B. W. Chen

The influence of acute or chronic nicotine treatment on ethanol-induced gastric mucosal damage in rats

The influences of acute or chronic nicotine pretreatment on ethanol-induced changes on gastric secretion, mucosal blood flow (GMBF), and glandular mucosal damage were studied in anesthetized rats. Ethanol administration decreased gastric acid secretion and GMBF, which were accompanied by a marked increase in gastric mucosal damage. Acute nicotine incubation 2 or 4 mg dose-dependently elevated both the titratable acid in the luminal solution and the gastric secretory volume; it also prevented the depressive action on GMBF and gastric mucosal damage in ethanol-treated animals. Chronic nicotine treatment for 10 days reduced the inhibitory action of ethanol on gastric acid secretion; the higher dose (25 μg/ml drinking water) potentiated the decrease of GMBF and the ulcerogenic property of ethanol. However, chronic treatment with the lower dose (5 μg/ml drinking water) had the opposite effects; it also markedly increased the gastric secretory volume. It is concluded that acute nicotine pretreatment elevates, whereas chronic nicotine pretreatment differentially affects GMBF. These effects could account for their protective or preventive actions on ethanol ulceration. The increase in nonacid gastric secretory volume by nicotine could partially explain its antiulcer effect. Furthermore, the acid secretory state of the stomach appears unrelated to the ulcerogenic property of ethanol.

Role of Gastric Mucosal Blood Flow in Cytoprotection

We compared the effects of graded doses of misoprostol (50-200 mg), omeprazole (12.5-50 mg), cimetidine (6.25-50 mg) and sucralfate (50-200 mg) on gastric mucosal blood flow as measured by laser Doppler flowmetry and gastric mucosal injury induced by ethanol. The results demonstrated that sucralfate, misoprostol and omeprazole, but not cimetidine, increased gastric mucosal blood flow in a dose-dependent manner and protected the mucosa against ethanol damage. The peak and summation blood flow were significantly greater with sucralfate than with misoprostol and omeprazole, but the degree of mucosal protection was similar. These results indicate that the increase in gastric mucosal blood flow, an action which is common to the three drugs, plays an important role in gastric mucosal protection, but other factors are also involved.

Endogenous prostaglandins: Its role in gastric mucosal blood flow and ethanol ulceration in rats

The involvement of endogenous prostaglandins (PGs) in modulating gastric mucosal blood flow (GMBF) is still unclear. The present study was designed to demonstrate the role of this autacoid in the basal GMBF and the restoration of blood flow after restriction of blood supply to the stomach. The ex-vivo gastric chamber was prepared and the GMBF was measured by a laser Doppler technique. 20% ethanol incubation for 10 min in the chamber increased the basal GMBF and lessened the reduction of blood flow induced by absolute ethanol. It also decreased lesion formation caused by ethanol. Indomethacin 5 mg/kg, given s.c 60 min before experimentation had the opposite effects. Ligation of the gastric artery for 20 min which reduced the GMBF by 60%, worsened ethanol ulceration. There was a marked rebound of the GMBF after the ligation was released. Indomethacin totally abolished the blood flow rebound and aggravated ethanol ulceration. However, 20% ethanol incubation significantly potentiated such a rebound in blood flow and reduced lesion formation. Indomethacin pretreatment reversed these actions, whereas misoprostol administration produced the similar effects as 20% ethanol. It is concluded that GMBF plays an important role in ethanol ulceration and both basal and rebound GMBF is probably modulated by endogenous PGs.

The role of the vagus nerve in the protective action of acid inhibitors on ethanol-induced gastric mucosal damage in rats

The role of vagus in the actions of different acid inhibitors on ethanol‐induced gastric damage and mucosal blood flow (GMBF) changes was studied in anaesthetized rats, using an ex vivo stomach chamber preparation. Subdiaphragmatic bilateral vagotomy decreased the basal gastric acid secretion and GMBF; it also intensified ethanol‐evoked lesions in the glandular mucosa. Misoprostol, omeprazole and cimetidine produced a similar degree of reduction in acid output. Misoprostol given subcutaneously (s.c.) (50 μg/kg), or added to the incubation solution (12.5 μg) for 15 min, markedly prevented ethanol‐induced lesion formation and reduction in GMBF. The reversing effect of s.c. injection of misoprostol on either lesion formation or on GMBF reduction was attenuated by vagotomy. Omeprazole protected against lesion formation only when present in the incubation solution (12.5 mg) of ex vivo chamber preparations of both vagus‐intact and vagotomized animals, but the effect was significantly less in the latter group. The drug also prevented the depressive action of ethanol in vagus‐intact animals. Cimetidine pretreatment (50 mg s.c. or 12.5 mg in incubation solution), however, did not modify the effects of ethanol on lesion formation and the GMBF. The findings indicate that the three different types of acid inhibitors exert different actions on ethanol‐induced gastric mucosal damage, although they produced similar inhibition of acid output. Vagotomy lowers the GMBF and attenuates the antiulcer action of misoprostol and omeprazole, especially when the drugs are given by the parenteral route.

The cytoprotective effect of zinc L-carnosine on ethanol-induced gastric gland damage in rabbits.

Abstract— The effects of zinc l‐carnosine on the damaging actions of ethanol were examined in rabbit isolated gastric glands. Ethanol (8%, v/v) incubation produced a 50% viability of the gland populations and released a significant amount (38%) of the total lactate dehydrogenase (an index of membrane injury) of the glands. Zinc l‐carnosine pre‐incubation for 15 min markedly prevented these actions of ethanol; however, l‐carnosine by itself did not have these effects. These findings indicate that zinc ion but not carnosine in the zinc l‐carnosine molecule possesses cytoprotective action against ethanol‐induced gastric gland damage in rabbits.

The effect of misoprostol, omeprazole and sucralfate on nicotine- and ethanol-induced gastric injury and gastric mucosal blood flow: A comparative study

Abstract Nicotine, which is thought to be responsible for part of the pharmacological effect of smoking, exacerbates gastric mucosal injury in rats. The effects of misoprostol (12.5 μg to 100 μg), omeprazole (12.5 mg to 100 mg) and sucralfate (50 to 400 mg) on gastric mucosal blood flow and mucosal injury induced by nicotine were studied in an ex vivo gastric chamber preparation in rats. Rats were pretreated with nicotine (25 μg/mL orally) for 10 days and ethanol was added to the gastric chamber preparation. Laser Doppler flowmetry was used to measure the gastric mucosal blood flow and mucosal damage (ulcer index) was assessed by the area of haemorrhagic lesions. The ulcer index was significantly higher in rats pretreated with nicotine. Treatment with misoprostol and omeprazole lowered the ulcer index significantly compared with controls. The peak and summation blood flows were lower in nicotine‐treated rats but failed to reach statistical significance. The peak blood flow (blood flow at 45 min) and the summation blood flow were significantly higher with all doses of sucralfate, misoprostol and omeprazole than in controls (P<0.05). The increase in gastric mucosal blood flow was significantly higher with sucralfate and misoprostol than with omeprazole. We conclude that sucralfate, misoprostol and omeprazole prevent nicotine‐ and ethanol‐induced gastric mucosal damage and are accompanied by an increase in gastric mucosal blood flow. This indicates that smoking exacerbates gastric mucosal injury and that cytoprotective and site‐protective agents can reduce injury by these noxious agents.

Assessment of hemodynamic changes in rat stomachs by laser Doppler velocimetry and reflectance spectrophotometry: effects of ethanol and prostaglandin E2 under ischemic and congestive conditions

One of the ulcerogenic mechanisms by which ethanol induces mucosal lesions in the stomach is the depression of gastric mucosal blood flow (GMBF). The goal of this study was to determine whether lesion formation is the result of vascular ischemia alone or ischemia combined with congestion. The aims of this study were to answer this question by evaluating the relationship between GMBF, oxygen saturation (ISO2) and hemoglobin volume (IHb) in the gastric mucosa under the influences of ethanol and prostaglandin E2 (PGE2) in the ischemic and congestive states, using a laser Doppler flowmeter and tissue spectrum analyzer. Ligation of the gastric celiac artery or vein markedly decreased the GMBF and the ISO2 level. The former procedure also reduced but the latter increased the IHb level. Ethanol administration produced effects similar to venous ligation, i.e. vascular stasis with ischemia. There was a negative correlation between GMBF and severity of lesion formation after ethanol administration. However, at the lesion site all the hemodynamic parameters were significantly reduced, indicating that a necrotic condition had occurred. PGE2 preincubation (25 micrograms) elevated GMBF, ISO2 and IHb levels. It also alleviated the reduction of blood flow induced by ethanol and increased the recovery rate of GMBF and ISO2 after the release of arterial or venous ligation. It is concluded that the decrease in blood flow due to ethanol is probably caused by constriction of venules rather than arterioles inside the mucosa, and this effect could lead to vascular congestion. PGE2 probably dilates both arterioles and venules in the gastric mucosa and thereby increases the blood flow in the gastric mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Can misoprostol and omeprazole reduce nicotine and ethanol induced gastric mucosal injury? A quantitative macroscopic and microscopic analysis in rats

We compared the effects of misoprostol, omeprazole and methylcellulose (control) on gastric mucosal injury induced by nicotine and/or ethanol. The results demonstrate that misoprostol and omeprazole each significantly reduce macroscopic injury and deep injury at a microscopic level (P < 0.05) induced by nicotine alone, ethanol alone or a combination of ethanol and nicotine. Misoprostol and omeprazole each reduced the leakage of fluorescein isothiocyanate‐albumin into the interstitium in the gastric mucosa. Misoprostol and omeprazole are each effective in preventing injury induced by nicotine and ethanol and vascular factors are involved.

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 2.8×10−5M)-dependent manner. The protective action was smaller in adenosine-treated groups, and yet the highest concentration (10−4M) 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.

Macroscopic and microscopic analysis of ethanol and nicotine damage to rat gastric mucosa after treatment with misoprostol and omeprazole

We compared the protective effects of misoprostol, a prostaglandin El derivative with both acid-inhibitory and cytoprotective actions, to omeprazole which possesses potent acid-inhibitory activity only on the injury to rat gastric mucosa induced by ethanol alone, and ethanol combined with nicotine, which was given to rats 25 μg/ml tap H2O for ten days before experiment. Assessment of macroscopic and microscopic mucosal damage were made in rats treated with ethanol and nicotine alone, or in combination with varied doses of Misoprostol, and Omeprazole topically The ulcer index was measured by the total area of macroscopic hemorrhagic necrosis in the glandular stomach. Microscopic examination of the tissue taken from the non-necrotic lesion areas of each rat stomach was carried out in order to determine the extent and depth of mucosal damage. The depth of mucosal damage was classified as O-damage; I-damage, II-damage and III-damage based on standardized criteria. In rats challenged with ethanol alone, the ulcer index, the total area of damaged gastric mucosa, and III damage in the non-necrotic lesion area of stomach were significantly lower in rats treated with all doses of misoprostol and high doses of Omeprazole vs low doses of Omeprazole and control (p Conclusion Misoprostol protects ethanol and nicotine induced mucosal injury better than omeprazole and control This indicates that cytoprotective action rather than acid-inhibition is more important in offering mucosal protection.