Effect of angiotensin II and telmisartan, an angiotensin1 receptor antagonist, on rat gastric mucosal blood flow

BACKGROUND: Angiotensin II (ATII) has been suggested to contribute to shock-induced dysfunction of the gastric circulation. AIM: To substantiate this conjecture, the effects on gastric mucosal haemodynamics and the hyperaemic response to acid back-diffusion of ATII and the angiotensin AT1 receptor antagonist, telmisartan, were examined in normal rats and in animals subjected to haemorrhage. METHODS: Gastric mucosal blood flow in phenobarbital-anaesthetized rats was recorded with the hydrogen clearance technique, and acid back-diffusion was induced by perfusing the stomach with ethanol (25%) in HCl (0.05 M). RESULTS: Intravenous infusion of ATII (0.3-10 nmol/min/kg) led to dose-dependent hypertension and a reduction of blood flow and vascular conductance in the gastric mucosa. The gastric hyperaemia caused by acid back-diffusion was attenuated by ATII (1 nmol/min/kg). These effects of ATII were antagonized by intravenous injection of telmisartan (1-10 mg/kg) which per se caused hypotension and dilated the gastric mucosal vasculature, but did not modify the gastric mucosal hyperaemia evoked by acid back-diffusion. Hypotension induced by haemorrhage (1.3 mL blood per 100 g body weight) failed to alter the hyperaemia due to acid back-diffusion, but caused gastric mucosal vasoconstriction, an effect that was left unaffected by telmisartan. CONCLUSIONS: ATII constricts the rat gastric microvasculature via an action involving AT1 receptors. The effects of telmisartan indicate that endogenous ATII contributes to the homeostatic regulation of gastric vascular tone but does not compromise the ability of the gastric microvasculature to react to influxing acid. These results negate the concept that ATII contributes to the gastric vascular perturbances in haemorrhagic shock.     

Stimulation of capsaicin-sensitive sensory peripheral nerves with topically applied resiniferatoxin decreases salicylate-induced gastric H+ back-diffusion in the rat

Capsaicin-sensitive sensory nerves (CSSN) exert local protective functions in the stomach and have been proposed to regulate gastric H⁺ back-diffusion. The present study aimed to evaluate the possible influence of stimulation of CSSN with the intragastrically (ig) applied capsaicin analogue, resiniferatoxin (RTX), on gastric H⁺ back-diffusion and mucosal injury caused by ig application of HCl (2 ml 0.15 mol/L) or acidified salicylate (200 mg/kg in 2 ml 0.15 mol/L HCl) after 1 or 2 h in the pylorus-ligated rat. Stimulation of CSSN with a low concentration (0.04 μg/ml) of RTX markedly decreased H⁺ back-diffusion caused by acidified salicylate. After acute bilateral truncal vagotomy or treatment with atropine sulphate, RTX did not inhibit gastric acid back-diffusion. Surgical vagotomy alone increased, while RTX or atropine markedly diminished, the development of gastric mucosal injury in these models. In saline-treated rats, RTX significantly reduced gastric secretory volume and acid output. The inhibitory effect lasted for 1 h. These data suggest an essential role for CSSN in regulation of gastric acid secretion and in maintaining the integrity of the gastric mucosa that appear to depend on intact vagal nerves.     

Dual modulation of the tension of isolated gastric artery and gastric mucosal circulation by hydrogen sulfide in rats

To clarify roles of H₂S in regulation of gastric circulation, we investigated effects of NaHS, a H₂S donor, on tension of isolated rat gastric artery and gastric mucosal blood flow in rats. In the precontracted ring preparations, NaHS caused contraction and relaxation at low and high concentrations, respectively. The NaHS-induced vasorelaxation was only partially blocked by glibenclamide, a K⁺ _ATP channel inhibitor. The contractile activity of NaHS disappeared by removal of the endothelium or by inhibition of nitric oxide synthase and the endothelium-derived hyperpolarizing factor (EDHF) pathways. Intravenous injection of NaHS caused transient increase followed by decrease in gastric mucosal blood flow in rats. Collectively, in the gastric artery, NaHS appears to cause relaxation through both K⁺ _ATP channel-dependent and -independent pathways and contraction through inhibition of NO and EDHF pathways. Together with the in vivo results, our study implies that H₂S plays multiple complex roles in regulation of gastric circulation.     

Tachykinin inhibition of acid-induced gastric hyperaemia in the rat.

1. Primary afferent neurones releasing the vasodilator, calcitonin gene-related peptide, mediate the gastric hyperaemic response to acid back-diffusion. The tachykinins neurokinin A (NKA) and substance P (SP) are located in the same neurones and are co-released with calcitonin gene-related peptide. In this study we investigated the effect and possible role of tachykinins in the acid-evoked gastric vasodilatation in urethane-anaesthetized rats. 2. Gastric acid back-diffusion, induced by perfusing the stomach with 15% ethanol in the presence of 0.05 M HCl, increased gastric mucosal blood flow by 60-90%, as determined by the hydrogen clearance technique. NKA and SP (0.14-3.78 nmol min-1 kg-1, infused intra-aortically) inhibited the gastric mucosal hyperaemic response to acid back-diffusion in a dose-dependent manner, an effect that was accompanied by aggravation of ethanol/acid-induced macroscopic haemorrhagic lesions. 3. The inhibitory effect of NKA (1.26 nmol min-1 kg-1) on the acid-induced gastric mucosal vasodilatation was prevented by the tachykinin NK2 receptor antagonists, MEN 10,627 (200 nmol kg-1) but left unaltered by the NK1 receptor antagonist, SR 140,333 (300 nmol kg-1) and the mast-cell stabilizer, ketotifen (4.6 mumol kg-1). 4. Under basal conditions, with 0.05 M HCl being perfused through the stomach, NKA (1.26 nmol min-1 kg-1) reduced gastric mucosal blood flow by about 25%, an effect that was abolished by SR 140,333 but not MEN 10,627 or ketotifen. 5. SR 140,333, MEN 10,627 or ketotifen had no significant effect on basal gastric mucosal blood flow nor did they modify the gastric mucosal hyperaemic reaction to acid back-diffusion. 6. The effect of NKA (1.26 nmol min-1 kg-1) in causing vasoconstriction and inhibiting the vasodilator response to acid back-diffusion was also seen when blood flow in the left gastric artery was measured with the ultrasonic transit time shift technique. 7. Arginine vasopressin (AVP, 0.1 nmol min-1 kg-1) induced gastric mucosal vasoconstriction under basal conditions but was unable to inhibit the dilator response to acid back-diffusion. 8. These data show that NKA has two fundamentally different effects on the gastric circulation. Firstly, NKA reduces gastric blood flow by activation of NK1 receptors. Secondly, NKA inhibits the gastric hyperaemic response to acid back-diffusion through an NK2 receptor-mediated mechanism. These two tachykinin effects appear to take place independently of each other since they are mediated by different receptors. This concept is further supported by the inability of AVP to mimic tachykinin inhibition of the gastric vasodilator response to acid back-diffusion.     

Participation of endothelium-derived nitric oxide but not prostacyclin in the gastric mucosal hyperaemia due to acid back-diffusion.

1. The possible participation of prostacyclin and nitric oxide (NO) in the gastric mucosal hyperaemic response to acid back-diffusion through a disrupted gastric mucosal barrier was examined. The experiments were carried out on anaesthetized rats in which acid back-diffusion was elicited by gastric perfusion with dilute ethanol in 0.15 M HCl and gastric mucosal blood flow (MBF) was measured by the hydrogen gas clearance technique. 2. Indomethacin (28 mumols kg-1, s.c.), an inhibitor of the formation of cyclo-oxygenase products including prostacyclin, failed to alter mean arterial blood pressure (MAP), basal MBF and the hyperaemic response to acid back-diffusion in urethane-anaesthetized rats. 3. NG-nitro-L-arginine methyl ester (L-NAME; 13 and 43 mumols kg-1, i.v.), an inhibitor of endothelium-derived NO formation, increased MAP in a dose-dependent manner. Whilst basal MBF in urethane-anaesthetized rats was not changed, the increase in MBF caused by gastric perfusion with dilute ethanol in acid was dose-dependently depressed by L-NAME. The loss of H+ ions from the gastric lumen, an indirect measure of acid back-diffusion, was significantly enhanced by 43 mumols kg-1 L-NAME. In contrast, D-NAME (13 and 43 mumols kg-1) was without effect on MAP, basal and stimulated MBF, and acid back-diffusion. 4. Unlike in urethane-anaesthetized rats, L-NAME led to a significant reduction of basal MBF in phenobarbitone-anaesthetized rats. MAP in the phenobarbitone-anaesthetized rats was significantly higher than in urethane-anaesthetized rats, and the hypertensive effect of L-NAME under phenobarbitone anaesthesia was significantly smaller than under urethane anaesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interactions between ethanol and acetylsalicylic acid in damaging the rat gastric mucosa

The interactions between ethanol (EtOH) and acetylsalicylic acid (ASA) in damaging the gastric mucosa were investigated in urethane-anaesthetised rats upon intragastric irrigation. The addition of 5, 10 or 20 mM ASA to 1 and 4 M EtOH instillates strongly aggravated lesion formation in the gastric mucosa and mucosal bleeding. ASA enhanced the back-diffusion of hydrogen ions into the mucosa induced by 1 M EtOH, whereas gastric mucosal blood flow, which is thought to dispose of the back-diffused acid from the mucosa, remained unchanged, thus resulting in an accumulation of acid within the gastric mucosa. ASA did not further enhance the strongly increased back-diffusion of hydrogen ions induced by 4 M EtOH, but it effectively inhibited EtOH-induced stimulation of the gastric mucosal blood flow, thus causing an increase in the ratio between hydrogen ion back-diffusion and gastric mucosal blood flow. The simultaneous presence of EtOH and ASA did not enhance the rates of absorption of each from the instillates. The results indicate that EtOH and ASA have a strong synergistic action in damaging the gastric mucosa in the rat. The mechanism of this interaction may be an increased accumulation of hydrogen ions within the gastric mucosa, resulting in excessive acidification of the mucosal tissue.     

Mechanisms underlying gastric mucosal damage induced by indomethacin and bile-salts, and the actions of prostaglandins.

1 The mechanisms by which -he bile salt, sodium taurocholate, potentiates the formation of gastric mucosal erosions induced by indomethacin has been investigated in the rat. 2 Systemic administration of indomethacin lowered resting mucosal blood flow but had no effect on the acid back-diffusion across the mucosa. 3 Gastric perfusion of taurocholate in acid solution increased acid back-diffusion and lowered the potential differences. This was accompanied by an increase in mucosal blood flow, which may represent a protective mechanism in the mucosa. 4 Administration of indomethacin during acid-taurocholate perfusion reduced this elevated mucosal blood flow without any further change in acid back-diffusion. 5 The results suggest that although a decrease in mucosal blood flow or an increase in acid back-diffusion can lead to a low incidence of erosions, a combination of both produces extensive mucosal damage. 6 The (15S)-methyl analogue of prostaglandin E2 reduced erosion formation induced by indomethacin and acid-taurocholate administration. 7 It is suggested that this protective action of the prostaglandin analogue may be linked to changes in gastric mucosal permeability and in mucosal blood flow.     

Modification of aspirin and ethanol-induced mucosal damage in rats by intragastric application of resiniferatoxin

The capsaicin analogue ‘resiniferatoxin’ (RTX) was used to investigate the role of capsaicin-sensitive sensory nerves in gastric mucosal injury caused by intragastric (ig) acidified aspirin (200 mg/kg in 2 ml of 0.15 N HCl) or ethanol (2 ml of 50% v/v or 96%) in pylorus-ligated rats. Animals were sacrificed 1, 2 and 4 h later, when gastric secretory responses, number and severity of mucosal lesions were calculated. Intragastric RTX (0.6–1.8 μg/kg) prevented mucosal injury in a dose-dependent manner induced by topical acidified aspirin. The protective effect lasted for 1h and was accompanied by inhibition of gastric acid secretion by RTX. RTX (0.6 and 1.0 μg/kg) co-administered with ethanol reduced mucosal injury caused by 50% ethanol; the protective effect of RTX being more apparent when the drug was given 15 min prior to 50% ethanol. Unexpectedly, RTX co-administered with absolute ethanol aggravated the ethanol-induced mucosal damage. It is concluded that capsaicin-sensitive sensory nerves mediated microcirculatory changes in gastroprotection and these involve inhibition of gastric acid secretion.     

Effects of osutidine (T-593) and its enantiomers on gastric mucosal hemodynamics and mucosal integrity in anesthetized rats

T-593 (osutidine, CAS 140695-21-2) is a new anti-ulcer agent that consists of two enantiomers, (+)-(R)-T-593 and (-)-(S)-T-593. The present study was designed to investigate the effects of T-593, (+)-(R)-T-593 and (-)-(S)-T-593 on ethanol-induced gastric damage in rats. Rats were given intraperitoneal administration of vehicle, racemic T-593, (+)-(R)-T-593 or (-)-(S)-T-593. 30 min later, the rats intragastrically received a 1-ml solution of 40% ethanol, and 30 min thereafter, they were sacrificed for assessment of gastric damage. Gastric hemodynamics were assessed by reflectance spectrophotometry and laser Doppler flowmetry during the experiment. Gastric damage was significantly suppressed by racemic T-593 in a dose-dependent manner. While 60 mg/kg of (+)-(R)-T-593 and (-)-(S)-T-593 also suppressed ethanol-induced gastric injury, the same dose of racemic T-593 exerted the most potent anti-ulcerative activity. Both (+)-(R)-T-593 and racemic T-593 increased gastric mucosal blood flow and abolished gastric mucosal blood flow stasis induced by 40% ethanol. Although (-)-(S)-T-593, which antagonizes histamine H2-receptors, exerts an antiulcerative effect, (+)-(R)-T-593 also protects the gastric mucosa from ethanol-induced injury, possibly by influencing gastric mucosal hemodynamics. Thus racemic T-593 may protect the gastric mucosa by antagonizing H2-receptors and by enhancing gastric circulation in rats.     

Mucosal acid causes gastric mucosal microcirculatory disturbance in nonsteroidal anti-inflammatory drug-treated rats

The mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) suppress gastric mucosal blood flow is not fully understood, although the depletion of mucosal prostaglandin E2 has been proposed as one possible explanation. We investigated the role of gastric acid on gastric mucosal blood flow in NSAID-treated rats. A rat stomach was mounted in an ex vivo chamber, and gastric mucosal blood flow was measured sequentially in a 5-mm2 area of the gastric corpus using a scanning laser Doppler perfusion image system. Results showed that diclofenac (5 mg/kg s.c.) and indomethacin (10 mg/kg s.c.) did not affect gastric mucosal blood flow, although both strongly decreased mucosal prostaglandin E2 when saline was instilled into the gastric chamber. On replacement of the saline in the chamber with 100 mM hydrochloric acid, these drugs caused a decrease in gastric mucosal blood flow levels within 30 min. The specific cyclooxygenase (COX)-2 inhibitors celecoxib (50 mg/kg s.c.) and rofecoxib (25 mg/kg s.c.) did not affect mucosal prostaglandin E2 level, nor did they decrease gastric mucosal blood flow, even when hydrochloric acid was added to the chamber. Furthermore, measurement of vasoconstrictive factors present in the mucosa showed that endothelin-1 levels increased after administration of diclofenac s.c. in the presence of intragastric hydrochloric acid. This indicates that the presence of mucosal hydrochloric acid plays an important role in the NSAID-induced decrease in gastric mucosal blood flow, while the COX-1-derived basal prostaglandin E2, which is unlikely to control gastric mucosal blood flow itself, protects microcirculatory systems from mucosal hydrochloric acid.     

Molecular pharmacological approach to drug actions on the afferent and efferent fibres of the vagal nerve involved in gastric mucosal protection in rats

Background Gastric mucosal protection is associated with the actions of anti-ulcer drugs or agents affecting on the afferent and/or efferent nerve fibres of the vagal nerve. Aims 1. To identify the dose-response curves of drugs (compounds) on the afferent vanilloid-receptor (capsaicin or resiniferatoxin-sensitive) and on efferent secretion (atropine, pirenzepine, cimetidine, ranitidine, famotidine, omeprazole, esomeprazole) basal gastric acid and stimulated gastric secretion in relation to the chemically-induced gastric mucosal damage in rats; 2. To determine the ED₅₀ (pD₂) and pA₂ on the calculation of affinity and intrinsic affinity curves for these agonists/antagonists, as an indication of relative potency of effects. Materials and methods The observations were carried out in rats (30 different models). Results The ED₅₀ values for affinities of capsaicin, resiniferatoxin were obtained in nmol/kg b.w. range, whereas the values were in the nmol/kg to μmol/kg b.w. ranges for effects on the gastric basal, stimulated (bethanechol, pentagastrin, histamine) gastric secretion, and the gastric mucosal damage-produced by different ulcerogenic agents (ethanol, HCl, aspirin, indomethacin). Conclusion From the observations, that agents acting on vanilloid (capsaicin) receptors were the most potent inhibitors of acid secretion and gastric lesions from necrotizing agents, suggests that the capsaicin sensitive afferent nerves have a primary place in the efferent regulated events leading to initiation of gastric mucosal damage. Received 11 July 2006; revised 27 August 2006; accepted 28 August 2006     

Dual effects of zinc sulphate on ethanol-induced gastric injury in rats: possibly mediated by an action on mucosal blood flow

The present study examines the protective effect of zinc sulphate against ethanol-induced gastric mucosal ulcers in rats. Absolute ethanol decreased the gastric mucosal blood flow and produced haemorrhagic lesions in the glandular mucosa. Zinc sulphate preincubation in an ex-vivo stomach chamber preparation prevented the formation of ethanol-induced lesions and attenuated the decrease of blood flow produced by ethanol. Subcutaneous injection of the same doses of the drug at 15 and 30 min before ethanol exposure, markedly reduced the blood flow and also aggravated ethanol-induced gastric injury; however, when injected at 23 and 24 h before ethanol administration, zinc sulphate protected against lesion formation but had no effect on the vascular changes induced by ethanol in the gastric glandular mucosa. These findings show that the antiulcer effect of zinc sulphate occurs only when the drug is given orally, or injected s.c. 23 and 24 h before ethanol challenge. Furthermore, this protective action is probably not entirely mediated by preservation of the gastric mucosal blood flow.     

Effects of zinc acexamate on gastric mucosal resistance factors

The effects of zinc acexamate on gastric defensive systems were evaluated in the rat. Gastric ulcers induced by oral administration of three necrotic agents (0.6 N HCl, 25% NaCl, 100% ethanol) were markedly reduced by different pretreatments with zinc acexamate. This cytoprotective effect was not modified by previous treatment with indomethacin (30 mg/kg orally). Zinc acexamate pretreatment also prevents the disruption of the gastric mucosal barrier induced by aspirin (40 mM) and increases mucus production in the gastric glands and tracheal walls. These observations suggest that the antiulcer effects described for zinc salts could be the result, at least partly, of an action increasing gastric mucosal defensive systems.     

Role of Acid Back-diffusion in the Formation of Mucosal Ulceration and Its Treatment with Drugs in Diabetic Rats

We have studied the role of acid back-diffusion in the formation of gastric mucosal ulceration and its treatment with several drugs in streptozotocin-induced diabetic rats. After vagotomy, the stomach of 1–8 week-old diabetic rats and age-matched control rats were irrigated with acid solutions of graded concentrations (50–150 mm HCl) for 1 or 3 h. A marked increase in acid back-diffusion and in haemorrhagic ulceration was found in diabetic rats. The extent of acid back-diffusion and the severity of mucosal ulceration were dependent on the concentration and the time of contact of acid solutions with the gastric mucosa. A high correlation (r = ?0·9227) between acid back-diffusion and mucosal ulceration was found in 3-h acid-irrigated diabetic rats. In the 2-week diabetic rat, intragastric cimetidine (300 mg kg^?1) or NaHCO₃ (52 mg kg^?1) significantly (P < 0·05) reduced both acid back-diffusion and haemorrhagic ulcer formation, while atropine (1·0 mg kg^?1) or bupivacaine (0·5%, 0·4 mL/rat) was ineffective. High blood glucose levels in diabetic rats were not influenced by these agents. Acid back-diffusion and ulceration in the diabetic rat were markedly reduced by daily administration but not single injection of insulin (50 units kg^?1, s.c.). Taken together, in the early stage of diabetes development, chronic insulin deficiency rather than nerve degeneration or hyperglycaemia may be responsible for the disruption of mucosal barriers. It is concluded that acid back-diffusion played an important role in the formation of acute haemorrhagic ulceration that can be inhibited by intragastric cimetidine, NaHCO₃ or daily injection of insulin.     

Acute normovolaemic anaemia prevents ethanol-induced gastric damage in rats through a blood flow related mechanism

The aim of the study was to assess whether changes in gastric mucosal blood flow induced by acute normovolaemic anaemia influence the susceptibility of the gastric mucosa to ethanol-induced damage, and the relationship of these changes with nitric oxide biosynthesis. Acute normovolaemic anaemia, promoted by exchanging 3 ml of blood by a plasma expander, induced a significant increase in gastric mucosal blood flow measured by hydrogen gas clearance, without changes in arterial blood pressure. After intragastric 60% ethanol administration, gastric blood flow was still significantly higher in anaemic than in control rats, and this was associated with a lower macroscopic and microscopic gastric damage. Following ethanol administration, anaemic rats pretreated with an inhibitor of nitric oxide biosynthesis (l-NMMA, 50 mg/kg, i.v.) had a lower gastric blood flow and a higher macroscopic gastric damage than anaemic rats without pretreatment. Anaemic rats pretreated with vasopressin also had after ethanol administration a lower gastric blood flow and a higher macroscopic gastric damage. It is concluded that acute normovolaemic anaemia protects the gastric mucosa against damage induced by intragastric ethanol. The inhibition of nitric oxide biosynthesis reverts in part this protective effect, and this seems to be related with the capability of nitric oxide to increase gastric mucosal blood flow, since vasoconstriction by a nitric oxide-independent mechanism causes a similar effect.     

High activity of endogenous opioid system protects against gastric damage development in mouse models of gastric mucosal injury

Background

Gastric mucosal injury appears when acid and pepsin production, simultaneously with inadequate mucosal response, overwhelms protective mechanism in stomach. Here we aimed to explore the linkage between gastric lesion formation and endogenous opioid system activity.

Role of bradykinin in the hyperaemia following acid challenge of the rat gastric mucosa.

1. This study examined whether the hyperaemia following acid challenge of the rat gastric mucosa involves bradykinin, a peptide formed in response to tissue injury. 2. Gastric mucosal blood flow in urethane-anaesthetized rats was assessed by the hydrogen gas clearance method. Infusion of a bradykinin solution (10 microM) into the gastric wall augmented gastric mucosal blood flow by a factor of 2.3, an effect that was prevented by the bradykinin B2 antagonist Hoe-140 (icatibant; 100 mumol kg-1, i.v.). 3. I.V. injection of bradykinin (20-60 nmol kg-1) caused a 2.3-3.5 fold increase in blood flow through the left gastric artery as measured by the ultrasonic transit time shift technique. The hyperaemic effect of bradykinin in this gastric artery was also prevented by Hoe-140 (100 mumol kg-1, i.v.). 4. Gastric acid backdiffusion was evoked by perfusing the stomach with 15% ethanol, to break the gastric mucosal barrier, in the presence of luminal acid. Depending on the concentration of acid (0.05 and 0.15 M HCl), this procedure increased gastric mucosal blood flow by a factor of 1.6-2.8 and caused formation of gross damage in 1.5-3% of the glandular mucosa. Hoe-140 (100 mumol kg-1, i.v.) failed to alter the moderate vasodilatation seen in the presence of 0.05 M HCl but significantly (P < 0.05) attenuated the marked hyperaemia and enhanced the gross mucosal damage observed in the presence of 0.15 M HCl. 5. These data show that bradykinin is able to enhance gastric mucosal blood flow via activation of B2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biochemical and Pharmacological Characteristics of 3-Butyryl-8-methoxy-4-[(2-thiophenyl)amino]quinoline,a New Proton-pump Inhibitor,in Rabbit Gastric Microsomes and in Rats

We have investigated the properties of the newly synthesized proton-pump inhibitor, 3-butyryl-8-methoxy-4-[(2-thiophenyl)amino]quinoline (YJA20379–6), on gastric mucosal proton-pump (H⁺/K⁺-ATPase) activity, gastric acid secretion and gastroduodenal lesions in experimental rats. YJA20379–6 markedly inhibited H⁺/K⁺-ATPase activity in rabbit isolated gastric mucosal microsomes, confirming its classification as a proton-pump inhibitor. The inhibitory efficacy of YJA20379-6 on the proton pump was approximately 14-times higher than that of omeprazole at pH 7.4. YJA20379–6 given intraduodenally had a potent inhibitory effect on gastric secretion in pylorus-ligated rats (ED50 22.9 mg kg^?1) but was less active than omeprazole. Pretreatment of rats with YJA20379-6 dose-dependently protected the gastric mucosa from damage induced by water-immersion stress, indomethacin and absolute ethanol, and the duodenal mucosa from damage induced by mepirizole. Repeated administration of YJA20379-6 also dose-dependently accelerated the spontaneous healing of acetic acid-induced gastric ulcers. These results suggest that YJA20379-6 has potent anti-secretory and anti-ulcer effects which are exerted by suppression of H⁺/K⁺-ATPase activity in gastric parietal cells. YJA20379–6 might be useful for the clinical treatment of peptic ulcer diseases.     

Measurement of gastric acid secretion by conductivity

Gastric acid secretion in the anaesthetized rat has been measured by continuously recording the conductivity of the effluent in the reperfusion system previously developed by the authors. (H⁺) and (Na⁺) were measured by titration and flame photometry respectively and compared with the total conductivity of the effluent. The differences between the calculated and measured conductance were within the experimental error of the observations. There was no clear relationship between rates of secretion of hydrogen ions and sodium ions in this preparation. Conductance was used to measure acid concentration and to assay inhibitors and stimulants of gastric acid secretion.A conductivity meter has been designed and used to measure gastric acid secretion in the perfused rat stomach preparation. Measurements of conductivity were shown to be a measure of the hydrogen ion concentration of the effluent. The quality and linearity of the response was superior to that achieved with pH methods. The sensitivity of the system has been increased which has enabled 10 ng of gastrin I to give a significant effect. It was possible to monitor six preparations with one meter during assays of urogastrone and gastrin.     

3-氧-乙酰-11-脱氧甘草次酸铝对大鼠胃溃疡的作用

给予大鼠ig 3-氧-乙酰-11-脱氧甘草次酸铝(ADA),50,100 mg·kg^-1,与阴性对照组相比,可显著降低对阿司匹林及应激性胃溃疡的溃疡面积,显著减少胃液量,降低胃液总酸度和胃蛋白酶活性;并且在相同剂量下,ADA对阿司匹林和醋酸诱发胃溃疡的抑制作用显著比甘珀酸组强,同样ADA还能显著增加胃内粘液量及胃壁内前列腺素E₂(PGE₂)量在醋酸型慢性胃溃疡模型中,ADA 125, 250 mg·kg^-1 (62.5,125 mg·kg^-1,早晚各一次),连续14 d,显著提高溃疡处胃粘膜血流量(GMBF)和溃疡治愈率,对血清钠,钾浓度无影响,相反甘珀酸可显著降低血清钾浓度. 结果表明,ADA可抑制溃疡形成及促进溃疡愈合,长期大剂量应用无甘珀酸引起的低血钾副作用,其抗溃疡机理可能与降低胃液总酸度,胃蛋白酶活性和促进胃粘液分泌,胃壁内PGE₂量及GMBF增加有关.