[Chinese herbal medicine and cytoprotection in gastrointestinal tract].
Explore the source record for details and available documents.
Animals↗
SEARCH · Search PubMed
Results for “Cytoprotection”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
[Ischemic syndrome: reperfusion and myocardial cytoprotection].
With regard to the concept of reperfusion injury, there is no doubt that the benefit of reperfusion can cause serious arrhythmias, mechanical stunning, myovascular damage, new necrosis, or as some people consider more likely, apotosis. Advances in cell biology of cardiomyocytes have been remarkable in recent years. However, it is still impossible to monitor all the events that occur in these cells, especially in relation to their function and dysfunction. Our understanding of cellular dysfunction would be enhanced if different types of morphological changes could be related to specific metabolic and functional disorders of the cells. The most important of these changes are those leading to cell necrosis. In terms of therapy, it is essential to identify and prevent the progression of these lethal processes. The concepts of modern interventional cardiology have shown that steps such as thrombolysis, primary angioplasty, relief of coronary spasm-calcium antagonists and drugs such as trimetazidine (myocardial protection) are all important to promote coronary flow and to improve tissue metabolism. The pre-treatment and treatment with trimetazidine during the experimental period is almost totally able to prevent ischemic contracture. The mode of action is metabolic. The site of action is not clear. There is a very interesting trial called EMIP, presently under way in Europe, on the use of trimetazine in early thrombolysis that may help to show that this drug could prevent reperfusion injury. The results have not yet been disclosed.
Free Radicals↗
[Treatment of embolic cerebral infarct via thrombolysis and cytoprotection with U-74389-G in rats].
INTRODUCTION: The best treatment for cerebral ischemic will probably comprise the association of inhibition of ischemia-reperfusion injury mediators and early reperfusion. OBJECTIVE: We tried to demonstrate if reperfusion by thrombolysis (rt-PA) and free radical scavenging (U-74389-G) reduces ischemic-reperfusion cerebral injury in a rat model of embolic brain infarction. MATERIAL AND METHODS: 39 female Long Evans rats were embolized in right hemisphere with an autologous clot. Three groups are considered; A: control (n = 15), B: rt-PA i.v., 20 mg/kg starting 90-120 minutes after embolization (n = 15), C: rt-PA, same dose, and U-74389-G i.v., 3 mg/kg before and after embolization (n = 9). Arterial blood pressure, gasometry, glycemia and temperature were controlled. Volume of cerebral lesion in surviving animals 24 hours was measured. Autopsy was performed to verify the cause of death in rats which died. RESULTS: Mortality: group A: 8/15; group B: 9/15; group C: 8/9. Early death was related to cerebral injury except for five rats which developed peritoneal bleeding. We found severe acidosis in rats from group C. Differences in mean volume of ischemic lesion in group A and B are nosignificant despite a tendency to a reduction after thrombolysis. CONCLUSIONS: In this model thrombolysis alone and in association with U-74389-G failed to reduce cerebral lesion and mortality.
Animals↗
Antisecretory, antiulcer, cytoprotective and diarrheogenic properties of prostaglandins.
Explore the source record for details and available documents.
Animals↗
Nitric oxide priming protects nitric oxide-mediated apoptosis via heme oxygenase-1 induction.
The role of nitric oxide (NO) as a cytotoxic effector molecule of the immune system is clearly established, but recent studies demonstrate cytoprotective functions of NO at low nontoxic concentrations. However, the mechanism of cytoprotection has not been defined completely. Thus, we investigate the involvement of heme oxygenase-1 (HO-1) in the cytoprotective effects of NO. Exposure of L929 cells to sodium nitroprusside (SNP) resulted in the induction of HO-1 protein expression and heme oxygenase activity. Pretreatment of the cells with a low dose of NO (200 microM SNP) significantly inhibited a high dose of (1000 microM SNP) NO-induced apoptosis in L929 cells. Cytoprotection by a low dose of NO was abrogated in the presence of the heme oxygenase inhibitor zinc protoporphyrin IX. A cytoprotective effect comparable to a low dose of SNP was observed when the cells were transfected with HO-1 gene or preincubated with another HO-1 inducer, hemin. Additional experiments revealed the involvement of carbon monoxide in the cytoprotective effect of SNP/HO-1 in L929 cells. Our results presented here provide evidence to support the essential role of HO-1 in the cytoprotective function of NO priming.
Animals↗
Pyruvate protects cerebellar granular cells from 6-hydroxydopamine-induced cytotoxicity by activating the Akt signaling pathway and increasing glutathione peroxidase expression.
Parkinson disease (PD) is the second-most common age-related neurodegenerative disease and is characterized by the selective destruction of dopaminergic neurons. Increasing evidence indicates that oxidative stress plays a crucial role in the pathogenesis of idiopathic PD. Anti-oxidant agents including catalase, manganese porphyrin and pyruvate confer cytoprotection to different cell cultures when challenged with 6-hydroxydopamine (6-OHDA). Herein we used rat cerebellar granular cell cultures to ascertain the plausible cellular pathways involved in pyruvate-induced cytoprotection against 0.1 mM 6-OHDA. Pyruvate provided cytoprotection in a concentration-dependent manner (2-10 mM). Consistent with its well-established anti-oxidant capacity, pyruvate (10 mM) prevented 6-OHDA-induced lipid peroxidation by blocking the rise in intracellular peroxides and maintaining the intracellular reduced glutathione (GSH) levels. Further experiments revealed that pyruvate increased Akt, but not extracellular signal-regulated kinase phosphorylation. Moreover, phosphatidylinositol 3-kinase (PI3K) inhibitors attenuated pyruvate-induced cytoprotection indicating that PI3K-mediated Akt activation is necessary for pyruvate to induce cytoprotection. On the other hand, pyruvate also up-regulated glutathione peroxidase mRNA levels, but not those of the anti-oxidant enzymes superoxide dismutase-1 and -2, catalase or the anti-apoptotic oncogenes Bcl-2 or Bcl-xL. In summary, our results strongly suggest that pyruvate, besides the anti-oxidant properties related to its structure, exerts cytoprotective actions by activating different anti-apoptotic routes that include gene regulation and Akt pathway activation.
Animals↗
Role of endogenous prostacyclin in gastric ulcerogenic and healing responses--a study using IP-receptor knockout mice.
Endogenous prostaglandins (PGs) play an important role in the cytoprotective and healing responses in the stomach, by altering various functions, i.e., an increase of the mucosal blood flow, yet the role of prostacyclin (PGI(2)) and its receptor (IP-receptor) in these responses remains unclarified. In the present study, we used IP-receptor knockout mice [IP (-/-)] and examined the importance of IP-receptors in gastric ulcerogenic, cytoprotective and healing responses in these animals. The studies included the ulcerogenic response to cold-restraint stress, the cytoprotective response to a mild irritant (20 mM taurocholate: TC) and capsaicin, and the healing response of chronic gastric ulcers induced by thermo-cauterization. We first checked the absence of IP-receptors by examining the effect of cicaprost (a PGI(2) agonist, topical mucosal application) on gastric mucosal blood flow and found that this agent increased the mucosal blood flow in wild-type [WT (+/+)] mice but not in IP (+/-) mice. Cold-restraint stress (4 h) induced gastric lesions in both groups of mice, but the severity of damage was significantly greater in IP (-/-) mice. Prior p.o. administration of both TC and capsaicin exhibited a marked cytoprotection against HCl/ethanol-induced gastric damage in WT (+/+) mice, both responses being significantly mitigated in the presence of indomethacin. The adaptive cytoprotection induced by TC was similarly observed in IP (-/-) mice, while the capsaicin protection was totally attenuated in the animals lacking IP receptors. On the other hand, the healing of gastric ulcers was significantly delayed by daily administration of indomethacin in WT (+/+) mice. However, this process was not altered in IP (-/-) mice. These results suggest that endogenous PGI(2) is involved in the gastric ulcerogenic response to stress, but not in the healing of pre-existing gastric ulcers. In addition, PGI(2) and its receptors may play a crucial role in capsaicin-induced gastric protection but not in the adaptive cytoprotection-induced by mild irritants.
Animals↗
Gastric blood flow and the gastric mucosal barrier.
The basic mechanisms underlying cytoprotection of gastrointestinal mucosae against damage are not understood. One hypothesis is that the initial and primary system affected by a cytoprotective agent is the local circulation of the tissue that is being protected. According to this circulatory hypothesis, a cytoprotective prostaglandin would increase gastric mucosal blood flow, thereby ameliorating the effect of topical damaging agents, such as ethanol, aspirin or bile salts. Four questions need to be considered in order to evaluate the circulatory hypothesis: (i) What degree of ischemia is necessary to break the gastric mucosal barrier? (ii) Is peptic ulcer disease due to local ischemia of the mucosa? (iii) Do mucosal damaging agents invariably reduce gastric blood flow? (iv) Do cytoprotective agents invariably increase gastric blood flow? A survey of available literature concerning blood flow and damage to the gastric mucosa suggests that: (i) severe degrees of gastric ischemia are necessary to impair vital functions of the epithelial cells of the stomach; (ii) peptic ulcer disease is not a manifestation of isolated gastric ischemia; (iii) mucosal damaging agents do not invariably reduce gastric blood flow; and (iv) cytoprotective drugs do not invariably increase gastric mucosal blood flow. The weight of available evidence does not support the circulatory hypothesis about the mechanism of cytoprotection.
Animals↗
Diazoxide-induced respiratory inhibition - a putative mitochondrial K(ATP) channel independent mechanism of pharmacological preconditioning.
The ischemic preconditioning biological phenomenon has been explored to identify putative pharmacologic agents to mimic this cytoprotective program against cellular ischemic injury. Diazoxide administration confers this cytoprotection, however, whether this is via direct activation of the putative mitochondrial K(ATP) (mK(ATP)) channel which was originally proposed has been questioned. Here, we present data supporting an alternate hypothesis evoking mitochondrial respiratory inhibition rather than mK(ATP) channel activation, as a mediating event in the diazoxide-activated cytoprotective program. Mitochondrial respiration and reactive oxygen species (ROS) production was measured in digitonin-permeabilized C2C12 myotubes, allowing for the modulation of mK(ATP) conductance by changing the potassium concentration of the medium (0-130 mM). Diazoxide dose-dependently attenuated succinate-supported respiration, an effect that was independent of mK(ATP) channel conductance. Similarly, 5-hydroxydecanoate (5-HD), a putative mK(ATP) channel blocker, released diazoxide-induced respiratory inhibition independently of potassium concentration. Since diazoxide-induced cytoprotection and respiratory inhibition are both integrally linked to ROS generation we repeated above experiments following ROS generation using DCF fluorescence. Cytoprotective doses of diazoxide increased ROS generation independently of potassium concentration and 5-HD inhibited ROS production under the same conditions. Collectively these data support the hypothesis that diazoxide-mediated cytoprotection is independent of the conductance of the mK(ATP) channel and rather implicate mitochondrial respiratory inhibition-triggered ROS signaling.
Adenosine Triphosphate↗
The neurotoxicants strychnine and bicuculline protect renal proximal tubules from mitochondrial inhibitor-induced cell death.
Glycine-induced cytoprotection of renal proximal tubules exposed to chemical- or hypoxic/anoxic-induced cell death is shared by a few amino acid agonists of the neuronal strychnine-sensitive glycine receptor. The goal of this study was to determine if antagonists of the strychnine-sensitive glycine receptor attenuated the cytoprotective effects of glycine. Strychnine did not antagonize the cytoprotective effects of glycine in proximal tubules exposed to antimycin A. In contrast, strychnine was cytoprotective, was equipotent as glycine (EC50 = 0.4 mM), and the combination of strychnine and glycine was additive. Likewise, bicuculline and norharmane were cytoprotective but 20-50% less potent than glycine. These results suggest that glycine and strychnine act as a common site to produce proximal tubule cytoprotection, but this site does not share the same potency and agonist/antagonist properties as the neuronal strychnine-sensitive glycine receptor.
Animals↗
Primary culture of rat gastric epithelial cells as an in vitro model to evaluate antiulcer agents.
Primary rat gastric cell cultures were investigated as an in vitro model for evaluating antiulcer agents. Following exposure to concentrations of up to 5 mg/mL of an antiulcer agent sucralfate, an aluminum hydroxide complex of sucrose octasulfate, cultured cells were treated with either pH 3.5 medium or 3.5 mM indomethacin. Cytoprotection was evaluated by colony forming efficiency, neutral red uptake, and 3-(4,5-dimethyl-2-thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) hydrolysis. By each measure, and depending on damaging agent, 2 and 5 mg/mL sucralfate provided partial (50% of untreated control) to near-complete (90% of untreated control) cytoprotection, respectively. Aluminum hydroxide also provided partial (55% of untreated control) to near-complete (more than 90% of untreated control) cytoprotection at 2 and 5 mg/mL, respectively, for the pH 3.5 medium-induced damage. Over a concentration range of 0.05 to 5 mg/mL, the potassium salt of sucrose octasulfate, KSOS, stimulated cell growth up to 40-60% over untreated controls but had little or no cytoprotective action in the presence of either 3.5 mM indomethacin or pH 3.5 medium. Overall results suggested that sucralfate may have at least two roles in influencing gastric epithelial cell function, cytoprotection and stimulation of cell growth in vitro. These observations serve as a basis for further study of in vitro models in evaluating the cytoprotective activity of antiulcer agents and their respective mechanisms of action.
Acids↗
A comparative study on the activity of lansoprazole, omeprazole and PD-136450 on acidified ethanol- and indomethacin-induced gastric lesions in the rat.
1. The proton pump inhibitors lansoprazole (LP) and omeprazole (OP) and the cholecystokinin (CCK)-receptor antagonist PD-136450 (PD) provide a broad spectrum of activities in their ability to inhibit gastric acid secretion and protect the stomach against ulcerogens. In the present study, we investigated the protective effects of these compounds against gastric ulcers induced by acidified ethanol (AE) and indomethacin. 2. Both AE (60% ethanol in 150 mmol/L HCl, 1 mL/rat) and indomethacin (30 mg/kg) produced gastric haemorrhagic lesions in the rat 1 and 6 h after oral administration, respectively. 3. The gastric mucosal protective effects of LP (1-20 mg/kg), OP (0.5-10 mg/kg) and PD (1-20 mg/kg), administered either orally or subcutaneously (s.c.) 30 min before the administration of AE or indomethacin, were dose dependent against both models of ulcer induction. 4. To determine whether the cytoprotective effect of LP, OP and PD (each 10 mg/kg) was mediated by endogenous prostaglandins (PG), indomethacin (10 mg/kg, s.c.) was administered 15 min before AE to inhibit prostanoids biosynthesis. Indomethacin reduced the cytoprotective effects of OP, but not LP, administered either orally or s.c. Indomethacin reduced the cytoprotective effect of PD administered orally, although the effect was much less significant than when PD was administered s.c. The results exclude the role of PG in mediating the protective effects of LP, whereas the possibility exists for PG to have a role in mediating the protective effects of OP and PD. 5. To investigate the possible involvement of endogenous nitric oxide (NO) in the cytoprotective action of LP, OP and PD, we treated rats with a selective inhibitor of NO synthesis, namely NG-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg, s.c.). Administration of L-NAME 15 min prior to LP, OP or PD (each 10 mg/kg) orally or s.c. and challenge with AE or indomethacin did not significantly increase the degree of the ulcer index and L-NAME was not able to antagonize the protective effects of LP, OP and PD, thus excluding the role of NO in mediating the protective effects of these drugs. However, the effects of PD in reducing the indomethacin-induced ulcer index were less significant in the presence than the absence of L-NAME (P < 0.05 vs P < 0.001, respectively), suggesting a role for NO. 6. In conclusion, the results of the present study suggest that LP and OP are equally effective against AE- as well as indomethacin-induced gastric ulcers and were more potent than PD in protecting the stomach against ulcer formation. Lansoprazole, OP and PD bring about their cytoprotective action through the reduction of acid secretion and some other unknown mechanisms. However, OP and PD may exert their cytoprotective action through PG and NO pathways.
2-Pyridinylmethylsulfinylbenzimidazoles↗
518A2 melanoma cells are protected by G3139 and other antineoplastic agents against the cytotoxic effects of DTIC.
G3139 is an antisense Bcl-2 phosphorothioate oligonucleotide that has been combined with DTIC in a phase III clinical trial in melanoma. However, its actual mechanism of action in melanoma is controversial. Treatment of 518A2 melanoma cells with either G3139 or G4126 (a two-base mismatch) and then with light-activated DTIC caused these cells (but not SK-Mel-30 or 346.1 cells) to be protected against the cytotoxic effects of DTIC. This cytoprotection was not recapitulated with a phosphodiester congener of G3139 nor with a small interfering RNA (siRNA) also targeted to the Bcl-2 mRNA. Administering the drugs in reverse order also did not produce cytoprotection, and an 18- mer phosphorothioate homopolymer of thymidine was also inactive. Subsequently, it was discovered that gemcitibine and cis-platinum also induced cytoprotection to DTIC in this cell line, suggesting that the cytoprotection is a stress response to chemical proapoptotic stress. Cytoprotection was completely inhibited by O(6)-benzylguanine, an inhibitor of O(6)-guanosine alkyltransferase (OGAT) activity. However, a direct assay of OGAT activity demonstrated that 518A2 melanoma cells are essentially completely devoid of it, either basally or induced. The cytoprotection may thus be caused by a chemical stress-induced increase in mismatch repair activity.
Antineoplastic Agents↗
Intracellular glutathione in the protection from anoxic injury in renal proximal tubules.
Previous results (Weinberg, J. M., J. A. David, M. Abarzua, and T. Rajan. 1987. J. Clin. Invest. 80:1446-1454) have shown that GSH and glycine (GLY) are cytoprotective during anoxia when added extracellularly. The present studies investigate the role that intracellular GSH plays in this cytoprotection. Proximal renal tubules in suspension prepared with either high (11 +/- 1 nmol/mg protein) or low (6 +/- 1 nmol/mg protein) GSH contents were subjected to 40 min of anoxia and 40 min of reoxygenation. Low GSH tubules were protected from plasma membrane damage during anoxia by exogenous addition of 1 mM GSH or GLY, reducing lactate dehydrogenase (LDH) release from 42 +/- 7 to 14 +/- 1 and 10 +/- 1%, respectively. High GSH tubules were equally protected from anoxic damage without exogenous additions. Since the high GSH content approximates the in vivo values, it may be concluded that GSH may be cytoprotective during anoxia in vivo. However, it is not the intracellular GSH itself that is cytoprotective; rather, this protection resides in the ability to produce GLY, which appears to be the cytoprotective agent. Alanine was also shown to have similar cytoprotective properties, although higher concentrations were required. Sulfhydryl reducing agents such as cysteine and dithiothreitol offered less, but significant protection from anoxic damage. Protection by GSH, GLY, or alanine was not associated with higher ATP levels during anoxia. Tubules that were protected from membrane damage during anoxia recovered oxygen consumption and K and ATP contents significantly better during reoxygenation than unprotected tubules.
Adenosine Triphosphate↗
A possible mechanism for the gastric mucosal protection by oren-gedoku-to (OGT), a traditional herbal medicine.
We investigated the involvement of sulfhydryl-compounds in the cytoprotective effect of Oren-gedoku-to (OGT) against ethanol-induced gastric lesions and potential difference (PD) reduction in comparison with those of sucralfate and glutathione in rats. Pretreatment with indomethacin (IND) had little influence on the cytoprotective effects of OGT and glutathione, but attenuated the effect of sucralfate. Pretreatment with N-ethylmaleimide (NEM) blocked the cytoprotective effects of these three drugs. Pretreatment with iodoacetamide diminished the cytoprotection of OGT and glutathione, but had little effect on that of sucralfate. The cytoprotective activities of OGT, glutathione and sucralfate were little affected by pretreatment with 6,6'-dithiodinicotinic acid. The inhibitory effects of OGT and glutathione against the PD reduction were completely blocked by pretreatment with NEM, while they were not influenced by pretreatment with IND. On the other hand, the inhibitory effect of sucralfate disappeared both by IND and NEM. These results suggest that the cytoprotective effect of OGT may be mediated by endogenous sulfhydryl compounds, but not by endogenous prostaglandins in the gastric mucosa.
Animals↗
Why do ulcers heal with sucralfate?
It is unknown why ulcers in general heal. Some clues are worth considering. What is known is (i) that ulcer healing occurs spontaneously, (ii) that ulcers heal more quickly in the duodenum than in the stomach, (iii) that mucosal blood flow at ulcer edge improves with healing, and (iv) that healing can be speeded up by (a) not smoking, (b) removing acid from the stomach, and (c) using non-antisecretory mucosal protective agents such as sucralfate and colloidal bismuth. The difference in healing rates between duodenal and gastric ulcers may be related to ulcer size, duodenal alkalinity due to the secretion of the Brunner's glands, and other uninvestigated factors such as epidermal growth factor and mucosal blood flow. The difference between smokers and non-smokers may be related to inhibition of prostaglandin synthesis and impairment of mucosal blood flow due to smoking and to higher acid secretion in smokers. The success with antisecretory agents indicates that acid inhibits the healing process. The success of sucralfate and bismuth indicates that cytoprotective mechanisms play a role in ulcer healing. The literature also shows that ulcer healing is less affected by smoking in patients treated with sucralfate than in those treated with antisecretory agents, suggesting that cytoprotective mechanisms play a more important part than acid inhibition in counteracting the adverse effects of smoking on healing. Furthermore, ulcer relapse occurs sooner in patients treated with antisecretory agents than in those treated with sucralfate or bismuth, suggesting that withdrawal of antisecretory agents speeds up relapse and/or that cytoprotective mechanisms are associated with longer-lasting remission. It is concluded that sucralfate healing involves cytoprotective mechanisms and that these cannot be ignored in the planning of any anti-ulcer therapy. Despite the understanding of the various site-protective and cytoprotective mechanisms, as discussed in the previous article, it is not clear why ulcers heal with sucralfate. In fact, there is no clear answer to the fundamental question as to why ulcers in general heal with the known therapeutic agents, including H2-receptor antagonists, antacids, proton pump inhibitors, anticholinergics, site-protective agents, and cytoprotective agents. This review examines this question, using sucralfate as a model.
Clinical Trials as Topic↗
Efficacy of novel calpain inhibitors in preventing renal cell death.
Inhibitors of calpains, calcium-activated neutral proteases, protect against cell death produced by anoxia and a variety of toxicants both in vitro and in vivo. The problems with known calpain inhibitors are a lack of specificity, low membrane permeability, and/or low potency. The goal of this study was to determine the effects of seven novel dipeptide and tripeptide calpain inhibitors on calpain activity and antimycin A-induced cell death in rabbit renal proximal tubule (RPT) suspensions. We chose the compounds based on their inhibitory constants for mu- versus m-calpain, specificity of the inhibitors for calpain, and membrane permeability. Only three of the compounds inhibited calpain in RPT and were cytoprotective (Z-Leu-Phe-COOH, Z-Leu-Abu-CONH-CH(2)-CH(OH)-Ph, and Z-Leu-Phe-CONH-Et). Interestingly, Z-Leu-Phe-COOEt, Z-Leu-Abu-CONH-CH(2)-CH(OH)-C(6)F(5), and Z-Leu-Abu-CONH-CH(2)-2-quinolinyl were greater than 60% cytoprotective but did not inhibit calpain in RPT. Z-Leu-Abu-CONH(CH(2))(3)-morpholine was neither cytoprotective nor inhibited calpain. Although these results suggest that six of the seven peptide calpain inhibitors are cell permeable, only three of them inhibited calpain activity in RPT and were cytoprotective. Their ability to inhibit calpain or produce cytoprotection did not correlate with their ability to selectively inhibit purified mu- or m-calpain. Thus it remains to be determined whether they inhibit mu-calpain, m-calpain, or both in RPT. These results also suggest that inhibition of other protease(s) in addition to calpains may be responsible for the cytoprotective actions of some compounds.
Animals↗
Gastric anti-ulcerogenic drug effect. A possible mechanism of its molecular basis.
During experimental gastric ulceration in rats an elevation in the mucosal cAMP/cGMP ratio can be encountered. The cause of this significant elevation is mainly (but not entirely) the dramatic fall of the cGMP level. Similar observations were obtained with prostacyclin application (100 micrograms/kg, p.o.), too. This prostaglandin derivative is well known, among others, because of its pronounced anti-ulcerogenic (cytoprotective) effect, too. Other substances of different molecular structure and properties may also exert such effect. The exact mechanism of action of this above-mentioned cytoprotection is still not completely understood. H2-receptor blocker drug cimetidine, given in such small dose (5 mg/kg, p.o.) which does not interfere with gastric acid secretion, also exerts very significant cytoprotective effect in stress (restraint)- and drug (indomethacin)-induced gastric ulcer models. Under cimetidine effect--together with a noticeable endogenous prostacyclin mobilization--the gastric mucosal cAMP/cGMP ratio was also strongly elevated. We conclude that this elevation in the mucosal cAMP/cGMP ratio might be a possible molecular basis of the gastric cytoprotective (anti-ulcerogenic) drugs but it needs further investigations whether all substances exerting cytoprotective effect, e.g. atropine, somatostatin, sulfhydryl drugs, etc., have the same "shifting" property or not? Moreover the phenomenon of the so-called "adaptive cytoprotection" can not be ruled out completely either, therefore this problem needs attention, too.
Animals↗