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PubMed1987

Cytoprotective doses of arbacet with minimal antisecretory properties are not effective in duodenal ulcer healing.

The efficacy of arbacet (a synthetic analog of prostaglandin E2) in definite cytoprotective but minimal antisecretory dose was evaluated in the treatment of duodenal ulcer. One hundred five patients with endoscopically proven duodenal ulcer were randomized in a double-blind manner to receive four times daily either arbacet 25 micrograms or placebo. Ulcer healing was assessed endoscopically after two and four weeks of treatment. The mean age, sex distribution, and tobacco and alcohol consumption were similar in the two treatment groups. The ulcers of 16 patients in both the placebo and the arbacet-treated group healed after 14 days of treatment. At the end of the study, healing of the ulcer was observed in 69.2% of the arbacet-treated patients and in 60.4% of patients in the placebo treated group. (Difference was not statistically significant). We conclude that cytoprotective doses of arbacet with minimal antisecretory properties are not effective in duodenal ulcer healing.

Adolescent↗
PubMed1986

Evaluation of cytoprotection against ethanol-induced injury in gastric mucosa pretreated with misoprostol, cimetidine, or placebo.

The authors have developed a primate model for evaluating cytoprotection against alcohol-induced injury in gastric mucosa pretreated with antiulcer agents. In the present study, groups of squirrel monkeys received either a single oral dose of misoprostol (500 or 200 micrograms/kg), cimetidine (3 or 6 mg/kg), placebo, or no treatment. After 30 min, 1 ml of 50% ethanol was administered to all animals, except for one of two untreated controls. At 90 min, stomachs from lethally anesthetized primates were processed for scanning electron and quantitative stereoscopic microscopy. Fifty percent ethanol alone damaged epithelial cells and produced submucosal hemorrhagic lesions. Pretreatment with misoprostol limited alcohol-induced injury to superficial erosion of epithelial cells. Cimetidine did not protect the mucosa against ethanol-induced injury. We conclude that misoprostol-conferred cytoprotection in primate gastric mucosa correlates with the endoscopic findings by others that misoprostol, but not cimetidine, protected human stomach against alcohol-induced injury.

Alprostadil↗
PubMed1985

Gastrointestinal cytoprotective effects of misoprostol. Clinical efficacy overview.

The cytoprotective effects of misoprostol, a synthetic analog of prostaglandin E1, were investigated in healthy human subjects using randomized and placebo-controlled studies. Misoprostol significantly inhibited established aspirin (975 mg q.i.d.)-induced gastric microbleeding at 50 micrograms q.i.d., and to some extent, but not significantly, at 25 micrograms q.i.d. Misoprostol also reduced acid and chloride secretion significantly at 50 micrograms q.i.d., but not at 25 micrograms q.i.d. When administered concurrently with aspirin 650 mg q.i.d., misoprostol 25 micrograms q.i.d. significantly inhibited aspirin-induced fecal blood loss without affecting plasma salicylate concentration. The fact that misoprostol was tested at a sub-therapeutic gastric antisecretory dose (25 micrograms) indicates that the inhibition of fecal blood loss was not due to its gastric antisecretory property. Misoprostol tended to reduce antral erosion and DNA content of gastric fluid, but increased mucus concentrations in subjects with ethanol-induced damage. However, the dose of ethanol used produced gastric damage in only six of the 10 subjects and did not provide a satisfactory baseline. Misoprostol attenuated the drop in transmucosal potential difference induced by sodium taurocholate. It is concluded that misoprostol has cytoprotective activity in man. These effects may be of great importance in the treatment of acid peptic disease of the gastrointestinal tract.

Adult↗
PubMed1995

The importance of gastric emptying and mucosal folds in the adaptive cytoprotection of mild irritants in rats.

This study examines the involvement of gastric emptying and mucosal folds in the adaptive cytoprotection of different mild irritants against 100% ethanol-induced gastric mucosal damage. Pre-exposure to either 20% ethanol, 5% NaCl or 0.3M HCl significantly reduced the gastric mucosal damage caused by 100% ethanol in rats. Administration of either one of the three mild irritants increased the basal gastric residual volume and decreased the area occupied by gastric mucosal folds, but only 20% ethanol reduced the gastric emptying rate. Indomethacin (5 mg/kg, s.c.) pretreatment did not affect ethanol ulceration and gastric emptying rate when given by itself, but reversed the flattening of mucosal folds produced by the three mild irritants, and abolished the protective effect of 20% ethanol. These results suggest that the gastric adaptive cytoprotection induced by the three mild irritants acts through luminal dilution of the noxious agent, possibly caused by gastric retention. The reduction of mucosal folds could also contribute to the anti-lesion action of 20% ethanol. It is therefore suggested that the protective actions of the three mild irritants act through different mechanisms.

Adaptation, Physiological↗
PubMed1989

Theoretical mechanism for the gastrointestinal safety of etodolac: selective sparing of cytoprotective prostaglandins.

The high concentrations of pro-inflammatory prostaglandins (PGs) produced in the joint during the initial stage of inflammation can be decreased by inhibiting their biosynthesis with nonsteroidal anti-inflammatory drugs (NSAIDs). The commonly encountered gastrointestinal intolerance in human subjects treated with NSAIDs is generally attributed to inhibition of PG synthesis in gastric mucosa, where the natural role of locally biosynthesized PGs is to protect the mucosa from necrosis upon exposure to noxious agents. The action of an ideal NSAID should therefore be tissue specific, i.e., it should inhibit PG formation at the sites of inflammation but not in gastric mucosa, where PGs are needed for cytoprotection. We believe that etodolac, a new, structurally distinct NSAID, meets this criterion, inhibiting PG synthesis in a tissue-specific fashion. Experimental data supporting this interpretation were obtained in rats by demonstrating that daily administration of orally effective anti-inflammatory doses of etodolac had no significant effect on gastric mucosal PGE2 or prostacyclin levels (measured as the stable metabolite, 6-keto-PGF1 alpha). In contrast, naproxen, piroxicam, and aspirin caused a statistically significant PG depletion. The results obtained in rats thus support the view that the favorable gastrointestinal safety profile of etodolac in human patients may be attributable to selective sparing of the cytoprotective PGs in gastric mucosa.

6-Ketoprostaglandin F1 alpha↗
PubMedDate not supplied

Cytoprotective response of A1, a Bcl-2 homologue expressed in mature human neutrophils and promyelocytic HL-60 cells, to oxidant stress-induced cell death.

The ability to generate reactive oxidative intermediates is one of the quintessential properties of mature human neutrophils. Endogenously generated oxidants have been shown to be an important mechanism underlying neutrophil cell death. In acute lung inflammation, newly recruited neutrophils further encounter external oxidants, including reactive oxygen and nitrogen intermediates. In our present study, we showed that A1, a constitutive and inducible Bcl-2 homologue expressed in mature circulating human neutrophils, might confer the protection from hydrogen peroxide (H(2)O(2))- and peroxynitrite (ONOO)-induced cell death. Utilizing the myeloid precursor cell line, HL-60, we further examined the hypothesis that A1 was capable of conferring cytoprotective activity against these oxidative stresses. Whereas the control-transfected HL-60 cells expressed small amounts of A1 and were sensitive to the biologically relevant, cell death-inducing oxidants, H(2)O(2) and ONOO, the stable transfectants that overexpressed A1 were significantly more tolerant. Furthermore, there was a correlation between the level of A1 expression and the antiapoptotic activity. Thus, our results suggest a cytoprotective role of A1 in mature human neutrophils under oxidant stresses in host defense and inflammation.

Apoptosis↗
PubMed2005

Cytoprotective effect of green tea extract and quercetin against hydrogen peroxide-induced oxidative stress.

In this study, we evaluated the cytoprotective effects of antioxidative substances in hydrogen peroxide (H2O2) treated Mel-Ab melanocytes. Tested substances include selenium, quercetin, green tea (GT) extract, and several vitamins (ascorbic acid, Trolox, and folic acid). Of these, both quercetin and GT extract were found to have strong cytoprotective effects on H2O2-induced cell death. We also examined additive effects, but no combination of two of any of the above substances was found to act synergistically against oxidative damage in Mel-Ab cells. Nevertheless, a multi-combination of GT extract, quercetin, and folic acid appeared to prevent cellular damage in a synergistic manner, which suggests that combinations of antioxidants may be of importance, and that co-treatment with antioxidants offers a possible means of treating vitiligo, which is known to be related to melanocyte oxidative stress.

Animals↗
PubMed1999

Co-regulation of mucosal nitric oxide and prostaglandin in gastric adaptive cytoprotection.

OBJECTIVE: The correlation between mucosal generation of nitric oxide (NO) and prostaglandin E2 (PGE2) in gastric adaptive cytoprotection was investigated. MATERIALS AND TREATMENT: Male Sprague-Dawley rats were pretreated with either N(w)-nitro-L-arginine methyl ester (L-NAME, 12.5 mg/kg i.v.) or indomethacin (5 mg/kg s.c.). Following that, mild irritant 20% ethanol was administered, 15 min prior to 100% ethanol challenge. METHODS: Macroscopic gastric mucosal damage, NO synthase activity, mucosal PGE2 and leukotriene C4 (LTC4) levels were measured. RESULTS: Administration of L-NAME and indomethacin significantly reduced the protective action of 20% ethanol against 100% ethanol-induced gastric mucosal damage. Besides, mucosal activity of constitutive NO (cNO) synthase, but not of the inducible isozyme (iNO synthase), was elevated following 20% ethanol treatment. This was accompanied by a reduction in mucosal leukotriene C4 level. Indomethacin significantly inhibited mucosal PGE2 biosynthesis but increased cNO synthase activity. Nevertheless, L-NAME reduced both cNO and iNO formation and prevented the increase in cNO formation caused by 20% ethanol, while enhancing mucosal PGE2 production. Combined L-NAME and indomethacin treatment markedly potentiated ethanol-induced mucosal damage, and completely prevented the increase in cNO or PGE2 biosynthesis when either compound was given alone. CONCLUSIONS: These findings suggest a co-regulatory relationship between mucosal NO and PG in the gastric defense system, which will be released after activation by the mild irritants to induce cytoprotection.

Animals↗
PubMed2005

Cytoprotective effects of amifostine and cysteamine on cultured normal and tumor cells treated with paclitaxel in terms of mitotic index and 3H-thymidine labeling index.

PURPOSE: In this study, the cytotoxic effects of paclitaxel (PAC) in normal and tumor cells were established, and the cytoprotective effects of amifostine (AMI) and cysteamine (CYS) against this cytotoxicity were examined. METHODS: Tumor cell lines used in this study were L-strain cells of mouse subcutaneous origin and human cervix carcinoma-derived HeLa cells. Mouse embryonic fibroblasts (MEFs) were used as the normal cell line. Results of the experiments were evaluated in terms of the mitotic index and the 3H-thymidine labeling index. PAC concentrations of 6 and 12 microg/ml were applied to the cells for 1-10 days either alone or in combination with 1 mug/ml of AMI and CYS. RESULTS: In terms of the above parameters, statistically significant effects were not seen in cultures of any of the cell lines treated with 1 microg/ml of AMI or CYS alone. In contrast, both concentrations of PAC caused increasing cytotoxic effects with increasing treatment time (P < .001). The cytotoxic effect of PAC appeared as mitotic phase accumulation (G2/M blockage) and a subsequent decline in the synthesis phase. HeLa cells were very sensitive to PAC treatment, whereas MEF cells were quite resistant compared with tumor cells. In cells treated with combined drugs to investigate the cytoprotective effects of AMI and CYS on normal and tumor cell lines, PAC continued to show cytotoxic effects in tumor cells, but this effect was reduced in the normal cells. CONCLUSIONS: AMI and CYS did not protect tumor cells against the cytotoxic effects of PAC, but protection was observed in normal cells. Furthermore, the protection provided by AMI was stronger than that provided by CYS.

Amifostine↗
PubMed2000

N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine (DPPE) a chemopotentiating and cytoprotective agent in clinical trials: interaction with histamine at cytochrome P450 3A4 and other isozymes that metabolize antineoplastic drugs.

PURPOSE: N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl (DPPE), an intracellular histamine (HA) antagonist with chemopotentiating and cytoprotective properties, is currently in phase 2 and 3 clinical trials in breast and prostate cancer. DPPE modulates growth at in vitro concentrations that antagonize HA binding to cytochromes P450 in rat liver microsomes. HA inhibits P450 metabolism of some drugs. Recent in vitro studies in human colon cancer cells have linked DPPE enhancement of paclitaxel, doxorubicin and vinblastine cytotoxicity to inhibition of the P-glycoprotein (P-gp) pump. Many substrates of P-gp are also substrates of CYP3A4, a P450 isozyme that metabolizes a variety of antineoplastic agents and is highly expressed in some malignant tissues. Therefore, we assessed whether (a) DPPE and HA interact at CYP3A4 and other P450 human isozymes, and (b) DPPE inhibits the catalytic activity of CYP3A4. METHODS: Using spectral analysis, we measured DPPE and HA binding to insect microsomes that express human P450 isozymes 1A1, 2B6, 2D6 or 3A4. Employing thin-layer chromatography, we assessed the metabolism of DPPE by each isozyme and DPPE inhibition of testosterone metabolism by CYP3A4 and by rat liver microsomes. RESULTS: (1) DPPE evoked "type I" (substrate site binding) absorbance-difference spectra with CYP2D6 (K(S) = 4.1 +/- 0.4 microM), CYP3A4 (K(S) = 31 +/- 15 microM) and CYP1A1 (K(S) = 40 +/- 9 microM), but not with CYP2B6. (2) In correspondence with the binding studies, DPPE was metabolized by CYP2D6, CYP3A4 and CYP1A1; no metabolism occurred with CYP2B6. (3) HA evoked "type II" (heme iron binding) absorbance-difference spectra with all four isozymes, with K(S) values in the range 80-600 microM. DPPE inhibited HA (600 microM) binding to CYP2D6 (IC50 = 4 microM, 95% CI= 1.8-8.9 microM) and CYP1A1 (IC50 = 135 microM: 95% CI = 100-177 microM), but stimulated HA (500 and 1000 microM) binding to CYP3A4 (EC50 = 155 microM, 95% CI = 104-231 microM). DPPE did not affect HA binding to CYP2B6. (4) DPPE inhibited the metabolism of testosterone by CYP3A4. The concentration/effect curve was biphasic: DPPE inhibited metabolism by 30% at the first site (IC50 = 3 microM, 95% CI = 0.5-25.5 microM), and an additional 70% inhibition occurred at the second site (IC50 = 350 microM, 95% CI = 215-570 microM). A similar result was observed with rat liver microsomes. CONCLUSION: DPPE is a substrate for CYP3A4, CYP2D6 and CYP1A1, but not CYP2B6. DPPE inhibits testosterone metabolism by interacting at two sites on CYP3A4, the first correlating with its K(S) value to bind the substrate site and the second, with its EC50 value to enhance HA binding to the heme iron. We postulate that (1) the inhibitory effect of DPPE on CYP3A4 activity is mediated directly at the substrate site and indirectly by its enhancement of the binding of HA to the heme moiety; (2) in tumor cells that express high constitutive levels of CYP3A4, potentiation of chemotherapy cytotoxicity by DPPE results, in part, from inhibition of CYP3A4-mediated metabolism and P-gp-mediated efflux of antineoplastic drugs; (3) in normal cells that express low constitutive levels of the isozyme, cytoprotection by DPPE results, in part, from induction of CYP3A4 and P-gp, resulting in an increase both in metabolism and efflux of antineoplastic drugs.

Adjuvants, Pharmaceutic↗
PubMed1989

Cerebrovascular, biochemical, and cytoprotective effects of isradipine in laboratory animals.

Dose-response curves of isradipine for blood pressure, total peripheral conductance, and regional cerebral conductances and blood flows were obtained in anesthetized cats and rabbits using the microsphere method. Cerebrovascular effects occurred at lower doses than systemic effects, and the effective duration was longer in the brain than in the periphery. In a rat model of embolic stroke (unilateral occlusion of the middle cerebral artery), isradipine has been shown to have cytoprotective efficacy (Sauter A, Rudin M: Stroke 1986; 17: 1228-1234; Rudin M, Sauter A, Wiederhold K-H: Therapie 1987; 42: 477-481; Sauter A, Rudin M, Wiederhold K-H: Neurochem Pathol 1989 [in press]). Using this model, dose-response curves for infarct size, measured by magnetic resonance imaging, and biochemical markers of infarction were obtained for various calcium antagonists. Isradipine showed the biggest improvements (50 to 60 percent at 2.5 mg/kg subcutaneously), followed by nimodipine (30 to 40 percent at 5 mg/kg subcutaneously), nitrendipine (30 to 40 percent at 10 mg/kg subcutaneously), darodipine (20 to 30 percent at 10 mg/kg subcutaneously), and nicardipine (10 percent at 10 mg/kg subcutaneously). It is concluded that isradipine differs in both efficacy and potency from the other calcium antagonists tested. The effects of isradipine, nimodipine, and darodipine on cerebral blood flow were further investigated in this model using the [14C]iodoantipyrine method. Despite systemic hypotension, cerebral blood flow was dose dependently increased in the normal and ischemic hemispheres. Isradipine elicited maximal improvements over a wider dose range than the other drugs tested (0.1 to 2.5 mg/kg), preferentially affecting cerebral blood flow in the ischemic areas, as further demonstrated using autoradiographic techniques. These effects are in good, quantitative agreement with the reductions in infarct size, observed by magnetic resonance imaging and histology, emphasizing the importance of cerebrovascular mechanisms for cytoprotection in stroke. The concurrence between cat, rabbit, and rat experiments suggests that the findings may also apply to humans.

Animals↗
PubMed1992

Do sensory neurons mediate adaptive cytoprotection of gastric mucosa against bile acid injury?

Pretreatment with the mild irritant 1 mmol acidified taurocholate protects the gastric mucosa from the injury induced by the subsequent application of 5 mmol acidified taurocholate, a phenomenon referred to as "adaptive cytoprotection." How this occurs remains an enigma. The purpose of this study was to investigate the role of sensory neurons and mucus secretion in this phenomenon. Prior to injury with 5 mmol acidified taurocholate (pH 1.2), the stomachs of six groups of rats were subjected to the following protocol. Two groups were topically pretreated with either saline or the mild irritant 1 mmol acidified taurocholate. Two other groups received the topical anesthetic 1% lidocaine prior to pretreatment with either saline or 1 mmol acidified taurocholate. The last two groups got the mucolytic agent 10% N-acetylcysteine (NAC) after pretreatment with either saline or 1 mmol acidified taurocholate. Injury was assessed by measuring net transmucosal ion fluxes, luminal appearance of deoxyribonucleic acid (DNA), and gross and histologic injury. Pretreatment with the mild irritant 1 mmol acidified taurocholate significantly decreased bile acid-induced luminal ion fluxes and DNA accumulation, suggesting mucosal protection (corroborated by gross and histologic injury analysis). This effect was negated by lidocaine but not by NAC. Thus, it appears that sensory neurons, and not increased mucus secretion, play a critical role in adaptive cytoprotection.

Acetylcysteine↗
PubMed1990

Cytotoxic and cytoprotective activities of curcumin. Effects on paracetamol-induced cytotoxicity, lipid peroxidation and glutathione depletion in rat hepatocytes.

The cytoprotective effect of curcumin, a natural constituent of Curcuma longa, on the cytotoxicity of paracetamol in rat hepatocytes was studied. Paracetamol was selected as a model-toxin, since it is known to be bioactivated by 3-methylcholanthrene inducible cytochromes P450 presumably to N-acetyl-p-benzoquinone imine (NAPQI), a reactive metabolite which upon overdosage causes protein- and non-protein thiol-depletion, lipid peroxidation and cytotoxicity measured as LDH-leakage. At low concentrations curcumin was found to protect significantly against paracetamol-induced lipid peroxidation, without protection against paracetamol-induced LDH-leakage and without protection against paracetamol-induced GSH-depletion. At a 100 times higher concentration of curcumin the observed protective effect on lipid peroxidation was accompanied with a tendency to increase cellular GSH-depletion and LDH-leakage. No time-dependency was found as to the curcumin-induced effects: treatment of the hepatocytes 1 hr before, concomitantly or 1 hr after the addition of paracetamol to the cells had similar effects. In contrast to what was expected on the basis of previous in vivo experiments, at higher concentrations curcumin itself was found to be slightly cytotoxic. Curcumin-induced LDH-leakage was accompanied by a significant depletion of GSH. It has been concluded that the observed cytoprotective and cytotoxic activities of curcumin may be explained by a strong anti-oxidant capacity of curcumin and the capability of curcumin to conjugate with GSH. Furthermore, it has been concluded that lipid peroxidation is not playing a causal role in cell-death induced by paracetamol or by curcumin.

Acetaminophen↗
PubMed1985

Gastric mucosal blood flow in rats after administration of 16,16-dimethyl prostaglandin E2 at a cytoprotective dose.

The purpose of the present study was to determine whether the gastric cytoprotective effect of a prostaglandin such as 16,16-dimethyl prostaglandin (dmPGE2) is mediated by an increase in mucosal blood flow. Gastric mucosal blood flow was measured in urethane-anesthetized rats by the hydrogen gas clearance technique. In control rats given no ethanol, intragastric administration of dmPGE2 (10 micrograms/kg body wt) produced a significant reduction (15.3%) in gastric mucosal blood flow 30 min after treatment. This dose of dmPGE2 significantly reduced the formation of the gross gastric lesions produced by absolute ethanol in anesthetized rats. In vehicle-pretreated animals, blood flow was invariably absent in the ethanol-induced mucosal lesion areas. In the nonlesion areas, gastric mucosal blood flow was the same in prostaglandin-pretreated and vehicle-pretreated animals as in control (no ethanol) rats. Thus, although dmPGE2 pretreatment protected against ethanol-induced gastric mucosal injury and prevented the accompanying blood flow stasis, it did not do this by an increase in gastric mucosal blood flow. The protection also is not due to a decrease in flow because, in separate groups of anesthetized rats, a 15% reduction in gastric mucosal blood flow induced by either hemorrhage or intravenous vasopressin did not protect the gastric mucosa against absolute ethanol-induced injury. Whether the maintenance of gastric mucosal blood flow is a primary or secondary effect of prostaglandin cytoprotection remains to be determined.

16,16-Dimethylprostaglandin E2↗
PubMed1987

Failure of a cytoprotective dose of arbaprostil to heal acute duodenal ulcers. Results of a multiclinic trial.

Previous therapeutic trials with prostaglandins have shown them to be effective in healing duodenal ulcers when used at doses that are highly effective suppressors of gastric acid secretion. We undertook this trial to determine if a cytoprotective dose of arbaprostil (10 micrograms q.i.d. for 4 wk) would also be efficacious in this disease state. Eighty-two patients between the ages of 19 and 72 yr with endoscopically documented duodenal ulcers were entered into this randomized double-blind placebo-controlled trial. The patients were monitored with biweekly endoscopies and laboratory examinations, weekly interviews during the period when drug was administered, and a follow-up interview plus laboratory examinations 1 wk after drug administration was completed. No statistically significant differences between the arbaprostil and placebo treatment groups were found for ulcer healing rates, pain relief, antacid consumption, side effects, or laboratory examinations. It is presumed that this prostaglandin may not have sufficient duodenal cytoprotective capacity to effectively heal duodenal ulcers, or that some suppression of gastric acid secretion may be required to achieve significant clinical efficacy.

Adult↗
PubMed1988

Evidence that adaptive cytoprotection in rats is not mediated by prostaglandins.

We investigated the proposition that adaptive cytoprotection (enhanced gastric mucosal integrity) caused by exposure to 20% ethanol in rats is mediated by endogenous prostaglandin synthesis. Experiments were performed both without and with indomethacin sufficient to inhibit ex vivo release of prostaglandin E2 by 56% +/- 9% (2.5 mg/kg) or 86% +/- 4% (10 mg/kg). Twenty percent ethanol significantly reduced both macroscopic and histologic signs of injury caused by subsequent exposure to 100% ethanol whether or not the rats were pretreated with indomethacin. Twenty percent ethanol itself caused extensive superficial disruption of the surface epithelium, so that about half of the mucosa was covered by desquamated debris, but did not stimulate prostaglandin release. We conclude that adaptive cytoprotection still occurs after doses of indomethacin sufficient to cause a profound depression of prostaglandin E2 release. The possibility that it could be due to formation of a protective covering of surface debris is worth further investigation.

Animals↗
PubMed1993

Hepatic and gastric cytoprotective effects of long-term prostaglandin E1 administration in cirrhotic rats.

BACKGROUND: Acute administration of prostaglandin E (PGE) may be cytoprotective for hepatocytes in acute hepatitis and for gastric mucosa in cirrhotic rats. We examined the effects of long-term PGE treatment on liver and stomach in cirrhotic rats. METHODS: Cirrhosis was induced by bile duct ligation. Controls had a sham operation. Half the rats received a PGE1 analogue, misoprostol (PGE1) (10 micrograms orally, daily) on days 1-29 postsurgery, and the others received vehicle only. On day 31, all rats underwent ex vivo gastric chamber procedures. Liver chemistry, portal pressures, and hepatic and gastric tissue levels of prostaglandin E2, leukotriene B4, myeloperoxidase, and collagen were determined. RESULTS: PGE1-treated cirrhotic rats had less hepatosplenomegaly, lower serum alanine aminotransferase levels, and portal pressures and higher arterial pressure than vehicle-treated cirrhotic rats. Hepatic and gastric leukotriene B4, myeloperoxidase and collagen levels were significantly lower in the PGE1-treated compared with vehicle-treated cirrhotic rats. Vehicle-treated cirrhotic rats had greater spontaneous and ethanol-induced gastric damage and failed to show a gastric hyperemic response to ethanol, whereas PGE1-pretreated rats did. PGE1 did not significantly affect sham-operated rats. CONCLUSIONS: Long-term PGE1 administration was cytoprotective for both the liver and gastric mucosa in cirrhotic rats. Clinical trials of PGE in human cirrhosis or portal hypertensive gastropathy may be warranted.

Alprostadil↗
PubMed1983

Effect of prostaglandin synthesis inhibitors on neurotensin and sodium salicylate-induced gastric cytoprotection in rats.

Sodium salicylate (SA) has been reported to inhibit the formation of gastric ulcerations induced by aspirin, indomethacin, and absolute ethanol. In this study, SA dose-dependently inhibited gastric ulcers induced by three hours of cold-restraint stress (CRS); SA-induced cytoprotection was prevented by both acetylsalicylic acid (aspirin) and indomethacin pretreatment. Neurotensin (NT), which has previously been demonstrated to prevent the development of CRS-induced gastric ulcerations after intracisternal administration, was found to be ineffective in animals pre-treated with aspirin, and with indomethacin, as previously described. These data suggest that in the CRS model both NT- and SA-induced gastric cytoprotection require a functionally intact gastrointestinal prostaglandin synthetic pathway.

Animals↗