea pig ileum was used to confirm the hypothesis that [6]-gingerol and lafutidine interact with capsaicin-sensitive neurons. Addition of 30 and 100 microM [6]-gingerol (a pungent constituent of ginger) induced contraction of the ileum immediately. Like capsaicin, [6]-gingerol-induced contraction was inhibited by antagonists of the vanilloid receptor (capsazepine and ruthenium red), tetrodotoxin, and atropine. Treatment with [6]-gingerol up to 0.3 microM, which alone had no effect, enhanced 3 microM capsaicin-induced contraction, but greater than 3 microM [6]-gingerol significantly inhibited capsaicin-induced contraction. Treatment with lafutidine (a new type of antagonist of the histamine H(2) receptor), which was suggested to interact with capsaicin-sensitive neurons in vivo, also showed both stimulatory and inhibitory effects on capsaicin-induced contraction depending on the concentrations. Lafutidine alone had no effect. The enhanced contraction induced by capsaicin in the [6]-gingerol- or lafutidine-treated ileum was also inhibited by antagonists of the vanilloid receptor, tetrodotoxin, and atropine. Capsaicin and [6]-gingerol, but not lafutidine, at 30 microM stimulated [(3)H]choline release from the prelabeled slices of the ileum. These findings suggest that [6]-gingerol and lafutidine act on capsaicin-sensitive cholinergic neurons and modulate the contraction in isolated guinea pig ileum.     

Role of central and peripheral ghrelin in the mechanism of gastric mucosal defence

Ghrelin, identified in the gastric mucosa, has been involved in the control of food intake and growth hormone (GH) release, but whether this hormone influences the gastric secretion and gastric mucosal integrity has been little elucidated. We compared the effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of ghrelin on gastric secretion and gastric lesions induced in rats by 75% ethanol or 3.5 h of water immersion and restraint stress (WRS) with or without suppression of nitric oxide (NO)-synthase or functional ablation of afferent sensory nerves by capsaicin. The number and the area of gastric lesions was measured by planimetry, the GBF was assessed by the H₂-gas clearance method and blood was withdrawn for the determination of the plasma ghrelin and gastrin levels. In addition, the gastric mucosal expression of mRNA for CGRP, the most potent neuropeptide released from the sensory afferent nerves, was analyzed in rats exposed to WRS with or without ghrelin pre-treatment. Ghrelin (5–80 μg/kg i.p. or 0.6–5 μg/kg i.c.v.) increased gastric acid secretion and attenuated gastric lesions induced by ethanol and WRS. This protective effect was accompanied by a significant rise in the gastric mucosal blood flow (GBF), luminal NO concentration and plasma ghrelin and gastrin levels. Ghrelin-induced protection was abolished by vagotomy and significantly attenuated by L-NNA and deactivation of afferent nerves with neurotoxic dose of capsaicin. The signal for CGRP mRNA was significantly increased in gastric mucosa exposed to WRS as compared to that in the intact gastric mucosa and this was further enhanced in animals treated with ghrelin. We conclude that central and peripheral ghrelin exerts a potent protective action on the stomach of rats exposed to ethanol or WRS, and these effects depend upon vagal activity and hyperemia mediated by the NOS-NO system and CGRP released from sensory afferent nerves.     

Role of capsaicin-sensitive afferent neurons in receptive relaxation induced by gastric distension in rats

We investigated the role of capsaicin-sensitive afferent neurons in receptive relaxation of the rat stomach in response to distension. Under urethane anesthesia, a balloon with barostat was inserted through the pylorus and placed in the forestomach. Isobaric distension was performed in a stepwise increment of 2 mmHg, each lasting for 2 min, while the corresponding intragastric volume was recorded. Gastric distension produced the intraballoon volume in a progressive manner with saturation, suggesting the occurrence of receptive relaxation of the stomach during distension. Intragastric application of capsaicin significantly enhanced the degree of receptive relaxation. The capsaicin-induced enhancement of receptive relaxation was totally abolished by bilateral vagotomy as well as chemical ablation of capsaicin-sensitive afferent neurons. Likewise, the enhanced receptive relaxation in response to stomach distension was also significantly attenuated by pretreatment of the animals with N^G-nitro-L-arginine methyl ester (L-NAME, an inhibitor of nitric oxide (NO) synthase), calcitonin gene related peptide (CGRP)_8-37 (CGRP antagonist), indomethacin and ONO-8711 (EP1 receptor antagonist). These results suggest that capsaicin significantly enhanced the receptive relaxation induced by gastric distention through both vagal nerves and capsaicin-sensitive afferent neurons. This process is intervened by endogenous NO and CGRP in addition to prostaglandins (PGs), and the effect of PGs may be mediated by EP1 receptors. Received 9 October 2006; accepted 10 November 2006     

Ecabet sodium raises plasma levels of calcitonin generelated peptide and substance P in healthy humans

Ecabet sodium (ecabet), a cytoprotective drug, produces an increase in mucosal blood flow. One of the gastrointestinal motility regulatory factors has been assumed to be the induction of changes in the levels of peptides (gastrin, somatostatin and motilin) in plasma. On the other hand, recently, capsaicinsensitive afferent nerves were shown to play an important role in gastric mucosal defensive mechanism. Capsaicin stimulates afferent nerves and enhances the release of calcitonin gene-related peptide (CGRP) and substance P in the stomach. We studied the effect of ecabet on human plasma gastrin-, somatostatin-, motilin-, CGRP- and substance P-like immunoreactive substance (IS) in healthy subjects. Ecabet sodium at a dose of 3.0 g, or placebo, was orally administered in five healthy males. The blood samples were taken before and at 20, 40, 60, 90, 120, 180 and 240 min after administration, subjected to extracting procedures, and submitted to a highly sensitive enzyme immunoassay system. Single administration of ecabet caused significant (P<0.05) increases in plasma CGRP-, substance P- and somatostatin-IS concentration compared with placebo. Ecabet significantly decreased plasma gastrin-IS levels compared with placebo. In this study, we hypothesized that ecabet might stimulate capsaicin-sensitive afferent nerves indirectly and improve mucosal blood flow; this might be a key mechanism underlying its gastroprotective action.     

Brainstem neuropeptides and vagal protection of the gastric mucosal against injury: role of prostaglandins, nitric oxide and calcitonin-gene related peptide in capsaicin afferents

Earlier experimental studies indicated that the integrity of vagal pathway was required to confer gastric protection against damaging agents. Several peptides located in the brainstem initially identified to influence vagal outflow to the stomach, as assessed by electrophysiological approach or by vagal dependent alterations of gastric secretory and motor function, were investigated for their influence in the vagal regulation of the resistance of the gastric mucosa to injury. Thyrotropin releasing hormone (TRH), or its stable TRH analog, RX-77368, injected at low doses into the cisterna magna or the dorsal motor nucleus (DMN) was the first peptide reported to protect the gastric mucosa against ethanol injury through stimulation of vagal cholinergic pathways, inducing the release of gastric prostaglandins/nitric oxide (NO) and the recruitment of efferent function of capsaicin sensitive afferent fibers containing calcitonin-gene related peptide (CGRP). Activation of endogenous TRH-TRH1 receptor signaling located in the brainstem plays a role in adaptive gastric protection against damaging agents. Since then, an expanding number of peptides, namely peptide YY, CGRP, adrenomedullin, amylin, glugacon-like peptide, opioid peptides acting on μ, δ1 or δ2 receptors, nocicpetin, nocistatin, ghrelin, leptin and TLQP-21, a peptide derived from VGF prohormone, have been reported to act in the brainstem to afford gastric protection against ethanol injury largely through similar peripheral effectors mechanisms than TRH. Therefore gastric prostaglandins and CGRP/NO pathways represent a common final mechanism through which brain peptides confer vagally mediated gastroprotection against injury. A better understanding of brain circuitries through which these peptides are released will provide new strategies to recruit integrated and multifaceted gastroprotective mechanisms.     

The mechanism of action of amtolmetin guacyl, a new gastroprotective nonsteroidal anti-inflammatory drug

Amtolmetin guacyl (2-methoxyphenyl-1-methyl-5-p-methylbenzoyl-pyrrol-2-acetamido acetate) (MED15) is a new nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic and antipyretic properties similar to the traditional drugs, but with unexpected gastroprotective effects. In an in vivo rat model, amtolmetin guacyl administered orally demonstrates inhibition of gastric acid secretion following stimulation by various agonists, and up-regulation of gastric bicarbonate production. Pretreatment with MED15 also shows a significant reduction of indomethacin-induced gastric damage in the rat. The reason behind this behaviour appears to be bound to the presence in the MED15 molecule of a vanillic moiety known to stimulate capsaicin receptors. In fact, the antisecretive effect of MED15 is blocked by capsazepine (a specific capsaicin receptor antagonist). This effect is confirmed by the interference found with anti-histamine H(1) drugs. Owing to the connection between capsaicin and calcitonin gene-related peptide (CGRP), a possible effect of MED15 on CGRP receptors was hypothesized, considering the leading role played on gastric mucosa by the predominant sensory neuropeptide of the stomach wall, CGRP. In fact, the anti-secretive and gastroprotective effect of MED15 is abolished by CGRP-(8-37) (the specific CGRP receptor antagonist). The unmodified MED15 molecule is found throughout the gastroenteric tract for long periods of time following oral administration, as further confirmation of the mechanism of action being based on the presence of the vanillic moiety at receptor level.     

The role of capsaicin-sensitive afferent nerves in protective effect of capsaicin against absolute ethanol-induced gastric lesions in rats

The role of capsaicin-sensitive afferent nerves in gastroprotection by capsaicin was investigated in the absolute ethanol-induced gastric lesion model in rats. Capsaicin (0.1 and 0.5 mg/kg, p.o.) inhibited the lesion formation dose-dependently. The protective effect of capsaicin was attenuated by indomethacin-pretreatment and disappeared in capsaicin-sensitive nerve degenerated rats. Capsaicin did not induce the distension of gastric mucosal folds. These results suggested that stimulation of capsaicin-sensitive afferent nerves by capsaicin would enhance the prostaglandin formation, leading to an inhibition of gastric lesions.     

内毒素引起离体大鼠脊髓降钙素基因相关肽释放

本文在离体灌流大鼠脊髓片观察内毒素对感觉神经元中枢端末梢降钙素基因相关肽（ＣＧＲＰ）释放的影响．结果显示内毒素及其主要毒性成分Ａ脂均能浓度依赖性地引起ＣＧＲＰ释放，内毒素的作用可被内毒素抑制剂与钠通道阻断剂河豚毒素所阻断．采用辣椒素预温育使感觉神经末梢递质耗竭，或用辣椒素受体阻断剂ｃａｐｓａｚｅｐｉｎｅ均能显著抑制内毒素引起ＣＧＲＰ释放的作用．上述结果提示内毒素是通过其主要毒性成分＃ＦＳＡ＃ＦＫ脂，刺激辣椒素敏感的感觉神经末梢而释放ＣＧＲＰ的     

High quality of ulcer healing in rats by lafutidine, a new-type histamine H2-receptor antagonist: involvement of capsaicin-sensitive sensory neurons

This study was conducted to determine whether the low recurrence rate of ulcers after treatment with lafutidine, an antiulcer drug possessing both an antisecretory and gastroprotective activities, was mediated by capsaicin-sensitive sensory neurons (CSSN). Chronic gastric ulcers in rats were induced by serosa-searing. The ulcer healing and recurrence were evaluated by endoscopy. Drugs were orally administered. Desensitization of CSSN was induced by pretreatment with capsaicin. Lafutidine (30 mg/kg) accelerated the ulcer healing significantly, and the recurrence rate was much lower than that for the vehicular control. In CSSN-desensitized rats, lafutidine also accelerated the ulcer healing significantly, but the low recurrence rate shown in normal rats was counteracted. The recurrence rate of the combination of famotidine (30 mg/kg) and teprenone (100 mg/kg) was lower than that of famotidine alone. In conclusion, the low recurrence rate of ulcers after lafutidine treatment in rats seems to depend on the gastroprotective mechanisms involving CSSN.