Increase In Mucosal Blood Flow Research Articles

Mechanisms Behind the Increased Vulnerability of the Aging Stomach to NSAID-Related Injury: Perhaps Not As Simple As We May Think

Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed to treat conditions such as arthritis and other musculoskeletal disorders in elderly patients. The usefulness of NSAIDs is, however, often limited by their associated gastrointestinal (GI) toxicity [1, 2]. Elderly patients taking long-term NSAIDs therapy are a particularly high-risk group for NSAIDs-related GI injury [3, 4]. NSAIDs-related GI injury is mainly a consequence of systemic inhibition of GI mucosal cyclooxygenase (COX) activity, which reduces levels of mucosa-protective prostaglandins (PG), for example prostaglandin E2 (PGE2), rather than a result of topical epithelial injury [5–7]. Inhibition of the two isozymes of COX, COX-1 and COX-2, is important in the pathogenesis of NSAIDs-related gastric injury [6]. COX-1 is a constitutive enzyme expressed in most cells of the body, including the stomach [6]. In contrast, COX-2 is an inducible enzyme, with increased expression in response to bacterial polysaccharides and proinflammatory cytokines [6]. Although non-selective NSAIDs (e.g., indomethacin) exert their GI ulcerogenic effects mainly through COX-1 inhibition, the GI ulcerogenic effects of NSAIDs require inhibition of both COX-1 and COX-2 [7, 8]. Mucosa-protective PGs (e.g., PGE2) contribute to gastric mucosal defense by reducing gastric acid secretion and by their nonantisecretory effects referred to as ‘‘cytoprotection’’ (e.g., stimulation of bicarbonate and glycoprotein secretion, increase in mucosal blood flow, among others) [9, 10]. It has been suggested that nitric oxide (NO) is the crucial intermediate in PGE2-mediated cytoprotection [11]. Hence, deficiency in mucosa-protective PGs or NO because of NSAIDs use is associated with compromise of gastric mucosal defense. Mechanisms independent of COX inhibition are also implicated in NSAIDs-related gastric injury. NSAIDs may also produce gastric mucosal injury by interfering with growth factors (e.g., TGF-b, TGF-a) and other mediators responsible for epithelial restitution and adaptive protection (e.g., trefoil family peptides) [12, 13]. Reactive oxygen species and apoptosis are also implicated in indomethacin-induced gastric injury [14]. Why aging stomachs are at greater risk of NSAIDsrelated injury is still poorly understood. Data from outcome studies have identified advanced age as one of the major risk factors for NSAIDs-related upper GI injury [1], possibly because of the finding that the aging gastric mucosa has reduced capacity for repair. A recent study investigating the effect of reactive oxygen species, apoptosis, and angiogenesis on the aging stomach has shown that aging gastric mucosa is gradually replaced by connective tissue, thus impairing gastric mucosal protection [15]. In rats of advanced age, angiogenesis is reduced as a result of reduced expression of VEGF and overexpression of PTEN [16]. Thus, reduction in mucosal defense mechanisms characteristic of the aging stomach may increase susceptibility to NSAIDs-related mucosal injury, although the underlying molecular pathogenesis remains poorly understood. In this issue of Digestive Diseases and Sciences, Hong et al. [17] report investigation of potential molecular mechanisms behind the increased susceptibility of the R. S. Tang (&) Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Room 94020, 7/F, Clinical Science Building, Shatin, New Territories, Hong Kong e-mail: rtang01@yahoo.com

Synthesis and Pharmacological Evaluation of Novel 1-(2-(Benzoyl-Substituted-2-phenyl-1H-Indol-5-Carbony) Hydrazinyloxy) Vinyl Nitrate Derivatives as Potent Non-Ulcerogenic, Analgesic and Anti-Inflammatory Agents

Six derivatives of 1-(2-(benzoyl-(substituted)-2-phenyl-1H-indole-5-carbony) hydrazinyloxy) vinyl nitrate were synthesized and tested in vivo for anti-inflammatory, analgesic, and ulcerogenic properties. Synthesized compounds shown significant anti-inflammatory activity comparable to that of Diclofenac sodium in the carrageenan-induced rat paw edema test and all of the compounds were found to be equipotent to Diclofenac sodium in the acetic acid induced writhing analgesic model. Out of six derivatives two derivatives found to produce no ulceration in stomach specimen of rats; nitric oxide seems to contribute to their excellent safety profile which supports several endogenous GIT defense mechanisms, including increase in mucus, bicarbonate secretions, increase in mucosal blood flow, and inhibition of the activation of pro-inflammatory cells by which NO-Indomethacin protects GI mucosa.

Ecabet sodium raises plasma levels of calcitonin gene-related 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.

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.

Role of Sensory Neurons in Restitution and Healing of Gastric Ulcers

It has been shown that capsaicin-sensitive afferent fibers play a crucial role in acute gastroprotection. Release of neurotransmitters such as calcitonin gene-related peptide (CGRP) and the consequent increase in mucosal blood flow have been identified as key factors in the protective effect of the stimulation of these fibers by capsaicin. Conversely the involvement of sensory nerves in the process of tissue repair after acute and chronic gastric mucosal damage has remained largely unexplored. Some studies, however, while demonstrating that the process of rapid repair (restitution) of the gastric mucosa damaged by ethanol is unaffected by capsaicin pretreatment, have shown that the recovery of gastric integrity after mucosal damage induced by sodium taurocholate or monochloramine, a known cytotoxic agent present in H. pylori patients, requires an intact sensory function and the maintenance of an adequate blood supply. In addition, a delayed healing (up to 1 week) of HCl-induced gastric lesions has been reported in capsaicin-deafferented rats, in association with a selective impairment of the hyperemic response to acid. Healing of gastric lesions induced by indomethacin, ischaemia and reperfusion, water restraint stress or concentrated ethanol was delayed in animals with functional ablation of sensory nerves. In a well-validated model, such as chronic gastric ulcers induced in rats by subserosal injection of acetic acid whose lesions last up to 4 weeks, the chemical ablation of sensory neurons negatively interferes with the process of chronic ulcer healing. The delay in ulcer healing was found to be associated with a persistent decrease in tissue levels of gastric CGRP and with a change of inflammatory mediators and growth factors, while gastric secretion and emptying were not concomitantly affected. Taken together, these data suggest that capsaicin-sensitive afferent nerves may play a role in the process of ulcer healing by mediating the hyperemic response through the release of CGRP and facilitating the acid disposal in the mucosa. From a therapeutic perspective, it is obvious that the compound acting on this system could have a role in the healing processes of the stomach damage.

Impaired mucus-bicarbonate barrier inHelicobacter pylori-infected mice

To resist the harsh intrinsic milieu, several lines of defense exist in the stomach. The aim of this study was to investigate the effect of the gastric pathogen Helicobacter pylori on these mechanisms in vivo. We used FVB/N mice expressing human alpha-1,3/4-fucosyl transferase (producing Lewis b epitopes) and inoculated with H. pylori 1. Mice were anesthetized with isoflurane or Hypnorm-midazolam, the stomach was exteriorized, and the surface of the corpus mucosa was exposed. Mucus thickness was measured with micropipettes, juxtamucosal pH (pH(jm)) was measured with pH-sensitive microelectrodes, blood flow was measured with laser-Doppler flowmetry, and mRNA levels of the bicarbonate transporter SLC26A9 were quantified with real-time PCR. The increase in mucosal blood flow seen in response to luminal acid (pH 1.5) in control animals (140 +/- 9% of control) was abolished in infected mice. The firmly adherent mucus layer was significantly thinner in infected mice (31 +/- 2 microm) than in control mice (46 +/- 5 microm), and no mucus accumulation occurred in infected mice. pH(jm) decreased significantly more on exposure to luminal acid in infected mice (luminal pH 1.5, pH(jm) 2.4 +/- 0.7) than in control mice (pH(jm) 6.4 +/- 0.5). Despite reduced pH(jm), SLC26A9 mRNA expression was significantly, by increased 1.9-fold, in infected mice. The reduction in pH(jm) by infection with H. pylori might be due to a reduced firmly adherent mucus layer, increased mucus permeability to H(+), and/or inhibition of bicarbonate transport. The upregulation of SLC26A9 in H. pylori-infected epithelium might be a result of continuous inhibition of the transporter, e.g., by ammonium, a H. pylori product, which has been previously shown to inhibit SLC26A9.

Comparison of the Effects of Cetraxate and its Major Metabolite on Human Plasma Gastrin, Somatostatin, Calcitonine Gene-Related Peptide and Substance P in Human Plasma

Cetraxate hydrochloride (cetraxate), an antiulcer drug, produces a dose related increase in mucosal blood flow. We have reported that cetraxate increases plasma calcitonin gene-related peptide (CGRP) and substance P in healthy human subjects (J. Pharm. Pharmacol., 56, p. 557, 2004). Cetraxate is rapidly metabolized to tranexamic acid in plasma. We investigated the effect of tranexamic acid on human plasma CGRP, substance P, gastrin and somatostatin. Tranexamic acid at a dose of 500 mg or placebo was orally administered in five healthy male volunteers. The blood samples were taken before and at 20, 40, 60, 90, 120, 180 and 240 min after administrations, followed by the extracting procedure, and submitted to the high sensitive enzyme immunoassay system for CGRP and substance P as previously developed. Single administration of tranexamic acid caused significant increases of plasma CGRP concentration at 60-90 min compared with placebo, but the level-time profile was a little different from that of cetraxate. Tranexamic acid had no significant effect on plasma gastrin, somatostatin and substance P levels compared with placebo. In this study, we thought that the gastroprotective effect of cetraxate might not be due to plasma metabolite, tranexamic acid, but direct stimulation of gastric mucosa.

Modulation of gastric function by proteinase‐activated receptors

AbstractProteinase‐activated receptor (PAR)1 and PAR2 are abundantly expressed in the gastric mucosa and smooth muscle. PAR2 modulates a variety of gastric functions, mediating secretion of mucus and pepsinogen, suppression of acid output, an increase in mucosal blood flow, and smooth muscle contraction/relaxation. PAR2 is considered primarily protective in the gastric mucosa. PARs other than PAR2 might also be involved in the modulation of gastric functions. PARs, especially PAR2, would thus appear to be novel targets for the development of drugs for treatment of gastric mucosal diseases. Drug Dev. Res. 60:9–13, 2003. © 2003 Wiley‐Liss, Inc.

Direct Detection of Nitric Oxide and its Roles in Maintaining Gastric Mucosal Integrity Following Ethanol-induced Injury in Rats

In gastric mucosal injury, nitric oxide (NO) plays both cytoprotective and cytotoxic roles, and the NO level is one determinant of these dual roles. We employed electron paramagnetic resonance (EPR)-spectrometry combined with an NO-trapping technique to directly evaluate NO production in ethanol-induced gastric injury in rats. The rat stomach, mounted on an ex vivo chamber, was perfused with ethanol (12.5 and 43%), and NO levels in mucosal tissues were measured during perfusion. Luminal nitrite/nitrate (NOx) content, mucosal blood flow, area of mucosal injury, transmucosal potential difference (PD), and luminal pH were simultaneously monitored with/without preadministration of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). NO levels in the gastric tissue increased during ethanol perfusion, and luminal NOx levels increased after the perfusion, accompanying an increase in the area of mucosal injury and changes in physiological parameters. Preadministration of L-NAME aggravated the gastric mucosal damage and suppressed increases in mucosal blood flow in a dose-dependent manner. These results demonstrate that endogenous NO produced in ethanol-induced gastric injury contributes to maintenance of mucosal integrity via regulation of mucosal blood flow.

Monochloramine impairs mucosal blood flow response and healing of gastric lesions in rats: relation to capsaicin-sensitive sensory neurons.

We examined the effects of monochloramine (NH2Cl) on the gastric mucosal blood flow (GMBF) response and the healing of ethanol-induced gastric lesions in rats. Rats fasted for 18 h were given the 99% ethanol p.o. for induction of gastric lesions, and were fed normally from 1 h later onwards. Monochloramine, at non-ulcerogenic doses (5 to approximately 20 mmol/L), was given p.o. twice daily for 7 days, starting 2 h after ethanol treatment. Gastric lesions caused by ethanol healed almost completely within 7 days with re-epithelialization. The repeated administration of NH2Cl significantly delayed the healing of ethanol-induced gastric lesions in a dose-dependent manner. The damaged mucosa showed a marked rise in H+ permeability, resulting in luminal acid loss, but this process was accompanied by an increase of mucosal blood flow. Monochloramine did not affect the increased mucosal H+ permeability observed in the stomach after damage by ethanol, but significantly inhibited the mucosal hyperemic response associated with luminal acid loss. Prior exposure of the mucosa to NH2Cl (20 mmol/L) did not affect the gastric hyperemic response caused by mucosal application of misoprostol (a prostaglandin E1 derivative) or NOR-3 (a nitric oxide donor), but totally attenuated the increase of GMBF in response to intragastric capsaicin. Impaired healing and GMBF responses were also observed in rats following chemical ablation of capsaicin-sensitive sensory neurons. These results suggest that NH2Cl impaired the healing of acute gastric mucosal lesions at low concentrations, and this action may be attributable, at least partly, to the impairment of gastric hyperemic response caused by the dysfunction of capsaicin-sensitive sensory neurons.

Effects of n–3 Polyunsaturated Fatty Acids and Vitamin E on Colonic Mucosal Leukotriene Generation, Lipid Peroxidation, and Microcirculation in Rats with Experimental Colitis

Aims: We investigated the effect of n–3 polyunsaturated fatty acids (PUFAs) on mucosal levels of leukotrienes (LTs) and lipid peroxide (LPO), and on mucosal microcirculation, in rats with experimental colitis induced by dextran sulfate sodium (DSS). Methods: We fed Wistar rats a perilla oil-enriched diet containing α-linolenic acid (63.2% of total fatty acids) with various doses of vitamin E for 4 weeks, with 4% DSS added to the drinking water during the last week. Control rats were fed a diet produced from soybean oil containing α-linolenic acid (5.1% of total fatty acids). Colonic mucosal blood flow was measured with a laser Doppler flowmeter. Results: The mucosal level of arachidonic acid was significantly lower and that of eicosapentaenoic acid was significantly higher in the experimental group. The mucosal level of LPO in the experimental group fed a trace or ordinary dose of vitamin E was significantly higher than that of the controls. The production of LTB₄ and LTC₄ from the colonic mucosa in the experimental group was significantly lower than that in controls. However, only the experimental group fed a vitamin E dose 4-fold higher than that given to the controls showed a significant increase in mucosal blood flow. Conclusion: These results suggest that n–3 PUFAs increase mucosal blood flow by inhibiting LT production when there is sufficient vitamin E to inhibit lipid peroxidation in rats with experimental colitis.

The roles of prostaglandin E receptor subtypes in the cytoprotective action of prostaglandin E2 in rat stomach.

To investigate the EP receptor subtype involved in the gastroprotective action of prostaglandin (PG) E2 using various EP receptor agonists in rats, and using knockout mice lacking EP1 or EP3 receptors. Male SD rats and C57BL/6 mice were used after an 18-h fast. Gastric lesions were induced by oral administration of HCl/ethanol (150 mM HCl in 60% ethanol). Rats were given various EP agonists i.v. 10 min before HCl/ethanol: PGE2, sulprostone (EP1/EP3 agonist), butaprost (EP2 agonist), 17-phenyl-omega-trinorPGE2 (17-phenylPGE2: EP1 agonist), ONO-NT012 (EP3 agonist) and 11-deoxyPGE1 (EP3/EP4 agonist). In a separate study, the effect of PGE2 on HCl/ethanol lesions was examined in EP1- and EP3-receptor knockout mice. Gastric lesions induced by HCl/ethanol were dose dependently prevented by PGE2: this effect was mimicked by sulprostone and 17-phenylPGE2 and was significantly antagonized by ONO-AE-829, an EP1 antagonist. Neither butaprost, ONO-NT012 nor 11-deoxyPGE1 exhibited any protective activity against HCl/ethanol-induced gastric lesions. PGE2 caused an inhibition of gastric motility as well as an increase of mucosal blood flow and mucus secretion, the effects being mimicked by prostanoids activating EP1 receptors, EP2/EP3/EP4 receptors and EP4 receptors, respectively. On the other hand, although HCl/ethanol caused similar damage in both wild-type mice and knockout mice lacking EP1 or EP3 receptors, the cytoprotective action of PGE2 observed in wild-type and EP3-receptor knockout mice totally disappeared in mice lacking EP1 receptors. The gastric cytoprotective action of PGE2 is mediated by activation of EP1 receptors. This effect may be functionally associated with inhibition of gastric motility but not with increased mucosal blood flow or mucus secretion.

Epidermal growth factor increases basal mucosal blood flow in the rat colon, a prostaglandin dependent effect.

Non-mitogenic biological activity such as modulation of mucosal blood flow is suspected to convey the protective effects of epidermal growth factor (EGF) in vivo. The aims of our present study were to determine the effects of EGF on colonic mucosal blood flow and injury induced hyperaemia in rats. Rats were pretreated with i.p. injections of vehicle, EGF, or indomethacin and EGF prior to mucosal injury. Basal mucosal blood flow and injury induced hyperaemia at the border of the damaged mucosa was determined by using reflectance spectrophotometry. EGF significantly increased basal mucosal blood flow but did not further enhance injury induced hyperaemia. The EGF induced increase in basal mucosal blood flow was completely abolished by indomethacin pretreatment. EGF induces an increase of basal mucosal blood flow through induction of prostaglandin synthesis. We hypothesize that the increase in mucosal blood flow contributes to the ability of EGF to protect the colonic mucosa against injury.

A model to explain the rapid pressure decrease after air-inflation of diseased middle ears.

Air-inflation in humans and monkeys with significant negative middle ear pressure or with middle ear inflammation was shown to cause greater than ambient middle ear pressure initially, followed by a rapid rate of pressure decrease to approach the preinflation value. A mathematical model of middle ear pressure regulation is presented and used to simulate air-inflation of the normal and diseased middle ear. The model represents the total volume of the middle ear as consisting of three subcompartments representing the airspace, effusion, and mucosa/blood. Gas exchange among those compartments was assumed to be diffusion limited, and the gas exchange between the mucosa/blood compartment and systemic blood was assumed to be perfusion limited. Disease was modeled as an increase in mucosal blood flow or, alternatively, as an increase in the volumes of the effusion and mucosa/blood compartments. The predictions of the model agree better with the experimental data when the increased rate of pressure change after middle ear inflation in diseased ears is driven by an increased volume of the effusion compartment as opposed to an increased perfusion rate. The responsible mechanism is a rapid redistribution among subcompartments of the gas volume introduced into the air compartment. These results suggest that middle ear inflation with inert gas can be used to diagnose the presence and relative amount of middle ear effusion, and that current protocols for treating otitis media with effusion using inflation need to be modified to optimize their intended effect.

Role of nitric oxide in mucosal blood flow response and the healing of HCl-induced lesions in the rat stomach.

The role of nitric oxide (NO) in the gastric mucosal blood flow response and the healing of HCl-induced gastric lesions was investigated in rats. After 18 h fasting rats were given 0.6 N HCl p.o. for the induction of gastric lesions, and 1 h later they were fed normally. After induction of gastric lesions, they were repeatedly administered the NO synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME 5-20 mg/kg p.o. twice daily) or aminoguanidine (20 mg/kg s.c. once daily) for 7 days. Gastric lesions caused by HCl healed almost completely within 5 days with granulation and to an extent with re-epithelialization. Repeated administration of L-NAME but not aminoguanidine significantly delayed the healing of gastric lesions in a dose-dependent manner. The damaged mucosa secreted less acid, but showed a marked rise in H+ permeability, resulting in luminal acid loss accompanied by an increase of mucosal blood flow. Aminoguanidine did not significantly affect any of these functional changes observed in the stomach after damage by HCl, whereas L-NAME treatment slightly reversed the decreased acid response, increased the luminal H+ loss, and totally inhibited the mucosal hyperemic response associated with luminal acid loss in the damaged mucosa. In addition, the deleterious influences of L-NAME on the mucosal blood flow response and the healing of gastric lesions were significantly antagonized by co-administration of L-arginine but not of D-arginine (500 mg/kg x 2, i.p.). Luminal output of NO2-/NO3- was significantly increased in pylorus-ligated stomachs in control rats on days 3 and 5 after damage, and such increases in gastric NO output were completely attenuated by L-NAME treatment. These results suggest that endogenous NO may contribute to the healing of acute gastric injury by mediating the mucosal hyperemic responses associated with acid back-diffusion and by facilitating acid disposal in the damaged mucosa. NO mediating such responses and participating in the healing aspect of gastric lesions may be produced by the constitutive type of NO synthase.

Effect of nitric oxide on stress-induced gastric mucosal injury in the rat.

Although nitric oxide (NO) has been known to play important roles in various biological events, the pathophysiological role of NO in the stomach remains to be elucidated. Since endotoxin induces NO synthase (NOS) in various tissues, the effect of lipopolysaccharide (LPS) on the stomach was studied in rats which were given water-immersion-restraint (WIR) stress. WIR treatment significantly increased the vascular permeability of gastric mucosa and induced mucosal injury. When LPS was injected intravenously to the rat, inducible-type NOS (iNOS) markedly increased in the gastric smooth muscular layer without affecting levels of brain-type isozyme (bNOS). LPS also increased gastric mucosal blood flow but suppressed the secretion of gastric acid. NG-(1-iminoethyl)-L-ornithine (NIO), a potent inhibitor of NOS, completely inhibited the LPS-induced increase in mucosal blood flow without affecting the acid secretion in control and LPS-treated rats. LPS markedly suppressed the WIR-induced mucosal injury by some NIO-inhibitable mechanism. These findings suggested that NO derived from gastric iNOS might play important roles in the suppression of stress-induced mucosal injury of the stomach.

Role of Capsaicin-Sensitive Sensory Neurons and Nitric Oxide in the Protective Effect of Lansoprazole, a Proton Pump Inhibitor, on the Gastric Mucosa in Rats

The mucosal protective effect of lansoprazole, a proton pump inhibitor, was examined in ethanol- and acidified taurocholate-induced rat gastric lesion models. The formation of gastric lesions was markedly inhibited by prostaglandin E2 but hardly inhibited by cimetidine, ranitidine and famotidine. Lansoprazole (3–30 mg/kg, p.o.) inhibited the formation of gastric lesions in a dose-dependent manner, with ID50 values of 8.5 (ethanol) and 4.1 mg/kg, p.o. (acidified taurocholate). The protective effect of lansoprazole was significantly decreased by functional ablation of capsaicin-sensitive sensory neurons or prior administration of indomethacin or Nω-nitro-L-arginine methyl ester (L-NAME), a selective inhibitor of nitric oxide (NO) synthesis. The inhibitory effect of L-NAME was antagonized by prior administration of L-arginine, a substrate of endogenous NO, but not D-arginine. The antisecretory effect of lansoprazole on the basal acid secretion in pylorus-ligated rats was not affected by any of these treatments. Lansoprazole (5 and 15 mg/ml) administered directly into the gastric chamber obviously increased both the production of NO in the mucosa and mucosal blood flow, which was prevented by pretreatment with L-NAME. These results suggest that capsaicin-sensitive sensory neurons, NO and prostaglandins are involved in the mucosal protection afforded by lansoprazole possibly via an increase in mucosal blood flow, but are not involved in the antisecretory action of lansoprazole.

Topical nicotine protects rat gastric mucosa against ASA-induced damage a role for mucosal fluid secretion in cytoprotection

Acute intragastric nicotine administration has previously been shown to protect against ethanol-induced gastric mucosal damage. The aim of this study was to examine the effects of acute nicotine exposure on ASA-induced gastric mucosal damage and to determine if nicotine's protective effect is secondary to an increase in mucosal blood flow or in mucosal fluid secretion, as reflected by changes in the juxtamucosal pH gradient and volume of intragastric fluid. Mucosal blood flow, using a laser Doppler flowmeter, juxtamucosal pH gradient (depth, magnitude, and surface pH), using antimony microelectrodes, and changes in volume of luminal bathing solutions were measured in rat ex vivo gastric chamber preparations prior to and after a 10-min exposure to topical nicotine (1 mg in 8 ml of 0.2 M mannitol in 50 mM HCl), or to mannitol-HCl solution (vehicle). This was followed by application of acidified ASA (80 mM in 160 mM HCl) to the chambered mucosae for 10 min. Lesion area, expressed as the percentage of total glandular mucosa which was damaged, was significantly (P < 0.05) reduced by nicotine pretreatment. Blood flow decreased with nicotine exposure by 18.4%, compared to 13.6% in the control group (NS). Both gradient depth and gastric fluid volume increased significantly in the nicotine group (P < 0.05) compared to controls. Yohimbine pretreatment prevented both the increase in juxtamucosal pH gradient depth and the protective effect of nicotine. These results suggest that acute intragastric nicotine exposure protects against ASA-induced gastric damage in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

EGF induced increase in mucosal blood flow in the rats is prostaglandin dependent

EGF induced increase in mucosal blood flow in the rats is prostaglandin dependent

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.