[Recent developments in drugs antagonistic to factors causing peptic ulcer--clinical efficacy and problems; gastric mucosa proton pump inhibitors].
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Animals↗
Biomedical subjects
S Okabe
Publications and source records attributed to S Okabe.
Mucosal protective action of histamine against gastric lesions induced by HCl in rats: importance of antigastric motor activity mediated by H2-receptors.
The present study was undertaken to investigate the possible mechanism of histamine cytoprotection against 0.6 N HCl-induced gastric lesions in rats by 1) examining functional alterations such as acid secretion, gastric motor activity and mucosal vascular permeability in response to histamine and by 2) comparing the effects of histamine with those of 2-(2-pyridil)-ethylamine (PEA), an H1-agonist and of dimaprit, an H2-agonist. Histamine (3-20 mg/kg s.c.) dose-dependently increased acid secretion, inhibited motor activity and reduced the mucosal lesions in response to 0.6 N HCl. Similar effects were observed dose-dependently with dimaprit (10-40 mg/kg s.c.), but not with PEA (10 mg/kg s.c.). The protective action of both histamine and dimaprit was attenuated significantly by cimetidine (100 mg/kg s.c.) and indomethacin (5 mg/kg s.c.), but not by tripelennamine (10 mg/kg s.c.), which by itself inhibited significantly motor activity and the lesions. Stimulation of acid secretion caused by histamine as well as dimaprit was antagonized significantly by cimetidine, whereas antigastric motor effects of these agents were decreased significantly by both cimetidine and indomethacin. Histamine and PEA increased significantly the vascular permeability as measured by Evans blue, but the increased vascular permeability caused by 0.6 N HCl was reduced markedly by both histamine and dimaprit. These results suggest that the mucosal protective action of histamine may be mediated at least partly by endogenous prostaglandins through stimulation of H2-receptors, and may be associated with the effect on gastric motor activity but not with that on the mucosal vasculature.
Animals↗
[Microorganisms isolated from urinary tract infection and their beta-lactamase production and evaluation of clinical efficacy of sulperazone].
Clinical survey of microorganisms isolated from urinary tract infection (UTI) was carried out at the four major hospitals in Mie Prefecture from May to July, 1987, and production of beta-lactamase of the microorganisms was determined by the acidimetric method, "beta-checker". Among the total of 460 strains isolated from urine samples, 135 of gram positive cocci and 325 of gram negative rods were contained. Sixty percent of the gram negative rods and 14% of gram positive cocci produced beta-lactamase. Pseudomonas aeruginosa, E. coli and Serratia marcescens were representative organisms which produced beta-lactamase. Acinetobacter, Klebsiella, Enterobacter and Citrobacter species produced beta-lactamase at a higher rate but those were not so frequently isolated. In the sensitivity test to Sulperazone, the representative organisms isolated from urine, as a whole, had a sensitivity of 74% and E. coli, Klebsiella, S. epidermidis and Pseudomonas aeruginosa were highly sensitive, while Enterobacter cloacae and Serratia marcescens showed low sensitivity. The clinical efficacy of Sulperazone was evaluated in 26 patients with complicated UTI. Overall effectiveness rate and eradication rate of beta-lactamase production organisms were 73.1 and 63%, respectively. Sulperazone is concluded to be a useful antibiotic for treating complicated UTI induced by beta-lactamase production organisms from the point of microbiology and safety.
Adult↗
Irritative and protective activity of mild irritants in rat stomach.
Exposure of the stomach for 30 min to acidified sodium taurocholate (TC) (1-20 mM) or sodium salicylate (SA) (10-80 mM) caused a reduction of transmucosal PD and an increase of luminal pH in anesthetized rats, in a concentration-related manner. Acidified aspirin (ASA) (10-80 mM) reduced PD in the same manner, without significant effect on pH. Histologically, these agents similarly produced damage to the surface cells. After a 30-min exposure to either 20 mM TC or 40 mM SA, acid secretion ceased and bicarbonate (0.5-1 mumol/10 min) appeared in the lumen, whereas acid secretion persisted in the stomach exposed to 40 mM ASA. However, under cimetidine infusion (8 mg/kg/hr) these agents produced similar degrees of luminal alkalinization (approximately 1 mumol/10 min). Pretreatment with indomethacin (5 mg/kg, subcutaneously) significantly inhibited the increase of pH seen after exposure to 20 mM TC, but had no effect on the increase of pH caused by 40 mM SA. Concurrent administration of 16,16-dmPGE2 (3 micrograms/kg, subcutaneously) significantly antagonized the effect of indomethacin in the stomach exposed to 20 mM TC and even increased the pH in the stomach exposed to 40 mM ASA. After a 3-hr exposure to these agents, there was macroscopically apparent damage only in the stomach exposed to ASA, although the PD was similarly reduced in response to either agent. The levels of PGE2 in the corpus mucosa were significantly increased in stomachs exposed to 20 mM TC and 40 mM SA, but decreased in those exposed to 40 mM ASA.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Role of local motility changes in the pathogenesis of duodenal ulcers induced by cysteamine in rats.
The possible role of local motility in the pathogenesis of duodenal ulcers was investigated in rats using cysteamine. Duodenal motor activity was measured as intraluminal pressure recordings by means of a balloon positioned in the proximal duodenum. Subcutaneous administration of cysteamine (100 mg/kg) produced two linear bandlike lesions in the proximal duodenum within 6 hr. This dose of cysteamine significantly increased gastric acid secretion in acute fistula rats, and decreased duodenal HCO3- secretion caused by acid. During this period, this agent inhibited gastric motility but did produce markedly enhanced contractions in the duodenum. The changes in duodenal motility appeared within 5-10 min and were dose-dependent for cysteamine (10-100 mg/kg). Pretreatment with subcutaneously administered atropine (10 mg/kg), 16,16-dmPGE2 (30 micrograms/kg) or dopamine (10 or 30 mg/kg) significantly reduced the development of duodenal lesions caused by cysteamine, the inhibition being 86.8%, 49.7%, 54.5% or 67.8%, respectively. In the presence of cysteamine, dopamine had minimal effect on both acid and HCO3- secretion, while atropine or 16,16-dmPGE2 markedly inhibited acid secretion or increased HCO3- secretion, respectively. The enhanced duodenal motility induced by cysteamine was blocked partially by atropine and only slightly by 16,16-dmPGE2. Dopamine showed a dose-dependent inhibition on the duodenal hypermotility following cysteamine, and at 30 mg/kg almost completely abolished the development of contractions. These results suggest that abnormal hypermotility in the duodenum may be partly involved in the pathogenesis of cysteamine-induced duodenal ulcers.
16,16-Dimethylprostaglandin E2↗
16,16-Dimethyl prostaglandin E2 aggravates gastric mucosal injury induced by histamine in rats. Possible role of the increased mucosal vascular permeability.
Histamine dihydrochloride (40 or 80 mg/kg, dissolved in 10% gelatin) subcutaneously administered to fasted rats induced few lesions in the gastric mucosa within 4 h. Pretreatment with subcutaneously administered 16,16-dimethyl prostaglandin E2 (dmPGE2; greater than or equal to 10 micrograms/kg) dose-dependently worsened mucosal injury induced by histamine, mostly with severe hemorrhage in the corpus mucosa along the greater curvature, although dmPGE2 alone did not induce any macroscopic damage. The mucosal vascular permeability as measured using Evans blue was slightly but significantly augmented by either dmPGE2 (30 micrograms/kg) or histamine (80 mg/kg) alone, but was markedly increased by histamine in the presence of dmPGE2. The increased vascular permeability occurred within 2 h, and preceded the appearance of hemorrhagic mucosal injury. Both the mucosal injury and the increased vascular permeability caused by histamine (80 mg/kg) in the presence of dmPGE2 (30 micrograms/kg) were significantly reduced by pretreatment with tripelennamine (30 mg/kg) and prednisolone (3 mg/kg), but not affected by atropine sulfate, cimetidine, methysergide, or indomethacin. The stimulation of acid secretion caused by histamine was significantly inhibited by dmPGE2 (30 micrograms/kg). Repeated administration of histamine (40 or 80 mg/kg) in the same area of the stomach in the presence of dmPGE2 (30 micrograms/kg), once or twice daily for 4 days to fed rats, induced more pronounced damage than single-dose treatment. These results suggest that dmPGE2 may aggravate gastric mucosal injury induced by histamine in rats probably due to potentiation of the increased vascular permeability caused by histamine through stimulation of H1-receptors.
Animals↗
16,16-Dimethyl prostaglandin E2 protects gastric mucosal surface epithelial cells from indomethacin-induced damage in rats.
The protective effect of 16,16-dimethyl prostaglandin E2 (dmPGE2) against early damage induced by indomethacin in the rat gastric mucosal surface epithelial cells was studied using a scanning electron microscope. Indomethacin (10 or 25 mg/kg, p.o.) induced a widespread exfoliation of the surface epithelial cells and an exposure of the lamina propria both in the corpus and antrum within 1 hr after the administration. Pretreatment with dmPGE2 (0.3, 3 or 30 micrograms/kg, p.o.) 30 min before indomethacin (25 mg/kg) dose-dependently inhibited these damages. The effects of dmPGE2, at least on the surface epithelial cells in the corpus, appear to be related to the prevention of damage formation itself and is unrelated to the enhancement of reconstitution of once damaged mucosa. Enhanced gastric motility by indomethacin was potently inhibited by pretreatment with 3 and 30 micrograms/kg of dmPGE2, but not with 0.3 micrograms/kg. dmPGE2 pretreatment (30 micrograms/kg) significantly decreased the absorption of indomethacin (25 mg/kg) when determined 10 min after giving indomethacin, but did not affect it when determined 30 and 60 min later. We conclude that dmPGE2 protects gastric mucosal surface epithelial cells from indomethacin injury at an early stage, partly by inhibiting gastric motility.
16,16-Dimethylprostaglandin E2↗
Effects of 16,16-dimethyl prostaglandin E2 on surface epithelial cell damage in the rat stomach induced by vagal nerve stimulation.
The effect of 16,16-dimethyl prostaglandin E2 (dmPGE2) on gastric surface epithelial cell (SEC) damage induced by vagal nerve stimulation (VS) in urethane-anesthetized rats was studied using scanning electron microscopy. VS (1.25-10 Hz, 0.2 mA, 2 msec, 10 min) resulted in a graded increase in the SEC damage, increased gastric contractions, increased gastric acid secretion, and a decrease in heart rate. Pretreatment with dmPGE2 (0.3-30 micrograms/kg, s.c.) significantly protected the SEC from VS-induced damage, inhibited the increase in gastric contractions and acid secretion, but had no influence on the decrease in heart rate. Atropine (1 mg/kg, s.c.) also protected the SEC from VS-induced damage and inhibited the alterations in response to VS. Timoprazole (30 mg/kg, s.c.) had no protective effects on SEC from VS-induced damage, no effect on increased gastric contractions and heart rate, but did inhibit the increase in gastric acid secretion, in response to VS. These results suggest that: VS-induced SEC damage was caused by increased gastric contractions and not by increased gastric acid secretion, and dmPGE2 protects against SEC damage by inhibiting gastric contractions.
16,16-Dimethylprostaglandin E2↗
Effects of prostaglandin biosynthesis inhibitors and ouabain on duodenal mucosa and HCO3- secretion in rats.
A single injection (s.c.) of prostaglandin biosynthesis inhibitors such as indomethacin (5 mg/kg), aspirin (200 mg/kg) and quinacrine (100 mg/kg) or a Na+.K+ ATPase inhibitor such as ouabain (10 mg/kg) significantly reduced the adaptive increase of HCO3- output caused by acid in the duodenum of anesthetized rats. These agents had no effect on basal duodenal HCO3- secretion and histamine-stimulated gastric acid secretion. Either of these agents, when given alone, had no effect on the duodenal mucosa of conscious rats, but produced damage in the proximal duodenum within 8 hr when given together with histamine (40 mg/kg X 3, s.c., every 2.5 hr). A significant relationship was found between the degrees of inhibition of acid-induced HCO3- output and the severity of duodenal lesions induced by these drugs (r = 0.8620, P less than 0.01). These results suggest that an impairment of the mechanisms related to acid-induced HCO3- secretion may be particularly relevant to the pathogenesis of duodenal lesions.
Animals↗
Lack of cytoprotection by acetaminophen against ethanol-, HCl.ethanol- and HCl.aspirin-induced gastric mucosal lesions in rats.
Effects of acetaminophen against gastric mucosal lesions induced by three different necrotizing agents were studied. Acetaminophen (30, 100 mg/kg), given p.o. 0.5 hr before absolute ethanol, HCl . ethanol, or HCl . aspirin administration, afforded no cytoprotection against gastric mucosal lesions induced by the above agents in 24 hr fasted rats. However, 16,16-dimethyl prostaglandin E2 (3 micrograms/kg), given p.o. 0.5 hr before these necrotizing agents, completely prevented development of these lesions.
16,16-Dimethylprostaglandin E2↗
Impairment of acid-neutralizing capacity and lesion formation in the rat duodenum during hemorrhagic shock: comparative study with indomethacin.
The effects of hemorrhagic shock (HE) on duodenal pH, acid-neutralizing capacity and mucosal tolerance to acid were investigated in anesthetized rats, and they were compared with those of indomethacin. HE was performed by bleeding from the carotid artery to reduce arterial blood pressure to about 55 mmHg (3 ml of bleeding per 200 g of body weight), and indomethacin was given s.c. in a dose of 5 mg/kg. Duodenal pH was determined in the outflow from the proximal duodenum (1.7 cm) which was perfused with 10(-4) M HCl, and acid-neutralizing capacity was measured by back-titration of the perfusate to pH 4.0 with 10 mM HCl. Under these conditions, duodenal pH was kept at around 6.0 as the result of neutralization in the loop (approximately 8 microEq/hr). Both HE and indomethacin significantly decreased the pH and acid-neutralizing capacity. Administration of 16,16-dimethyl prostaglandin E2 (16-dmPGE2: 30 micrograms/kg, s.c.) significantly increased both pH and acid-neutralizing capacity in normal and indomethacin-treated rats, but failed to affect these parameters in rats under HE conditions. When the duodenal loop was perfused with 50 mM HCl for 1.5 hr, both HE and indomethacin induced extensive damage in the mucosa. Pretreatment with 16-dmPGE2 significantly reduced the formation of duodenal lesions induced by indomethacin but not by HE. These results suggest that HE as well as indomethacin impaired duodenal acid-neutralizing capacity to reduce the tolerance to acid of the mucosa. The deleterious effects of HE on the mucosa may be mainly due to a decreased mucosal blood flow, but not due to a deficiency of endogenous prostaglandins.
Acid-Base Equilibrium↗
Roles of gastric motility changes in cytoprotection induced by acetazolamide and cysteamine in rats.
The present study was undertaken using acetazolamide (AZ) and cysteamine (Cys) to investigate the relationship between gastric motor activity and the phenomenon of "cytoprotection" in rats. Both AZ (10-100 mg/kg) and Cys (10-100 mg/kg), given either p.o. or s.c., significantly reduced the formation of gastric mucosal injury caused by HCl-ethanol (1 ml of 60% ethanol in 150 mM HCl, p.o.). The protective effect of Cys appeared within 10 min, reached the maximal levels 30 min later, while that of AZ appeared from 30 min after administration and became potent with a latency period after treatment. Neither indomethacin (IM: 5 mg/kg, s.c.) nor N-ethylmaleimide (NEM: 5 mg/kg, s.c.) significantly affected the protective effect of Cys, whereas that of AZ was almost totally antagonized by IM. Both AZ and Cys, given either intragastrically or s.c., significantly inhibited gastric motor activity measured as intraluminal pressure recordings, but had minimal effect on acid and alkaline secretion. IM significantly attenuated the inhibitory effect of AZ on the motor activity, while NEM did not affect the inhibited motor responses caused by AZ and Cys. A significant relationship was found between the inhibitory effects of these two drugs on gastric motor activity and HCl-ethanol-induced mucosal injury, the correlation coefficient being 0.819 (P less than 0.01). When the mucosal folds were visualized with Gentian Violet (1 ml of 0.5% v/v, p.o.), both AZ and Cys significantly prevented the localized staining along the mucosal folds, suggesting dissolution of the folds. These results suggest that both AZ and Cys protect the gastric mucosa against injury caused by HCl-ethanol, probably through a dissolution of mucosal folds due to inhibition of gastric motor activity.
Acetazolamide↗
Cytoprotective action of histamine against 0.6 N HCl-induced gastric mucosal injury in rats; comparative study with adaptive cytoprotection induced by exogenous acid.
We examined the effects of histamine 2HCl (a stimulator of endogenous acid production) and exogenous acid on transmucosal potential difference (PD) and pH of anesthetized rat stomachs, in order to investigate the mechanism underlying the protective action of histamine against 0.6 N HCl-induced gastric mucosal injury in conscious rats. Subcutaneously administered histamine (3-20 mg/kg) dose-dependently produced a decrease in the PD and pH, and it reduced the severity of gastric mucosal injury caused by 0.6 N HCl. Both indomethacin (5 mg/kg, s.c.) and cimetidine (100 mg/kg, s.c.) completely reversed the protection afforded by histamine (20 mg/kg), although the decreased PD and pH responses were unaffected or inhibited, respectively, by indomethacin or cimetidine. Protective action of histamine was also partially mitigated by omeprazole (30 mg/kg, s.c.) which completely abolished histamine-induced acid secretion. On the other hand, exposure of the stomach for 10 min to exogenous acid (0.1-0.35 N HCl) caused a PD reduction and an increase of pH, in a concentration-related manner. The injury caused by 0.6 N HCl was prevented by prior exposure to these low concentrations of HCl, and the degrees of inhibition were associated with the concentration of HCl and the magnitude of PD reduction caused by HCl. The pretreatment with indomethacin, but not cimetidine or omeprazole, significantly antagonized the increased pH and mucosal protection induced by 0.35 N HCl. These results suggest that histamine protected the gastric mucosa against 0.6 N HCl-induced injury by two different ways, mediated with endogenous prostaglandins, (a) mainly through stimulation of H2-receptors and (b) partly through adaptive cytoprotection induced by acid.
Adaptation, Physiological↗
Effects of NC-1300 and its degradation products on gastric secretion and HCl.ethanol-induced gastric lesions in rats.
The proton pump inhibitor NC-1300 has antisecretory and cytoprotective activities in rats. The compound is labile at an acidic pH and degrades into various products. We attempted to identify these products after treatment at different pHs in vitro using HPLC. We also examined whether (A) NC-1300 treated at acidic pHs loses its efficacy on gastric secretion and gastric lesions and (B) whether the degradation products of NC-1300 have pharmacological effects in rats. The acidic degradation products proved to be mainly NC-1300-sulfide and partly o-dimethylaminobenzylalcohol (o-DMABA) and benzimidazole (BI). NC-1300, pretreated at pH 1.0, 1.25 or 1.5 for 30 min and given p.o. at 30 mg/kg, significantly inhibited gastric acid secretion in pylorus ligated rats and prevented development of HCl X ethanol-induced gastric mucosal lesions. The degree of antisecretory and cytoprotective activities by NC-1300 treated at pH 1.5 was almost the same as that obtained by NC-1300 treated at pH 7.0. NC-1300-sulfide or mixtures of degradation products, with or without unchanged NC-1300, also significantly inhibited the gastric acid secretion and lesion formation. We conclude that while NC-1300 degrades at low pHs, the compound treated at such a low pH exerts pharmacological effects presumably by the unchanged form of NC-1300 and/or its degradation products.
2-Pyridinylmethylsulfinylbenzimidazoles↗
Effect of 16,16-dimethyl prostaglandin E2 on gastric surface epithelial cell damage induced by 20% ethanol in rats.
Prostaglandins protect against the gross damage of gastric mucosa induced by 50-100% ethanol, but do not protect surface epithelial cells (SEC) from necrosis. Since this induced damage to SEC is so severe, we attempted to determine the effects of a prostaglandin on slightly induced SEC damage and gastric potential difference (PD) in response to low concentrations of ethanol. The necrotizing effects of graded concentrations of ethanol (10-50%) to SEC on the rat gastric mucosa were studied by scanning electron and light microscopy. Intragastric instillation of 20% ethanol (v/v, 1 ml/100 g body wt.) to pylorus-ligated rats for 10 min induced slight and reproducible SEC damage consisting mainly of the apical cell membrane erosion of SEC. Pretreatment with 16,16-dimethyl prostaglandin E2 (dmPGE2, 3 or 30 micrograms/kg, p.o. or s.c.) afforded protection of the SEC from 20% ethanol-induced damage. However, the cytoprotective effects of dmPGE2 were abolished when gastric contents were emptied prior to 20% ethanol instillation. Intragastric instillation of ethanol immediately reduced PD in a concentration-related manner. dmPGE2 (3 or 30 micrograms/kg, s.c.) had no effect on the reduction of gastric PD after 20% ethanol treatment and the recovery of reduced PD to normal levels. We conclude that dmPGE2 has no cytoprotective effect on 20% ethanol-induced SEC damage in rat gastric mucosa.
16,16-Dimethylprostaglandin E2↗
Surface epithelial cell damage induced by restraint and water-immersion stress in rats effects of 16,16-dimethyl prostaglandin E2 on stress-induced gastric lesions.
The time-course of gastric mucosal surface epithelial cell damage and macroscopically visible lesions in response to restraint and water-immersion stress (22 degrees C) in rats was examined, and the effects on it of 16,16-dimethyl prostaglandin E2 (dmPGE2) were compared with those of papaverine, timoprazole and atropine. The stress produced surface epithelial cell damage prior to visible lesion, the former increasing in severity with time and reaching a plateau 60 min later, by which time exfoliation of surface epithelial cells was observable along the mucosal folds. In contrast, macroscopically visible lesions appeared 2 hr after stress, and severity continued to increase with time. Pretreatment injections (s.c.) of dmPGE2 (3, 30 micrograms/kg), papaverine (100 mg/kg) and atropine (1 mg/kg) protected the surface cells against stress (1 hr)-induced damage, and inhibited visible lesion formation after 4 hr stress. Timoprazole (30 mg/kg, s.c.) did not protect the surface cells, but did markedly inhibit visible lesion formation. dmPGE2, papaverine and atropine, but not timoprazole, inhibited stress-induced increases in gastric contractions. dmPGE2, timoprazole and atropine, but not papaverine, inhibited acid secretion in stress-conditions. These results indicated that stress induced damage to the gastric mucosa within 1 hr due to increased gastric contractions, and the surface epithelial cell damage developed into macroscopically visible lesions in the presence of acid, and that dmPGE2 protected the surface epithelium against stress-induced damage probably by inhibiting gastric contractions.
16,16-Dimethylprostaglandin E2↗
[Intracranial bacterial aneurysms--report of two cases with special reference to operative indications].
Two cases of intracranial bacterial aneurysms caused by bacterial endocarditis are reported. Case 1 was a 20-year-old male who underwent mitral valve annuloplasty because of mitral regurgitation due to mitral valve prolapse syndrome 3 year prior to this admission. He was referred when a large intracerebral hemorrhage of the right frontal lobe ruptured into the lateral ventricle was seen in computed tomography (CT) scan on admission. An aneurysm at the distal portion of precentral artery of the middle cerebral artery (MCA) was found by right carotid angiography. Emergency evacuation of the hematoma and trapping of the aneurysm were performed. Another three aneurysms, located at the distal portion of contralateral left precentral artery of MCA, the left posterior cerebral artery (PCA) and the right anterior falx artery were found in the subsequent angiogram. The latter two aneurysms developed while receiving antibiotics. The aneurysms of PCA and MCA were trapped surgically. However, the aneurysm of anterior falx artery disappeared spontaneously under antibiotic therapy without surgery. Case 2 was a 21-year-old female who underwent cardiac surgery one month prior to presentation for aortic insufficiency and coarctation of the aorta. She was referred to our clinic because of sudden loss of consciousness, aphasia and right hemiparesis. CT scan and left carotid angiography showed a large hematoma in the left frontal lobe and an aneurysm at the distal portion of the opercular-frontal artery. Emergency ventricular drainage was performed. The operation for evacuation of the hematoma and clipping of aneurysm was performed 10 days later. However, at the operation the aneurysm neck was only partially clipped in order to prevent the obstruction of efferent vessels.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Importance of gastric motility in the pathogenesis of indomethacin-induced gastric lesions in rats.
Effects of indomethacin on gastric motility and secretion, and levels of endogenous prostaglandins (PGs) were investigated in rats, in attempts to elucidate the factors involved in the pathogenesis of indomethacin-induced macroscopic gastric lesions. Subcutaneous administration of indomethacin had no effect on the gastric mucosa at doses of 1 and 5 mg/kg, but induced visible lesions dose dependently at over 10 mg/kg within 4 hr. At 25 mg/kg, there were apparent nonhemorrhagic lesions within 1 hr, and these lesions became hemorrhagic with time. Acid secretion was not affected by this agent at either dose level, but pepsin or acid-induced HCO3- secretion was significantly increased or decreased, respectively, at a dose less than 5 mg/kg, which did not induce any lesion. Gastric motility, however, was dose dependently increased after administration of indomethacin, and its effect was significant at 10 mg/kg or greater. Time-course changes in the motility were in parallel with those of the lesion formation. PGE2 and 6-keto PGF1 alpha levels in the corpus mucosa were reduced around 80-90% for more than 4 hr from 30 min after administration of 5 mg/kg or more of indomethacin. When all the above changes caused by indomethacin were plotted for the various doses, a significant correlation (r = 0.958, P less than 0.01) was found between the lesion index and the changes in motility, but not in other factors, including PG levels. These results indicate that gastric motility may be an important factor in the pathogenetic mechanism of indomethacin-induced gastric lesions in rats. A deficiency of endogenous PGs may be a prerequisite for later extension of the lesions.
6-Ketoprostaglandin F1 alpha↗