Gastric Blood Flow Research Articles

Gastric adaptation to aspirin and stress enhances gastric mucosal resistance against the damage by strong irritants.

Gastric mucosal adaptation to injury induced by repeated application of aspirin (ASA) or stress is a well-documented phenomenon, but it is known whether such adaptation affects the mucosal tolerance to other strong irritants. In this study gastric adaptation was induced by repeated daily administration of acidified ASA for 4 consecutive days (Series A) or by 3.5H of water immersion and restraint stress (WRS) applied every other day for up to 8 days (series B). When the adaptation to ASA or WRS was fully developed, rats of series A and B were challenged with strong irritants such as 100% ethanol, 200 mM acidified taurocholate (TC), or 25% NaCl for 1 h or with WRS for 3.5 h. ASA or WRS applied once produced numerous gastric lesions and deep histologic necrosis accompanied by a decrease in gastric blood flow. With repeated application of ASA or stress the mucosal adaptation to ASA and WRS developed; the area of gastric lesions was reduced by 86% and 56%, respectively, and this was accompanied by a marked decrease of superficial and deep necrosis, and increase in gastric blood flow (GBF) and the enhancement of mucosal regeneration. An increase in mucosal and luminal contents of epidermal growth factor (EGF) and in mucosal expression of EGF receptors was also observed in the mucosa adapted to ASA or stress. In rats adapted to ASA or stress and then challenged with 100% ethanol, 200 mm TC, 25% NaCl, stress or ASA, the areas of macroscopic gastric lesions and deep histologic necrosis were remarkable reduced as compared with those in non-adapted vehicle-treated rats. This was also accompanied by a significant decrease in (GBF), a marked increase of mucosal and luminal contents of EGF and expression of its receptors, and enhanced mucosal cell proliferation. Gastric adaptation to ASA or stress enhances mucosal resistance to the injury induced by strong irritants, and this appears to be mediated by mucosal regeneration, probably resulting from increased luminal and mucosal contents of EGF and excessive expression of its receptors.

Mucosal irritation, adaptive cytoprotection, and adaptation to topical ammonia in the rat stomach.

The urease-ammonia (NH4OH) system has been proposed to play a major role in the pathogenesis of the Helicobacter pylori-associated gastritis, but the mechanism of the mucosal damage has not been fully explained. This study was designed to examine possible adaptive cytoprotection and the adaptation of rat gastric mucosa to the irritant action of NH4OH and urease. Single application of NH4OH alone in various concentrations (15-500 mM) caused concentration-dependent mucosal damage starting with 30 mM and reaching a maximum at 250 mM NH4OH, similar to that obtained with 100% ethanol; it was accompanied by a decrease in gastric blood flow (GBF) to approximately 30% of the normal value. When the mucosa was first exposed to the low, non-damaging concentration (15 mM) of NH4OH and then insulted with 100% ethanol, the extent of ethanol damage was greatly attenuated as compared with that caused by ethanol alone. This adaptive cytoprotection was accompanied by the rise in GBF and reversed, in part, by the pretreatment with indomethacin, an inhibitor of prostaglandin (PG)-cyclooxygenase; with L-NAME, a blocker of NO-synthase; or with capsaicin deactivating the sensory nerves. Damaging concentrations of NH4OH (125 mM) caused widespread mucosal damage after the first application, but with repeated insults with 125 mM NH4OH a gradual reduction in the mucosal lesions, accompanied by enhanced mucosal cell proliferation and over-expression of epidermal growth factor (EGF) (using immunocytochemistry) and mRNA of EGF (using trans-reverse polymerase chain reaction), were observed. NH4OH alone damages gastric mucosa only at the concentration exceeding that found in H. pylori-infected stomachs, whereas at lower concentrations it acts as 'mild' irritant to induce adaptive cytoprotection. This adaptive cytoprotection appears to be mediated, in part, by endogenous PG, sensory nerves, and an arginine-NO-dependent pathway, and repeated applications of NH4OH induce gastric adaptation, probably mediated by enhanced expression of EGF and its receptors and by an increased cell proliferation.

Prostaglandins modulate the responsiveness of the gastric microcirculation of sodium nitroprusside in cirrhotic rats

Cirrhotic rats have an increased susceptibility to ethanol-induced gastric injury, related to an inability to mount a defensive gastric hyperemic response to luminal irritants, and associated with an impaired reactivity of the gastric microcirculation to nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)-dependent vasodilators. Whether this hyporesponsiveness is in some way related to depressed prostaglandin synthesis by the stomach of cirrhotic rats is not clear. The aims of this study were to evaluate the role of NO and prostaglandins in the regulation of the gastric microcirculation under resting conditions and in response to administration of sodium nitroprusside, as well as to investigate the mechanisms of the hyporesponsiveness of the gastric microcirculation to nitrovasodilators. Cirrhosis was induced in rats by bile duct ligation, and controls had sham-operation. NG-nitro-L-arginine-methyl-ester (L-NAME) and indomethacin administration produced a greater reduction in gastric blood flow in cirrhotic rats than controls. Indomethacin pretreatment almost completely abolished the responsiveness to sodium nitroprusside (NaNP) in cirrhotic rats, while not affecting controls. Long-term administration of misoprostol to cirrhotic rats restored to normal the responsiveness to NaNP, whereas long-term administration of aspirin to healthy rats resulted in a hyporesponsiveness of the gastric microcirculation to NaNP similar to that seen in cirrhotic rats. We conclude that there are interactions between NO and prostaglandins in regulating gastric blood flow in both healthy and cirrhotic rats. The hyporesponsiveness of the gastric microcirculation of cirrhotic rats to a nitrovasodilator may occur as a consequence of prolonged depression of gastric prostaglandin synthesis.

Gastric mucosal damage and adaptive protection by ammonia and ammonium ion in rats.

Helicobacter pylori (Hp) is considered as the major pathogen in Hp-associated gastritis but the mechanism of its action has not been fully explained. We investigated both the damaging and protective effects of intragastric (i.g.) application of ammonia (NH4OH) and ammonium ion (NH4Cl), the major products of Hp-derived urease, on the rat stomach with intact and capsaicin-deactivated sensory nerves or suppressed prostaglandin (PG) and nitric oxide (NO) synthesis. NH4OH given i.g. resulted in a concentration-dependent mucosal damage starting at 30 mM and reaching maximum at 250 mM (pH 11), the extent of damage being similar to that obtained with 100% ethanol. NaOH solution (1 mM) at pH 11 given i.g. did not affect mucosal integrity. The damage caused by NH4OH was accompanied by the fall in gastric blood flow (GBF) reaching at 250 mM NH4OH about 30% of the vehicle control value. The NH4OH-induced gastric damage was augmented by capsaicin-induced deactivation of sensory nerves, the suppression of nitric oxide (NO) synthase with L-NAME or the decrease of i.g. acidity by ranitidine. The pretreatment with scavengers of reactive oxidants significantly reduced the area of NH4OH-induced gastric lesions. When the mucosa was first exposed to a low 15-mM concentration of NH4OH and then insulted with large 250 mM NH4OH or with 100% ethanol, the lesion area was markedly reduced as compared to that obtained with 250 mM NH4OH or 100% ethanol alone. This adaptive protection by 'mild' concentration of NH4OH against strong irritants (250 mM NH4OH or 100% ethanol) was reversed, in part, by pretreatment with L-NAME and indomethacin. NH4Cl (60-500 mM) given i.g. alone failed to affect the mucosal integrity but when applied before 100% ethanol it produced a concentration-dependent fall in the mucosal damage by these irritants. We conclude that; (1) ammonia at higher concentrations damages the gastric mucosa, while ammonium ion exerts the protective activity; (2) the ammonia-induced gastric damage may involve the formation of reactive oxidants; (3) ammonia at lower concentration acts like a mild irritant via the activation of sensory nerves, NO-arginine pathway and PG.

Prostaglandins modulate the responsiveness of the gastric microcirculation of sodium nitroprusside in cirrhotic rats

Cirrhotic rats have an increased susceptibility to ethanol-induced gastric injury, related to an inability to mount a defensive gastric hyperemic response to luminal irritants, and associated with an impaired reactivity of the gastric microcirculation to nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)-dependent vasodilators. Whether this hyporesponsiveness is in some way related to depressed prostaglandin synthesis by the stomach of cirrhotic rats is not clear. The aims of this study were to evaluate the role of NO and prostaglandins in the regulation of the gastric microcirculation under resting conditions and in response to administration of sodium nitroprusside, as well as to investigate the mechanisms of the hyporesponsiveness of the gastric microcirculation to nitrovasodilators. Cirrhosis was induced in rats by bile duct ligation, and controls had sham-operation. NG-nitro-L-arginine-methyl-ester (L- NAME) and indomethacin administration produced a greater reduction in gastric blood flow in cirrhotic rats than controls. Indomethacin pretreatment almost completely abolished the responsiveness to sodium nitroprusside (NaNP) in cirrhotic rats, while not affecting controls. Long-term administration of misoprostol to cirrhotic rats restored to normal the responsiveness to NaNP, whereas long-term administration of aspirin to healthy rats resulted in a hyporesponsiveness of the gastric microcirculation to NaNP similar to that seen in cirrhotic rats. We conclude that there are interactions between NO and prostaglandins in regulating gastric blood flow in both healthy and cirrhotic rats. The hyporesponsiveness of the gastric microcirculation of cirrhotic rats to a nitrovasodilator may occur as a consequence of prolonged depression of gastric prostaglandin synthesis. (Hepatology 1996 Jan;23(1):123-9)

Dobutamine increases oxygen consumption during constant flow cardiopulmonary bypass

We have studied the effects of flow and dobutamine on systemic haemodynamic variables, oxygen delivery (DO2) and oxygen consumption (VO2) in 20 patients during cardiopulmonary bypass (CPB) with mild hypothermia (34 degrees C). In a subgroup of seven patients, we also studied the effects on gastric microcirculatory blood flow (MCF) using laser Doppler flowmetry. During CPB, measurements were made before and after two interventions: the first consisted of increasing flow from 2.4 to 3.0 litre min-1 m-2 for 10 min; the second consisted of an infusion of dobutamine at a rate of 6 micrograms kg-1 min-1 for 10 min during constant flow CPB. There were no significant differences in DO2, VO2 or haemodynamic variables between the two baseline measurements. The increase in flow raised DO2 (27%, P < 0.001), mean arterial pressure (P < 0.01) and MCF (P < 0.01), but failed to increase VO2. In contrast, dobutamine infusion increased VO2 (11%, P < 0.001) during constant flow CPB without significant changes in DO2, systemic haemodynamic variables or MCF. These results indicate that increases in VO2 during dobutamine may be flow-independent.

Gastric acid secretion after blockade of angiotensin AT 1 receptors in the Na +-depleted rat

This study tested the hypothesis that angiotensin II acting through the angiotensin AT 1 receptor plays an important role in the control of gastric acid secretion. Basal gastric acid secretion and gastric blood flow were lower in Na +-depleted animals, in which the renin-angiotensin system was activated, than in animals maintained on a normal Na + diet. Intravenous infusion of pentagastrin at 0.6 μg/kg/min increased gastric acid secretion to a greater extent in normal Na + than in Na +-depleted animals. In addition to stimulating gastric acid secretion, pentagastrin increased gastric blood flow by proportionally the same amount in both normal and low Na + animals. However, because basal gastric blood flow was considerably reduced in Na +-depleted animals, the increase produced by pentagastrin extended only to the levels observed in non-pentagastrin-treated normal Na + animals. Lower gastric blood flow in response to pentagastrin may explain the smaller increase in gastric acid secretion observed in Na +-depleted animals. In Na +-depleted animals, the selective angiotensin AT 1 receptor antagonist losartan did not affect basal gastric acid secretion or gastric blood flow, suggesting the involvement of mechanisms other than angiotensin II. Following blockade of angiotensin AT 1 receptors, pentagastrin significantly increased gastric blood flow in Na +-depleted animals to levels observed with infusion of the pentapeptide in normal Na + animals. The results suggest that the decrease in pentagastrin-stimulated acid secretion in Na +-depleted animals is mediated by angiotensin II acting through the angiotensin AT 1 receptor, most probably through vascular mechanisms.

Gastric adaptation to injury by repeated doses of aspirin strengthens mucosal defence against subsequent exposure to various strong irritants in rats.

Gastric adaptation to injury during repeated doses of acetyl salicylic acid (ASA) is a well documented finding but it is not known whether this adaptation affects the tolerance of the mucosa to other strong irritants. Gastric adaptation was induced by repeated daily doses of acidified ASA (100 mg/kg in 1.5 ml of 0.2 N HCl) given intragastrically (series A rats). Control rats with an intact stomach were given daily intragastric vehicle only (1.5 ml of 0.2 N HCl) (series B). After full adaptation to ASA (5 days), rats were challenged again with acidified ASA or, for comparison, with strong irritants such as 100% ethanol, 200 mM acidified taurocholate, or 25% NaCl for 1 hour or with water immersion and restraint for 3.5 hours. The first dose of ASA produced numerous gastric lesions and deep histological necrosis accompanied by a fall in the gastric blood flow, negligible expression of epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) or their receptors, and no evidence of mucosal proliferation. As adaptation to ASA developed, however, the areas of gastric lesions were reduced by more than 80% and there was a noticeable decrease in deep necrosis, a partial restoration of gastric blood flow, an approximately four-fold increase in EGF expression (but not in TGF alpha) and its receptors, and an appreciable increase in mucosal cell proliferation compared with vehicle treated rats. Increases in the mucosal expression of EGF receptors and the luminal content of EGF were also found in ASA adapted animals. In ASA adapted rats subsequently challenged with 100% ethanol, 200 mM TC, 25% NaCl, or stress, the area of the gastric lesions and deep histological necrosis were appreciably reduced compared with values in vehicle treated rats. This increased mucosal tolerance to strong irritants was also accompanied by the return of the gastric blood flow towards control levels and further significant increases in the mucosal expression of EGF receptors and mucosal cell proliferation. Gastric adaptation to ASA enhances the mucosal resistance to injury by strong irritants probably as a result of the restoration of the gastric blood flow and increased cell proliferation that may result from increased mucosal expression of EGF and its receptors.

Anemia increases gastric blood flow in noncirrhotic and cirrhotic patients

Background: Previous studies in rats have demonstrated that anemia induces a significant increment in gastric mucosal blood flow. In the present study, we investigated whether chronic anemia induces similar changes in gastric blood perfusion in humans, and if this effect is also present in cirrhotic patients in whom gastric blood flow is usually increased in basal conditions. Methods: Gastric mucosal blood perfusion was assessed by means of laser-Doppler flowmetry and reflectance spectrophotometry applied through the endoscope. Results: Anemia significantly increases laser-Doppler signal in cirrhotic (2.3 ± 0.11 vs 2.9 ± 0.22 volts, p < 0.05) and noncirrhotic patients (1.71 ± 0.15 vs 2.24 ± 0.17, p < 0.05). In anemic patients the index of hemoglobin concentration of the gastric mucosa, assessed by reflectance spectrophotometry, was significantly decreased in cirrhotic patients (107.6 ± 4.7 vs 95.5 ± 3.3, p < 0.05) and noncirrhotic patients (93.9 ± 4.1 vs 76.1 ± 4.2, p < 0.01), whereas the index of oxygen saturation was increased (36.7 ± 0.7 vs 40.4 ± 1.4, p = 0.05; and 36.4 ± 1.1 vs 43.2 ± 1.9, p < 0.01, respectively). Conclusions: In conclusion, chronic anemia is associated with an enhanced gastric blood perfusion reflected by an increased laser-doppler signal and gastric mucosal oxygen index despite a decrease in gastric hemoglobin concentration. In cirrhotic patients, anemia promotes a further increment in its basal gastric hyperemia. (Gastrointest Endosc 1995;42:403-7.)

Role of gastric blood flow in impaired defense and repair of aged rat stomachs.

To study impaired gastric mucosal tolerance against noxious agents in aged rats, possible factors underlying this observation were compared in anesthetized Fisher 344 young and aged rats. The gastric mucosa was damaged by in situ exposure to 80% ethanol for 30-45 s and by 1 M NaCl for 10 min followed by saline (pH = 1.0) for 60 min in chambered stomachs. The lesion area was significantly larger and epithelial restitution was significantly slower in aged than in young rats after both types of injury. Changes in gastric blood flow were monitored by laser-Doppler velocimetry. Young, but not aged, rats showed a marked increase in gastric blood flow in response to 1 M NaCl, acid challenge, and 640 microM capsaicin for 60 min. Young rats showed a higher density of calcitonin gene-related peptide (CGRP)-staining nerve fibers around submucosal blood vessels and higher mucosal release of prostaglandin E2 and leukotriene C4 than did aged rats. These data suggest that impaired mucosal defense and reduced restitution in aged rats is related to lack of hyperemic response caused by mucosal injury and H+ back-diffusion, which is probably due to decreased density of CGRP-staining nerve fibers and prostaglandin biosynthetic capacity in the mucosa.

The role of glucagon in the gastric hyperdynamic circulation of cirrhotic portal hypertensive rats.

The role of glucagon as a mediator of gastric hyperdynamic circulation, induced by carbon tetrachloride (CCl4), was assessed in cirrhotic rats. A selective elimination of pancreatic glucagon from the circulation was achieved by the intravenous infusion of a glucagon antiserum. Gastric blood flow was measured by laser-Doppler flowmetry. The glucagon antiserum had no effect on the blood flow in the stomach in control rats, while in cirrhotic portal hypertensive rats, the glucagon antiserum significantly reduced gastric blood flow (30%). The glucagon antiserum did not completely exclude the gastric hyperdynamic state in the cirrhotic rats. It would thus appear that glucagon contributes to a portion of the gastric hyperdynamic circulation associated with cirrhotic portal hypertension.

Gastric microcirculatory disturbance and behaviour of leucocytes after thermal injury: intravital observation of arteriovenous shunting channels in the gastric submucosal layer.

In order to investigate the pathogenesis of acute gastric mucosal lesion after thermal injury, microcirculatory disturbance was assessed and observation of the behaviour of leucocytes was performed. Gastric blood flow decreased at 15 min post-thermal injury, and partially improved at 2 h; however, it decreased again at 5 h post-thermal injury. Mucosal microcirculatory disturbance was observed by using vascular labelling with monastral blue B. Deposits of monastral blue B were observed centring mainly on collecting venules but were also observed in the capillaries. Submucosal microcirculatory disturbance was observed through an intravital microscope. The irregularity of the wall and segmental constriction in the venules and presence of an arteriovenous shunting channel was observed in the submucosal layer at 5 h post-thermal injury. The percentage of rolling or sticking leucocytes that passed the confluence of a prevenule and a venule were significantly increased at 5 h after thermal injury. The present study revealed depression of gastric blood flow, mucosal and submucosal microcirculatory disturbance, and a significant increase of rolling and sticking leucocytes in the peripheral part of venules after thermal injury. Leucocyte-endothelial interactions may occur under such conditions and this interaction may play an important role in inducing the microcirculatory disturbance that results in an acute gastric mucosal lesion after thermal injury. The present study also demonstrated the possibility of intravital study of gastric submucosal arteriovenous shunting channels.

Effects of medical vagotomy and sympathectomy on gastric mucosal prostaglandins in water immersion restrain rats

Ulcer index (UI), gastric submucosal blood flow (SMBF), gastric fundic mucosal content of 5 prostaglandins (PGE2, TXB2, PGF2 alpha, PGD2, 6-keto-PGF1 alpha) were measured in water immersion restrain rats under medical vagotomy (MV) or medical sympathectomy (MSp). UI decreased under MV and MSp with 6 hours stress. SMBF decreased less under MV and MSp than control rats. PGE2 of control rats decreased under stress, but increased under MV and MSp. It is resulted that MV and MSp effect PGE2 to increase, inhibition of SMBF decreasing because of increasing PGE2 were recognised and there for stress ulcer were inhibited.

P-342 The changes of gastric wall blood flows after portal pressure depression in portal hypertension due to liver cirrhosis - Comparison of portal pressure and endoscopic and color Doppler-endoscopic ultrasonic findings between before and after tipss-

P-342 The changes of gastric wall blood flows after portal pressure depression in portal hypertension due to liver cirrhosis - Comparison of portal pressure and endoscopic and color Doppler-endoscopic ultrasonic findings between before and after tipss-

Reduction of gastrointestinal injury in acute endotoxic shock by flurbiprofen nitroxybutylester

Nitric oxide has been reported to have paradoxical effects in experimental endotoxic shock, contributing to the hemodynamic consequences of endotoxin administration, but apparently protecting the gastrointestinal mucosa. A novel class of nitric oxide-releasing nonsteroidal anti-inflammatory drug (NSAID) derivatives has recently been described which exert anti-inflammatory activities but produce significantly less gastrointestinal injury than the parent nonsteroidal anti-inflammatory drugs from which they are derived. Thus, the present study was performed to determine the effects of one of these derivatives, flurbiprofen 4-nitroxybutylester, compared to the native nonsteroidal anti-inflammatory drug, flurbiprofen, in an experimental model of endotoxic shock. Intravenous administration of endotoxin from Salmonella typhosa to rats pretreated with flurbiprofen produced a profound decrease in systemic arterial blood pressure, an increase in hematocrit and extensive gastric and small intestinal damage. In rats pretreated with flurbiprofen 4-nitroxybutylester, endotoxin produced comparable changes in blood pressure and hematocrit to those seen in rats treated with flurbiprofen; however, the severity of gastrointestinal damage was significantly reduced. Gastric blood flow was profoundly decreased following endotoxin administration, but was significantly higher in rats pretreated with flurbiprofen 4-nitroxybutylester than in rats pretreated with flurbiprofen. These results demonstrate that despite not affecting the acute systemic effects of endotoxin administration, flurbiprofen 4-nitroxybutylester is capable of protecting the gastrointestinal mucosa from injury, possibly through preservation of mucosal blood flow.

Evidence against a role for inducible nitric oxide synthase in the hyperdynamic circulation of portal-hypertensive rats

Background/Aims Excessive nitric oxide biosynthesis caused by expression of inducible NO synthase has been implicated in the hyperdynamic circulation of portal hypertension. The aim of the study was to investigate whether inducible NO synthase is expressed in portal hypertension and accounts for the hyperdynamic circulation. Methods In study 1, NO synthase activities were measured by the conversion of l-arginine to citrulline in tissues from portal-hypertensive, cirrhotic, and sham-operated rats and from normal rats pretreated with endotoxin and after long-term administration of dexamethasone, which inhibits the expression of inducible NO synthase. In study 2, systemic and splanchnic hemodynamics (radiolabeled microspheres) and gastric blood flow (hydrogen gas clearance and reflectance spectrophotometry) were measured in portal-hypertensive rats after long-term administration of dexamethasone (0.25 mg·kg −1·day −1) or vehicle. Results In study 1, constitutive and inducible NO synthase activities in portal-hypertensive or cirrhotic rats were similar to those observed in sham-operated rats. The significant increase in the inducible activity observed after endotoxin injection was prevented when rats received long-term treatment with dexamethasone. In study 2, cardiac index, portal-pressure, portal venous inflow, and gastric blood flow were similar in dexamethasone or vehicle-treated portal-hypertensive rats. Conclusions These results do not support a role for an increased expression of the inducible NO synthase in the hyperdynamic circulation of portal hypertension.

Effect of nitric oxide on integrity, blood flow and cyclic GMP levels in the rat gastric mucosa: modulation by sialoadenectomy.

1. The effects of the nitrosothiol, S-nitroso N-acetylpenicillamine (SNAP) which liberates nitric oxide (NO), on ethanol-mediated gastric damage, blood flow and cyclic GMP levels in siaoloadenectomized (SALX) rats have been investigated. 2. Intraluminal instillation of ethanol (5-50% w/v) dose-dependently induced haemorrhagic damage and decreased NO synthase activity in the gastric mucosa. Both the extent of mucosal damage and inhibition of NO synthase activity were exacerbated in SALX rats. 3. Epidermal growth factor administration (5 and 10 micrograms kg-1, s.c.) reduced mucosal damage but did not restore NO synthase activity in ethanol-treated SALX rats. 4. SNAP infusion (0.01-1.0 micrograms kg-1 min-1, i.v.) attenuated haemorrhagic damage in ethanol-treated rats. The reduction in mucosal damage was significantly greater in SALX rats. 5. SNAP administration also caused an increase in gastric mucosal blood flow and cyclic GMP levels in control rats and both responses were augmented in SALX animals. 6. These data suggest that SALX is associated with increases in mucosal susceptibility to ethanol-mediated damage and reduces mucosal NO synthase activity. Epidermal growth factor does not appear to influence mucosal NO synthase in ethanol-treated rats. Furthermore, SALX augments the responsiveness of the gastric mucosa to NO administration. Therefore, factors from the salivary glands influence gastric NO formation and mucosal responsiveness to a NO donor.

Role of endogenous gastrin in gastroprotection

Gastrin has a potent influence on gastric acid secretion and mucosal growth but its role in mucosal integrity has been little studied. This study investigated in rats whether gastrin protects the gastric mucosa against the damage by 100% ethanol and what are the possible mechanisms of this protection. Exogenous gastrin-17 (0.6–5.0 pmol/kg) injected subcutaneously (s.c.) reduced dose dependently ethanol-induced mucosal damage and the dose decreasing the ethanol lesions by 50% was about 1.8 pmol/kg. The protection afforded by gastrin-17 was accompanied by a dose-dependent increase in gastric blood flow and these effects were almost completely abolished by the pretreatment with specific CCK B (L-365,260) but not CCK A receptor antagonist (loxiglumide). Endogenous gastrin released by intragastric (i.g.) peptone meal or s.c. injection of gastrin-releasing peptide prevented the formation of acute ethanol-induced lesions and these effects were also abolished by the pretreatment with L-365,260 but not by loxiglumide. The inhibition of nitric oxide (NO) synthase, by N G-nitro- l-arginine methyl ester almost completely eliminated both the protective and hyperemic effects of gastrin-17 and the addition of l-arginine (but not d-arginine) to N G-nitro- l-arginine-methyl ester restored, in part, these effects of gastrin-17. Deactivation of sensory nerves with capsaicin did not influence the protective or hyperemic effects of gastrin-17. We conclude that both exogenous and endogenous gastrin exert its protective activity against ethanol damage of gastric mucosa and this effect is mediated through the interaction with specific CCK B receptors and arginine-NO pathway, but does not involve sensory nerves.

Impaired vasodilatory responses in the gastric microcirculation of anesthetized rats with secondary biliary cirrhosis

Background/Aims : The increased susceptibility of the stomach to injury observed in portal hypertension may be related to a defect in the hyperemic response to luminal irritants. The aim of this study was to evaluate the components that mediate this hyperemic response in a rat model of cirrhosis and portal hypertensive gastropathy. Methods : Cirrhosis was induced by bile duct ligation, whereas controls underwent sham operation. Gastric blood flow responses to topical application of acid, capsaicin, nitrovasodilators, misoprostol, 8-bromo-cyclic guanosine monophosphate, and 8-bromo-cyclic adenosine monophosphate were measured by laser Doppler flowmetry using an ex vivo gastric chamber preparation. Calcitonin gene-related peptide immunoreactivity was used as an index of the anatomic integrity of the sensory afferent neurons of the stomach. Results : Blood flow responses to acid, capsaicin, nitrovasodilators, and 8-bromo-cyclic guanosine monophosphate were significantly depressed in cirrhotic rats, whereas they were augmented after topical application of misoprostol and 8-bromo-cyclic adenosine monophosphate. Calcitonin gene-related peptide immunoreactivity was similar in the stomachs of cirrhotic and control rats. Conclusions : Gastric vasodilation after stimulation of sensory afferent neurons is impaired in cirrhotic rats despite the normal anatomic distribution of these nerves. This effect seemed to be related to a depressed response of the gastric microcirculation to cyclic guanosine monophosphate-dependent vasodilators. This alteration may contribute to the increased susceptibility to gastric ulceration in cirrhotics.

Interaction between nitric oxide and prostaglandins in regulating gastric blood flow in cirrhotic rats

Interaction between nitric oxide and prostaglandins in regulating gastric blood flow in cirrhotic rats