Prostaglandin E2 in basal gastric secretion and during stimulation of muscarinic receptors in man. Measurements with gas chromatography--mass spectrometry

The physiological importance of prostaglandin E2 (PGE2) biosynthesis in the gastric mucosa is unknown. A role of endogenous prostaglandins in protecting the gastrointestinal epithelia has been suggested, but the evidence is insufficient and rarely supported by concomitant measurement of PG production. Amounts of PGE2 in luminal gastric contents which can be sampled atraumatically may reflect PGE2 synthesis in the gastric mucosa in vivo. To confirm earlier reported measurements made with radioimmunoassay we have measured by gas chromatography - mass spectrometry (GC-MS) PGE2 in gastric juice of five healthy men under basal conditions and during stimulation of muscarinic receptors with iv. bethanechol which in dog is reported to enhance PGE2 output. PGE2 was detected in all basal samples. The output was in median 32.1 pmol/15 min (range 17.0-105.4, 1 pmol = 0.352 ng), which is similar to results from earlier studies. Bethanechol infusion (60 micrograms . kg-1 . h-1) did not affect PGE2 outputs systematically in spite of a significant increase in outputs of acid and chlorides. Stimulation of muscarinic receptors does not seem to influence PGE2 synthesis in gastric mucosa in vivo. Alternatively changes in PGE2 synthesis may be masked by rapid chemical or enzymatical degradation or reabsorption of PGE2. Studies are under way to explore those phenomena.     

Aspirin,prostaglandins and mucopolysaccharide/glycoprotein secretion

The object of the present study was to investigate the possibility that the ulcer-protective action of prostaglandins (PGs) in eliciting mucus discharge in the stomach could be due to their effect in enhancing the biosynthesis of mucus.Intraperitoneal injection of 2.5 mg/kg PGE₂, or the same dose of PGE₂ plus 200 mg/kg aspirin (p.o.), both failed to cause any statistically significant changes in the incorporation of radioactive sulphate into gastric mucus glycoproteins in vivo compared with controls. Aspirin, under these conditions, inhibits mucus synthesis and this effect may be related to the development of gastric mucosal damage by this drug. In contrast, PGE₂ administration reverses the gastric mucosal damage induced by aspirin so that the ulcer-protective effect of PGE₂ appears to be unrelated to mucus synthesis. PGE₂ (0.125–1.25 g/ml) inhibited oxygen consumption and¹⁴CO₂ output from 1-¹⁴C-, and 6-¹⁴C-glucose in rat gastric mucosal slices in vitro. Thus the absence of effect of PGE₂ on mucus biosynthesis may be due to an effect of this PG in reducing the capacity of the mucosa to yield energy (ATP) from the metabolism of glucose.     

Effect of atrial natriuretic factor on renal prostaglandin E2 release in the anaesthetized dog

Experiments were undertaken in two groups of barbiturate anaesthetized dogs to examine whether atrial natriuretic factor (ANF) exerts an effect on renal release of prostaglandin E₂ (PGE₂). In the first group, intravenous infusion of ANF (50 ng min^-1kg^-1body wt) reduced basal PGE₂ release from 4.4 ± 0.8 pmol min^-1to 1.8 ± 0.7 pmol min^-1. In the second group, intrarenal infusion of an α-adrenoceptor agonist, phenylephrine (2.5–6.75 μg min^-1), raised PGE₂ release from 2.7 ± 0.5 pmol min^-1to 7.5 ± 1.3 pmol min^-1. During continuous α₁-adrenergic stimulation, intravenous infusion of ANF (100 ng min^-1kg^-1body wt) reduced PGE₂ release to 3.5 ± 1.0 pmol min^-1. These results demonstrate that ANF reduces basal and α₁-adrenergic stimulated renal PGE₂ release.     

Effects of prostaglandin E1, E2 and 16,16-dimethyl-E2 on gastric mucosal microcirculation and basal acid output in the rat*

The effects of prostaglandins E, (PGE₁), E₂ (PGE₂) and 16, 16-dimethyl-E₂ (16, 16-dm-PGE₂) on the gastric mucosal microcirculation and (spontaneous) acid output were studied in anaesthetized rats. The superficial mucosal vessels were monitored on a TV screen using a microscope, TV camera and videorecorder for off-line analysis of red cell velocities (V_RBC) and vessel diameters, from which the blood flow (Q_RBC) was calculated. The prostaglandins were either applied topically to the solution bathing the exposed mucosa or administered intravenously as a continuous infusion. Topical application of PGE₁ (0.5 or 5 μgml^-1), PGE₂ (5 or 50 μg ml^-1) or 16, 16-dm-PGE₂ (0.005, 0.05 or 0.5 μg ml^-1) increased V_RBC dose-dependently without altering acid output, except for the highest dose of PGE₂ (50 μg ml^-1) which inhibited acid output. The latter occurred in spite of a seven-to eight-fold increase in V_RBC. Mucus secretion (evidenced by an impaired resolution of the TV image) also increased during topical application of the prostaglandins especially at higher doses. Intravenous PGE₁, PGE₂ (2.0 μg kg^-1 min^_1) or 16, 16-dm-PGE₂ (0.02 μg kg^-1 min^_1) caused an initial and transient (5–10 min) fall in systemic arterial blood pressure and a decrease in V_RBC and acid output. Intravenous 16, 16-dm-PGE₂ in a dose which did not affect secretion or systemic arterial blood pressure (0.002 μg kg^-1 min^-1) still significantly reduced V_RBC. Thus, topically applied PGE₁, PGE₂ or 16, 16-dm-PGE₂ dose-dependently increase V_RBC while intravenous administration of the same prostaglandins reduce V_RBC.     

Cholinergic mechanisms involved in release and effect of prostaglandin E2 in HCI-stimulated duodenal HCO-3 secretion in the conscious rat

Using a proximal duodenal loop in conscious rats, we investigated interactions between prostaglandin E₂ and nicotinic and muscarinic receptor mechanisms previously found to be involved in the duodenal HCO-₃ response to HC1. In previous studies using the same model, a 5-min perfusion of the duodenal loop with 150 mmol 1^-1 HC1 produced a marked and sustained HCO-₃ response. In the present study, the identical challenge produced a rapid 20-fold increase in the luminal output of prostaglandin E₂ during acid exposure, followed by a sustained more than twofold elevation above the basal level during the 45 min monitored. The prostaglandin synthesis inhibitor indomethacin (4 mg kg^-1 i.p.) suppressed the output of prostaglandin E₂ during the HC1 challenge from 131 ± 84 to 15.4 ± 10.0 pmol cm^-1 h^-1, and in the post-stimulatory period from 17.3 ± 9.1 to 4.4 ± 2.2 pmol cm^-1 h^-1. The nicotinic receptor antagonist hexamethonium (20 mg kg^-1 i.v.) had no effect on the output of prostaglandin E₂. The muscarinic receptor antagonist atropine (0.5 mg kg^-1 s.c.) had no effect on the output of prostaglandin E₂ during HC1 challenge, but reduced the post-stimulatory output to 7.7 4PL 4.1 pmol ch^-1 h^-1. Perfusion of the duodenal loop with 0.1 mmol 1^-1 prostaglandin E₂ produced a HCO-₃ response that was abolished by hexamethonium (20 mg kg^-1 i.v.), but not affected by atropine (0.5 mg kg^-1 s.c). The results indicate that muscarinic receptor mechanisms are involved in the HCI-stimulated local formation of prostaglandin E₂ and that nicotinic receptor mechanisms are required for the duodenal HCO-₃ secretion stimulated by prostaglandin E₂.     

Comparison of PGE2, 6-keto PGF1α and renin release from dog kidneys

Several renal cell types synthesize prostaglandin E₂ (PGE₂) and prostacyclin (PGI₂). To examine whether the release of these prostaglandins varies in proportion, prostaglandin synthesis was stimulated in anaesthetized dogs by renal arterial constriction, ureteral occlusion, intrarenal angiotensin II infusion and infusion of arachidonic acid, the precursor of PG synthesis. PGI₂ was measured as its stable hydrolysed product, 6-keto PGF_1α. The two former procedures raised PGE₂ release to 13 ± 2 pmol min^-1, 6-keto PGF_1α release to 5 ± 2 pmol min^-1 and renin release to 23 ± 5 μg AI min^-1, Angiotensin II infusion, reducing the renal blood flow by 30%, increased PGE₂ and 6-keto PGF_1α release only half as much as ureteral and renal arterial constriction, and exerted no significant effect on renin release. By increasing the infusion rate of angiotensin II up to 10 times, the renal blood flow remained unaltered in four dogs and fell to 50% of control in two dogs, but PGE₂ and 6-keto PGF_1α release did not increase further in any of the experiments. Arachidonic acid, infused at 40 and 160 μg kg^-1 min^-1, increased prostaglandin release in proportion to the infusion rate. At the highest infusion rate, PGE₂ release averaged 166± 37 pmol min^-1 and 6-keto PGF_1α release 98 ± 28 pmol min^-1. All procedures increased PGE₂ and 6-keto PGF_1α release in a fixed proportion of about 2.5:1, whereas renin release increased only during autoregulatory vasodilation.     

Significance of radioautography of soluble compounds in analysis of cholinergic innervation in rat gastric mucosa

To clarify the cholinergic regulation of the gastric mucosa, the localization of the muscarinic receptors in the rat fundic mucosa was studied using the radioautography of soluble compounds of³H-quinuclidinyl benzilate (QNB) and³H-pirenzepine (PZ) in comparison with the routine fixation method. Through the radioautography of soluble compounds, the binding sites of PZ, corresponding to the localization of M₁ receptors, were located on the nerve endings and enterochromaffin-like (ECL) cells; while the binding sites of QNB, representing the muscarinic receptors, were seen on the epithelial cells, endothelial cells and smooth muscle cells as well as on the nerve endings and ECL cells. By contrast, the routine fixation method was of little use in showing the localization of diffusible compounds in the gastric mucosa.     

Renal venous and urinary PGE2 output during intrarenal arachidonic acid infusion in dogs

Inferences about total renal (venous and urinary) PGE₂ output from determinations of urinary excretion rates (U_PGE2V) cannot be made unless the distribution of PGE₂ between renal venous plasma and urine is known. Therefore, in the present study on intact kidneys of anesthetized dogs both urinary excretion of PGE₂ and the renal venous output (the product of plasma flow and venous concentration of PGE₂) was determined during low and high rates of renal PGE₂ synthesis. PGE₂ was measured in urine and arterial and renal venous plasma by radioimmunoassay during the following conditions: (1) Hydropenia. In the control condition U_PGE2V averaged 0.041±0.012 pmol/g·min and varied between 4 and 70% of the total PGE₂ output. With infusion of arachidonic acid (AA, 160 μg/kg·min) into the renal artery total PGE₂ output increased from 0.18±0.03 to 3.23±0.51 pmol/g·min, whereas arterial concentrations of PGE₂ were unchanged. The urinary fraction still varied between 6 and 46% of total renal PGE₂ output. (2) High urine flows caused by mannitol, saline or saline and ethacrynic acid (ECA) infusion. These procedures did not stimulate total renal PGE₂ output and the urinary fraction varied between 4 and 49%. ECA combined with saline infusion increased the urinary fraction significantly to 34.7±4.0%. AA increased the total PGE₂ output as during hydropenia, but the urinary fraction fell to 13% in 13 dogs and was unchanged at about 8% in six dogs. On average the urinary fraction of total PGE₂ output was significantly lower than in hydropenia. Thus, the urinary fraction of total renal PGE₂ output is not constant, and urinary excretion of PGE₂ does not give reliable information about renal synthetic rates of prostaglandins.     

IgA from HIV+ haemophilic patients triggers intracellular signals coupled to the cholinergic system of the intestine

IgA was obtained from HIV-infected haemophilic patients and the intracellular signals triggered by its reaction with isolated rat intestinal strips were studied. HTV⁺ IgA stained intestinal microvilli with a granular immunofluorescence pattern and bound to the muscarinic acetylcholine receptor (mAChR), displacing the specific muscarinic cholinergic antagonist QNB in a non-competitive manner. It triggered the signals that are the consequence of mAChR stimulation in die intestine. Thus, it decreased cAMP synthesis and increased guanosine 3′:5′-cyclic monophosphate (cGMP) formation and phosphoinositide (PI) turnover of the intestine. In addition, it stimulated prostaglandin E₂ (PGE₂) synthesis by intestinal strips. Through its effect on PGE₂ synthesis, HIV⁺ IgA could have a dual action. On the one hand, it could enhance immunosuppression at a local level, favouring pathogen growth and subsequent intestinal dysfunction. On the other hand, PGE₂ could directly increase intestinal motility and electrolyte/fluid loss. Both effects could be involved in intestinal damage in AIDS.     

Fluid secretion caused by aerolysin-like hemolysin of Aeromonas sobria in the intestines is due to stimulation of production of prostaglandin E2 via cyclooxygenase 2 by intestinal cells

To clarify the mechanisms of diarrheal disease induced by Aeromonas sobria, we examined whether prostaglandin E₂ (PGE₂) was involved in the intestinal secretory action of A. sobria hemolysin by use of a mouse intestinal loop model. The amount of PGE₂ in jejunal fluid and the fluid accumulation ratio were directly related to the dose of hemolysin. The increase over time in the level of PGE₂ was similar to that of the accumulated fluid. In addition, hemolysin-induced fluid secretion and PGE₂ synthesis were inhibited by the selective cyclooxygenase 2 (COX-2) inhibitor NS-398 but not the COX-1 inhibitor SC-560. Western blot analysis revealed that hemolysin increased the COX-2 protein levels but reduced the COX-1 protein levels in mouse intestinal mucosa in vivo. These results suggest that PGE₂ functions as an important mediator of diarrhea caused by hemolysin and that PGE₂ is produced primarily through a COX-2-dependent mechanism. Subsequently, we examined the relationship between PGE₂, cyclic AMP (cAMP), and cystic fibrosis transmembrane conductance regulator (CFTR) Cl⁻ channels in mouse intestinal mucosa exposed to hemolysin. Hemolysin increased the levels of cAMP in the intestinal mucosa. NS-398 inhibited the increase in cAMP production, but SC-560 did not. In addition, H-89, a cAMP-dependent protein kinase A (PKA) inhibitor, and glibenclamide, a CFTR inhibitor, inhibited fluid accumulation. Taken together, these results indicate that hemolysin activates PGE₂ production via COX-2 and that PGE₂ stimulates cAMP production. cAMP then activates PKA, which in turn stimulates CFTR Cl⁻ channels and finally leads to fluid accumulation in the intestines.     

Protection of the rat gastric mucosa by prostaglandin E2: Possible relation to stimulation of the alkaline secretion

Exogenous prostaglandins have specific protective effects on the gastric mucosa called cytoprotection which is proposed to be connected to the stimulatory effects of prostaglandins on the gastric nonparietal secretions. The protection by oral prostaglandin E₂ (PGE₂) against indomethacin-induced gastric erosions was studied in the rat, as was the effect on the protection of blocking the gastric alkaline secretion by acetazolamide. PGE₂ reduced dose-dependently the indomethacin gastric erosion formation, confirming previous results from others. Acetazolamide caused very little damage when given alone but potentiated the indomethacin erosion formation in a dose-related way. PGE₂ was less protective or without effect against lesions caused by indomethacin when given together with acetazolamide, but protection could be obtained by increasing the doses of PGE₂. Indomethacin and acetazolamide are both blockers of the gastric bicarbonate secretion, which is stimulated by PGE₂. The potentiation of indomethacin induced lesions by acetazolamide and the antagonistic actions between acetazolamide and PGE₂ on mucosal protection are compatible with the hypothesis that stimulation of the alkaline secretion is one mechanism of cytoprotection of the gastric mucosa by PGE₂.     

Renal degradation and distribution between urinary and venous output of prostaglandins E2 and I2

Renal degradation and distribution between urinary and venous output of prostaglandins E₂ and I₂ Acta Physiol Scand 130 , 467–474. Received 25 November 1986, accepted 11 February 1987. ISSN 0001–6772. University of Oslo, Institute for Experimental Medical Research, Ullevaal Hospital, Oslo, Norway. To examine renal degradation and distribution between urine and renal venous blood, prostaglandins E₂ and I₂ (PGE₂ and PGI₂), and a metabolite of PGI₂, bketo-PGF_1α, were infused into the suprarenal aorta of anaesthetized dogs after blocking prostaglandin synthesis by indomethacin, 10 mg kg^-1 body wt iv. During one passage through the kidney 80% of PGE, and only 25% of PGI₂ and 6-keto-PGF_1α, were metabolized. Prostaglandin degradation and arterial input were proportional (r > 0.90). To stimulate the intrarenal prostaglandin synthesis in unblocked kidneys, arachidonic acid was infused at rates ranging from 24 to 160 μg min^-1 kg^-1 body wt. During arachidonic acid and PGE₂ infusion the urinary excretion of PGE₂ was about 20% of the renal venous output over a wide range of infusion rates. During arachidonic acid and PGI₂ infusion urinary excretion of bketo-PGF_1α was about 10% of total renal output, but failed to increase further when total renal output exceeded 70 pmol min^-1. Further increase in output occurred only in the renal vein. In contrast, during 6-keto-PGF_1α infusion the urinary excretion and the renal venous output of this metabolite were related as 1:2 over a wide range of infusion rates. Thus, PGI₂ is much less degraded by renal tissue than PGE₂, and the distribution patterns differ. Similar distributions between urine and renal venous blood during aortic infusion and stimulated intrarenal synthesis suggest a pre-glomerular vascular origin of both prostaglandins.     

The muscarinic agonist pilocarpine inhibits DNA and interferon-γ synthesis in peripheral blood mononuclear cells

Lymphocyte basal DNA synthesis and proliferative responses to phytohemagglutinin (PHA) showed a dose-dependent (5 × 10⁻⁵ − 5 × 10⁻³ M) inhibition by the muscarinic agonist pilocarpine, in contrast to the basal enhancing effect produced by the M₂ muscarinic-nicotinic agonist carbacol. The effect of pilocarpine was reversed by both atropine (1 × 10⁻⁶ M) and pirenzepine (1 × 10⁻⁷ − 1 × 10⁻⁸ M), M₁ − M₂ and M₁ muscarinic antagonists, respectively. The effect of pilocarpine may thus be specific for the M₁ muscarinic receptor. Pilocarpine also inhibited interferon-gg (IFN-γ)-PHA induced production, but was unable to reverse the pokeweed mitogen (PWM)-induced DNA synthesis. Distinct immunoregulatory activities are suggested for cholinergic muscarinic receptors M₁ and M₂.     

Prostaglandin E2 Is the Major Arachidonic Acid Metabolite Secreted by Esophageal Mucosal Cells in Rabbits

Unlike gastric mucosa, it has been considered that lipoxygenase metabolites protect the esophageal mucosa and that prostaglandins are only secreted in the presence of esophageal inflammation. The aim of this study was to determine the profile of arachidonic acid metabolites and their response to regulatory compounds in rabbit esophageal mucosal cells in culture. Eicosanoids secreted into the medium were extracted and identified by HPLC and RIA. Esophageal mucosal cells in culture metabolized arachidonic acid mainly through the cycloxygenase pathway and PGE₂ was the major arachidonic acid metabolite secreted. The addition of IL-1 and A23187 (calcium ionophore) stimulated PGE₂ synthesis. In basal conditions neither leukotrienes nor HETEs were detected. However, the addition of the NDGA induced the secretion of lipoxygenase metabolites identified as 12–15 HETEs. In conclusion, rabbit esophageal epithelial cells in culture metabolize arachidonic acid via both cycloxygenase and lipoxygenase pathways. In our system, PGE₂ was the main arachidonic acid metabolite.     

Effect of a milk diet on rat gastric mucosa: Receptor activity,histamine metabolism and ultrastructural analyses

A bovine milk diet (BM) resulted in remarkable changes in histamine H₂ receptor activity (sensitization) and PGE₂ receptor activity (desensitization) in gastric glands isolated from adult rats. In contrast, the receptor-cAMP systems sensitive to glucagon(s) and secretin in parietal cells and muco-peptic cells were unaffected. In the two experimental groups, cimetidine produced a parallel displacement of the histamine dose-response curve, suggesting competitive inhibition between this classical H₂ receptor antagonist and histamine. The BM diet reduced the histidine decarboxylase activity in rat gastric mucosa; the histamine content was not significantly different in control and BM-fed rats. There was no alteration of the circadian rhythm of the parietal cell (ultrastructural changes: microvilli, tubulovesicles) determined at intervals of 6 hours in milk-fed rats.Prostaglandins and other components in milk (EGF, somatostatin, etc.) might therefore protect gastric mucosa by a differential control of PGE₂ and histamine H₂ receptor activity, eitherdirectly (PGE₂ and EGF in milk) orindirectly (inhibition of endogeneous histamine synthesis/release and stimulation of prostaglandin synthesis/release).     

Eicosanoid and gastroprotection by copper derivatives and NDGA

We investigated the effect of oral administration of graded doses of: nordihydroguaiaretic acid (NDGA), CuNSN, a bis(2-benzimidazolyl)thioether and CuCl₂ on ethanol-induced gastric damage in the rat and the role of leukotrienes and prostaglandins in attenuating this damage. In the experiments we determinedex-vivo eicosanoid release in the rat gastric mucosa pretreated with the above-mentioned compounds. The results indicate that the gastric lesion is accompanied by an increase in mucosa-synthesize LTC₄, while PGE₂ formation remains unchanged. Pretreatment with NDGA, CuNSN and CuCl₂, protects the gastric mucosa from damages and reduces the increase in LTC₄ mucosal formation. CuNSN and CuCl₂ increase the PGE₂ release, while NDGA has no effect on this pathway. These results suggest that one of the possible mechanisms of the NDGA protective effect is related to the inhibition of LTC₄ formation, while the PGE₂ increase in synthesis together with the leukotriene inhibition could contribute to the protective effect of CuNSN and CuCl₂.     

The gastric cytoprotective action of adenosine and prostaglandin E2 in rabbits

The direct protective action of adenosine and prostaglandin E₂ (PGE₂) was examined in an isolated gastric gland preparation in rabbits. Ethanol, (8%, v/v) incubation markedly increased the release of lactate dehydrogenase (LDH) and number of non-viable glands in the preparation. Both effects were prevented by PGE₂ preincubation in a concentration (10^–6, 1.4×10^–5 or 2.8×10^–5 M)-dependent manner. The protective action was smaller in adenosine-treated groups, and yet the highest concentration (10^–4 M) of the compound also significantly inhibited the cytotoxic effects of ethanol. These findings indicate that both adenosine and PGE₂ possess cytoprotective action on gastric glands in rabbits, but the former compound exerts its action beyond physiological concentrations. It is concluded that endogenous PGE₂, but not adenosine may act as an ulcer modulator in the stomach.     

Pathogenesis of aspirin-exacerbated respiratory disease

The underlying respiratory disease is activated by unknown mechanism and results in an intense infiltration of mast cells and eosinophils into the entire respiratory mucosa. These cells synthesize leukotrienes (LTs) at a very high rate and mast cells also release histamine and tryptase and synthesize PGD₂ a vasodilator and bronchoconstrictor. Furthermore, AERD patients under synthesize from arachidonic acid (AA) a peculiar product called lipoxins, which opposes inflammation generated by leukotrienes. Finally, cysLT₁ receptors are over expressed and highly responsive to LTE₄, further augmenting the underlying inflammatory disease. This inflammatory condition is partly inhibited by synthesis of PGE₂ through COX-1. PGE₂ partially inhibits 5-lipogygenase conversion of AA to LTA₄ and blocks release of histamine and tryptase from mast cells. When COX-1 is inhibited by ASA or NSAIDs, PGE₂ synthesis stops and an enormous release of histamine and synthesis of LTs occurs. The upper respiratory reaction is mediated by both histamine and LTs but the bronchospastic reaction is mediated by LTs. The systemic effects of flush, gastric pain and hives are mediated by histamine. Aspirin desensitization can not be explained by disappearance of LT synthesis since urine LTE₄ levels are still elevated at acute ASA desensitization. However, mast cell products such as histamine, tryptase and PGD₂ are no longer released or synthesized at acute desensitization. It is more likely that a diminution in number or function of cysLT receptors accounts for the diminished inflammatory response found in ASA desensitization.     

Cytoprotective Activity in the Gastric Mucosa of Rats Exposed to Carbon Tetrachloride-Induced Liver Injury

The present study was undertaken to evaluate the cytoprotective activity in the gastric mucosa of rats subjected to CCl₄-induced liver injury. Response of gastric mucosa to absolute ethanol insult or acid (pylorus ligation) after CCl₄ challenge was analyzed. Intraperitoneal administration of CCl₄ increased plasma AST and ALT, but liver protein and glycogen levels were decreased; in addition, gastric acid secretion was significantly increased with respect to control animals (1541 ± 266 vs. 629 ± 25 eq H⁺; p < 0.001). Microscopical gastric erosions were observed in 3/10 animals after CCl₄ challenge. Pylorus-ligated as well as CCl₄-challenged rats developed increased susceptibility to gastric lesions, compared to control (lesion indices: 4.6 ± 0.20 vs 2.8 ± 0.13; p < 0.05), while showing increased resistance to absolute ethanol-induced gastric damage (30.4 ± 11.2 vs 89.7 ± 9.7 mm, p < 0.01). PGE₂ levels in the gastric mucosa were not influenced by exposure to CCl₄. Ultrastructural studies revealed the presence of continuous ethanol-resistant and apparently more adherent layer of mucus in CCl₄-challenged animals. Morphological evaluation revealed an increase in Alcian blue-stained mucus. A dual condition of enhanced sensitivity to HCl with increased tolerance to ethanol was observed in gastric mucosa of CCl₄-treated animals. These observations could be explained by the amount and/or composition of protective mucus layer in the gastric mucosa.