Changes of gastric mucosal architecture during long-term omeprazole therapy: results of a randomized clinical trial.

BACKGROUND: The impact of long-term acid suppression on the gastric mucosa remains controversial. AIM: To report further observations on an established cohort of patients with gastro-oesophageal reflux disease, after 7 years of follow-up. METHODS: Of the original cohort randomized to either antireflux surgery or omeprazole, 117 and 98 patients remained in the medical and surgical arms, respectively. Gastric biopsies were taken at baseline and throughout the study. RESULTS: Fifty-three antireflux surgery and 39 omeprazole-treated patients had Helicobacter pylori infection at randomization. Eighty-three omeprazole-treated and 60 antireflux surgery patients remained H. pylori negative over the 7 years, and no change was observed in mucosal morphology except for a change in endocrine cell population (linear and diffuse hyperplasia, P = 0.03). During the 7-year study many patients, who were initially H. pylori infected, had the infection eradicated leaving only 13 omeprazole and 12 antireflux surgery patients still infected. In these patients, omeprazole induced a deterioration of the mucosal inflammation scores (P = 0.01) with a numerical increase of glandular atrophy. CONCLUSIONS: Long-term omeprazole therapy does not alter the exocrine oxyntic mucosal morphology in H. pylori-negative patients, but mucosal endocrine cells appear to be under proliferative stimulation; in H. pylori-positive patients there are changes in mucosal inflammation and atrophy.

Cure of Helicobacter pylori infection in patients with reflux oesophagitis treated with long term omeprazole reverses gastritis without exacerbation of reflux disease: results of a randomised controlled trial.

BACKGROUND: Helicobacter pylori gastritis may progress to glandular atrophy and intestinal metaplasia, conditions that predispose to gastric cancer. Profound suppression of gastric acid is associated with increased severity of H pylori gastritis. This prospective randomised study aimed to investigate whether H pylori eradication can influence gastritis and its sequelae during long term omeprazole therapy for gastro-oesophageal reflux disease (GORD). METHODS: A total of 231 H pylori positive GORD patients who had been treated for > or =12 months with omeprazole maintenance therapy (OM) were randomised to either continuation of OM (OM only; n = 120) or OM plus a one week course of omeprazole, amoxycillin, and clarithromycin (OM triple; n = 111). Endoscopy with standardised biopsy sampling as well as symptom evaluation were performed at baseline and after one and two years. Gastritis was assessed according to the Sydney classification system for activity, inflammation, atrophy, intestinal metaplasia, and H pylori density. RESULTS: Corpus gastritis activity at entry was moderate or severe in 50% and 55% of the OM only and OM triple groups, respectively. In the OM triple group, H pylori was eradicated in 90 (88%) patients, and activity and inflammation decreased substantially in both the antrum and corpus (p<0.001, baseline v two years). Atrophic gastritis also improved in the corpus (p<0.001) but not in the antrum. In the 83 OM only patients with continuing infection, there was no change in antral and corpus gastritis activity or atrophy, but inflammation increased (p<0.01). H pylori eradication did not alter the dose of omeprazole required, or reflux symptoms. CONCLUSIONS: Most H pylori positive GORD patients have a corpus predominant pangastritis during omeprazole maintenance therapy. Eradication of H pylori eliminates gastric mucosal inflammation and induces regression of corpus glandular atrophy. H pylori eradication did not worsen reflux disease or lead to a need for increased omeprazole maintenance dose. We therefore recommend eradication of H pylori in GORD patients receiving long term acid suppression.

Myocardial morphology and cardiac function in rats with renal failure.

The effects of chronic renal failure on cardiac performance and myocardial morphology were studied in rats: 17 with 5/6 nephrectomy (CRF rats) and 12 with sham operation (controls). Cardiac function was assessed 8 weeks postoperatively, using the Langendorff technique for an isolated working heart model. After the hemodynamic study the hearts were fixed for electron and light microscopy. In the CRF rats left ventricular systolic pressure was significantly higher at all preloads (10-20 cmH2O) and afterloads (70-90 cmH2O), and left ventricular stroke work was significantly increased at preload 20 cmH2O with afterloads 70 or 90 cmH2O. Light microscopy revealed fibronecrotic lesions consisting of fibroblastic proliferation with newly formed collagen interposed between or entrapping degenerative myocytes. The changes were focally distributed, with perivascular accentuation and were most frequent in the basal half of the ventricular wall. Electron microscopy of non-necrotic myocytes showed intact myocytes, with mitochondria morphometrically similar in the 2 groups, but a significantly lower incidence of mitochondrial granules in the CRF rats. Thus 8 weeks of CRF showed no cardiac dysfunction associated with the focally distributed fibronecrotic myocardial lesions and decrease in mitochondrial granules. The precise mechanism of the discrepancy between the morphological change and the cardiac function is unclear. One possible explanation may be that because the pathological changes in the myocardium were focal or mild to moderate, some compensation mechanism may be involved or it may be the turning point of functional change from acute renal failure to the chronic state.

Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa.

BACKGROUND & AIMS: The efficacy and safety of long-term acid suppression remains a subject for debate. We report data from patients with refractory reflux esophagitis who were undergoing maintenance therapy with >/=20 mg omeprazole daily for a mean period of 6.5 years (range, 1.4-11.2 years). METHODS: Patients with severe reflux esophagitis resistant to long-term therapy with H(2)-receptor antagonists and who were not eligible for surgery were evaluated at least annually for endoscopic relapse and histological changes in the gastric corpus. RESULTS: In 230 patients (mean age, 63 years at entry; 36% were >/=70 years), there were 158 relapses of esophagitis during 1490 treatment years (1 per 9.4 years), with no significant difference in relapse rates between Helicobacter pylori-positive and -negative patients. All patients rehealed during continued therapy with omeprazole at the same or higher dose. The annual incidence of gastric corpus mucosal atrophy was 4.7% and 0.7% in H. pylori-positive and -negative patients, respectively, which was mainly observed in elderly patients who had moderate/severe gastritis at entry. In patients with baseline moderate/severe gastritis, the incidences were similar: 7.9% and 8.4%, respectively. Corpus intestinal metaplasia was rare, and no dysplasia or neoplasms were observed. The adverse event profile was as might be expected from this elderly group of patients. CONCLUSIONS: Long-term omeprazole therapy (up to 11 years) is highly effective and safe for control of reflux esophagitis.

Lack of effect of acid suppression therapy on gastric atrophy. Nordic Gerd Study Group.

BACKGROUND & AIMS: A hypothesis suggesting that profound acid inhibition therapy facilitates and hastens the development of gastric glandular atrophy in patients infected with Helicobacter pylori was investigated in this randomized study comparing omeprazole therapy with antireflux surgery (ARS) for chronic gastroesophageal reflux disease (GERD). METHODS: Patients with esophagitis and/or chronic GERD were enrolled; 155 patients were randomized to ARS and 155 to long-term omeprazole therapy. Baseline data were obtained and repeated after 3 years in 131 ARS patients and in 139 omeprazole-treated patients. Histopathologic status of the oxyntic mucosa was assessed according to the Sydney system. RESULTS: Forty omeprazole-treated patients were infected with H. pylori compared with 53 in the ARS group. Basal gastrin levels were significantly higher in H. pylori-infected patients, particularly in the omeprazole group. No further increases in serum gastrin levels were observed during 3 years. Despite 3 years of therapy, only slight changes were found in the prevalence of inflammation in the corpus mucosa of H. pylori-infected subjects. A slow progression of gastric glandular atrophy was observed in these patients irrespective of therapy with no obvious difference between treatment regimens. Intestinal metaplasia (all of type I) was only exceptionally observed with no difference between the treatment arms. CONCLUSIONS: Acid-suppressive therapy in the form of omeprazole maintained for 3 years facilitates neither the development of gastric glandular atrophy of the corpus mucosa nor the occurrence of intestinal metaplasia in H. pylori-infected GERD patients.

Omeprazole and ranitidine in the prevention of relapse in patients with duodenal ulcer disease.

BACKGROUND: Although the eradication of Helicobacter pylori is of primary importance when initiating treatment, it is also important to have a strategy for patients who are H pylori-negative, fail to demonstrate eradication or have a tendency to become re-infected or relapse. PATIENTS AND METHODS: In a double-blind, parallel-group clinical trial of 928 patients (from 70 centres in 16 countries) with duodenal ulcers who after a short term study had relief of symptoms and healed ulcers proved endoscopically, 308 were randomly assigned to receive omeprazole 10 mg in the morning, 308 to receive omeprazole 20 mg in the morning and 312 to receive ranitidine 150 mg at bedtime for up to 12 months. Symptoms were assessed every three months and endoscopy repeated at three, six and 12 months, or more often if indicated by recurrence of symptoms. The safety screening included basal serum gastrin concentrations and gastric mucosal histopathology. RESULTS: The remission rates up to 12 months were 87% for the omeprazole 20 mg group, 71% for the omeprazole 10 mg group and 63% for the ranitidine group. Omeprazole 20 mg differed significantly from both omeprazole 10 mg (P=0.0001, 95% CI 9 to 23) and ranitidine (P=0.0001, 95% CI 17 to 31). There was no statistically significant difference between omeprazole 10 mg and ranitidine over the 12-month period, but the 95% confidence interval allowed differences between 0% and 16% in favour of omeprazole at 12 months. A Cox regression analysis revealed that longer treatment courses to heal, smoking, a long ulcer history and young age negatively contributed to the odds of staying in remission. The treatments were well tolerated. There was a slight increase in basal serum gastrin concentrations, reflecting the different degrees of acid inhibition induced by the three treatments. No dysplastic or neoplastic lesions were found in any biopsies. CONCLUSIONS: More duodenal ulcer patients are maintained in remission with omeprazole 20 mg daily than with omeprazole 10 mg daily or with ranitidine 150 mg at bedtime.

Follow-up of Helicobacter pylori positive gastritis and argyrophil cells pattern during the natural course of gastric ulcer.

BACKGROUND: A follow-up of argyrophil cell hyperplasia in Helicobacter pylori-positive corpus gastritis in gastric ulcer patients during the natural course of ulcer disease. METHODS: Endoscopic biopsies (4 specimens) were obtained step-wise from the posterior wall of the corpus mucosa in 55 gastric ulcer (GU) patients. The natural course of GU was followed up in 38 patients during more than 10 years (maximum 19 years), and altogether 115 endoscopic examinations were made: 20 patients were re-examined once, 14 twice, and 4 three times. A total of 364 biopsies from 307 biopsy sites were stained by Grimelius' silver, hematoxylin-eosin, and Giemsa method for the analysis of the argyrophil endocrine cells, chronic gastritis, and H. pylori colonization, respectively, according to the Sydney System. RESULTS: Of 307 biopsy sites, 153 (50%) showed some grade of ACH. Focal (linear/micronodular) hyperplasia was found in 118 (77%) of biopsy sites; it was detected in 78 (66%) cases of atrophic corpus mucosa, but was present in only 14 (12%) cases of gastritis without atrophy or in the normal mucosa. In the follow-up patients, ACH evolved in 17 and progressed in 6 cases, and a simultaneous development of atrophic corpus gastritis was found in 20 cases. CONCLUSION: This study demonstrates that ACH evolves during the natural course of GU, alongside the development of chronic atrophic gastritis.

Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication.

BACKGROUND: Helicobacter pylori infection plays an important part in the development of atrophic gastritis and intestinal metaplasia, conditions that predispose patients gastric cancer. Profound suppression of gastric acid is associated with increased severity of gastritis caused by H. pylori, but it is not known whether acid suppression increases the risk of atrophic gastritis. METHODS: We studied patients from two separate cohorts who were being treated for reflux esophagitis: 72 patients treated with fundoplication in Sweden and 105 treated with omeprazole (20 to 40 mg once daily) in the Netherlands. In both cohorts, the patients were followed for an average of five years (range, three to eight). After fundoplication, the patients did not receive acid-suppressive therapy. The presence of H. pylori was assessed at the first visit by histologic evaluation in the fundoplication group and by histologic and serologic evaluation in the omeprazole group. The patients were not treated for H. pylori infection. Before treatment and during follow-up, the patients underwent repeated gastroscopy, with biopsy sampling for histologic evaluation. RESULTS: Among the patients treated with fundoplication, atrophic gastritis did not develop in any of the 31 who were infected with H. pylori at base line or the 41 who were not infected; 1 patient infected with H. pylori had atrophic gastritis before treatment that persisted after treatment. Among the patients treated with omeprazole, none of whom had atrophic gastritis at base line, atrophic gastritis developed in 18 of the 59 infected with H. pylori(P<0.001) and 2 of the 46 who were not infected (P=0.62). CONCLUSIONS: Patients with reflux esophagitis and H. pylori infection who are treated with omeprazole are at increased risk of atrophic gastritis.

Drug-induced hypergastrinemia: absence of trophic effects on colonic carcinoma in rats.

BACKGROUND/AIMS: Published studies suggest that hypergastrinemia stimulates growth of normal or malignant colon tissue. Other studies dispute these findings. This study was designed to test the hypothesis that hypergastrinemia enhances progression or invasiveness of colon cancer. METHODS: Colonic carcinomas were induced in male Sprague-Dawley rats by six weekly intraperitoneal injections of methylazoxymethanol. Four weeks after the last injection of carcinogen, the animals were randomized into four treatment groups, including vehicle control, low- and high-dose omeprazole, and ranitidine. After 10 weeks of treatment, the animals were bled, stomach weights were recorded, and colon tumors were mapped, enumerated, measured, and scored histopathologically by Dukes' classification. Crypt and mucosal heights were determined in colonic mucosa unaffected by tumor. RESULTS: Drug administration induced a sustained hypergastrinemia that did not enhance tumor burden or invasiveness or crypt height/mucosal height ratios. Ranitidine-treated rats consumed less food, weighed less, and developed fewer tumors. This group also had lower crypt and mucosal heights than rats in the vehicle- or omeprazole-treated rats. CONCLUSIONS: The results suggest that endogenous hypergastrinemia induced by these acid-suppressing drugs has no stimulatory effect on colon mucosal growth or progression or biological behavior of experimental rat colon cancer.

Omeprazole or ranitidine in long-term treatment of reflux esophagitis. The Scandinavian Clinics for United Research Group.

BACKGROUND/AIMS: Patients with reflux esophagitis have rapid relapses after treatment withdrawal. This study was designed to investigate the relapse rate of symptomatic esophagitis during maintenance treatment with omeprazole or ranitidine. METHODS: Patients with endoscopically verified acute erosive or ulcerative esophagitis were initially treated with 20-40 mg omeprazole daily for 8-12 weeks. After healing, the patients were randomized to maintenance treatment with omeprazole (20 or 10 mg each morning) or ranitidine (150 mg twice daily). Control endoscopy was performed at the end of the healing phase and after 12 months of maintenance treatment or symptomatic relapse. RESULTS: Of 426 initially treated patients, 392 were healed and entered the maintenance study. The months of maintenance treatment with 20 mg omeprazole once daily (n = 131), 10 mg omeprazole once daily (n = 133), and 150 mg ranitidine twice daily (n = 128) were 72%, 62%, and 45%, respectively. Both the 10- and 20-mg doses of omeprazole were significantly better than the dose of ranitidine (P < 0.001 and P < 0.005, respectively). There was no significant difference between the 10- and 20-mg doses of omeprazole (P = 0.06). CONCLUSIONS: Maintenance treatment with omeprazole (20 or 10 mg once daily) is superior to ranitidine (150 mg twice daily) in keeping patients with erosive reflux esophagitis in remission over a 12-month period.

Long-term treatment with omeprazole for refractory reflux esophagitis: efficacy and safety.

OBJECTIVE: To evaluate the long-term efficacy and safety of omeprazole in patients with gastroesophageal reflux disease resistant to treatment with histamine-2 (H2)-receptor antagonists. DESIGN: Cohort analytic study with a mean follow-up of 48 months (range, 36 to 64 months). SETTING: Patients receiving ambulatory care from referral centers. PATIENTS: 91 patients with gastroesophageal reflux disease resistant to treatment with an H2-receptor antagonist but subsequently responsive to 40 mg of omeprazole daily. INTERVENTION: Open maintenance therapy consisting of 20 mg of omeprazole daily in 86 patients and 40 mg daily in 5 patients. OUTCOME MEASURES: Endoscopy to assess healing; side effects, laboratory values, fasting serum gastrin level, and gastric corpus biopsies to assess safety. RESULTS: Esophagitis recurred in 47% of the patients receiving 20 mg of omeprazole daily, but all rehealed after the dose was doubled. Seven of 40 patients (18%) had a second relapse after a mean follow-up time of 24 months (range, 9 to 36 months) that was successfully treated with a further 20-mg dose increment for a mean period of 36 months (range, 6 to 39 months). Median gastrin levels increased initially from 60 ng/L before study entry to 162 ng/L (P < 0.01) with treatment and reached a plateau during maintenance treatment. Very high gastrin levels (> 500 ng/L) were observed in a subgroup (11%) of patients. The incidence of micronodular hyperplasia increased from 2.5% of the patients at first biopsy to 20% at the last biopsy (P = 0.001), with a corresponding progression of gastritis to subatrophic or atrophic gastritis from less than 1% to 25% (P < 0.001), which was more pronounced in patients with very high serum gastrin levels. CONCLUSIONS: Maintenance therapy with omeprazole was effective for at least 5 years in patients with gastroesophageal reflux disease resistant to treatment with H2-receptor antagonists. Treatment was accompanied by a persistent increase in serum gastrin levels and an increase of micronodular argyrophil cell hyperplasia and subatrophic or atrophic gastritis.

Effect of 7 years' daily oral administration of omeprazole to beagle dogs.

Ten beagle dogs were given omeprazole orally at a dose of 0.17 mg/kg (0.5 mumol/kg) daily for 7 years. Six dogs served as controls. Regularly evaluated criteria were clinical signs, body weight, food consumption, rectal temperature, electrocardiography, hematology, blood chemistry, urinalysis, ophthalmoscopy, gastroscopic examination including gastric mucosal biopsy sampling for histological evaluation, pharmacokinetics of omeprazole, and plasma gastrin levels. After approximately 5 years, a quantitative gastric acid secretion test was performed. No treatment-related adverse clinical signs or effects were observed in the dogs, and all animals survived to term. The annual gastroscopy with histological examinations of gastric mucosa did not show any treatment-related changes. At all investigations and in all dogs, the parietal cells were morphologically normal, and there were no changes of pattern or any increase in the number of argyrophil enterochromaffin-like cells compared to the control animals. In the plasma samples collected 24 h after dosing, there were no significant differences in either basal or meal-stimulated gastrin levels between the controls and the omeprazole-treated animals. Peak plasma concentration of omeprazole occurred within 2 h of dosing. The area under the concentration curve (AUC) was not affected by dosing over 7 years and was in good agreement with the AUC in humans given a dose of 20 mg omeprazole daily. Acid secretion tests after 5 years of treatment showed that the mean inhibition of acid secretion by omeprazole 4-7 h after dosing was as expected--about 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

General toxicity of the new calcium antagonist felodipine in dogs.

Felodipine 4-(2,3-dichlorophenyl)-1,4-dihydropyridine-2,6-dimethyl-3,5- dicarboxylic 3-ethyl ester and 5-methyl ester, CAS 72509-76-3) is a new selective calcium antagonist for use in the management of hypertension or other cardiovascular disease, which requires reduction of peripheral vascular resistance. A combined 6- and 12-month study in dogs has been performed as a part of the preclinical safety program. 30 dogs, 5 males and 5 females per group, were treated with felodipine for 12 months. Additional 18 dogs, 3 males and 3 females per group, were interim-sacrificed after 6-month treatment. The dose levels were 2 x 0.38, 2 x 1.2 and 2 x 2.3 mg/kg daily. Initially, 2 x 3.8 mg/kg/d was used as a high dose. At this dose level 2 animals died preterminally after 4 days of dosing. They were replaced and the high dose level was reduced. Two similar control groups were given a placebo formulation for 12 and 6 months, respectively. All animals were treated b.i.d. using a 4-h time interval. Mucosal hyperemia and tachycardia, as an expression of the vasodilating properties of felodipine, were observed in a somewhat variable but dose-related manner. Noninflammatory gingival hyperplasia, similar to that after treatment with phenytoin and the calcium antagonist nifedipine, occurred with a propensity for the males after 12 months of treatment. Slight-degree gingival hyperplasia was also noted after 6 months of treatment. This change occurred dose- and time related in the medium and high dose groups but was absent in the low dose group.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of chronic felodipine treatment on renal function and morphology in SHR.

To investigate if blood pressure reduction per se may prevent progressive renal disease in aging spontaneously hypertensive rats (SHR), 15-month-old SHR were treated with the calcium antagonist felodipine, with the beta-blocker metoprolol or with the combination for six months. The combined regimen caused the greatest blood pressure reduction over time, metoprolol caused the least, while felodipine had an intermediate effect. At the end of treatment, urinary protein excretion and endogenous creatinine clearance were determined in rats kept in individual metabolic cages. At autopsy, the kidneys were histologically examined and indices of chronic progressive nephrosis and glomerular sclerosis were determined. A positive correlation was found between urinary protein excretion and glomerular sclerosis. Glomerular sclerosis was low in the groups of rats with high endogenous creatinine clearance. In both groups treated with felodipine, glomerular sclerosis and urinary protein excretion were significantly reduced compared to untreated controls. These results illustrate that the calcium antagonist felodipine attenuates proteinuria and glomerular sclerosis in aging SHR. The blood pressure reduction may be of major importance in this respect, although a direct action on the sclerotic process within the glomeruli may also contribute.

Gastric endocrine cells and gastritis in patients receiving long-term omeprazole treatment.

Both argyrophil endocrine cells and gastritis were investigated in 2,120 biopsies of gastric corpus mucosa from 443 out of 448 patients receiving long-term (for periods ranging from several months to 4 years) omeprazole treatment. None of the patients showed neoplasia or dysplasia, either endocrine or non-endocrine. In 123 out of 443 patients (27.8%), endocrine hyperplasia of diffuse (9.3%), linear (4.1%) or micronodular (14.4%) type was detected either before or at some time during treatment. Chronic atrophic gastritis was found in 45 (10.2%) patients, 60% of whom also showed micronodular hyperplasia. In patients with chronic atrophic gastritis, micronodular hyperplasia occurred in 49% of 96 biopsies, compared with 6% of 1,083 biopsies from patients with non-atrophic chronic gastritis and 2% of 941 biopsies from patients with no evidence of gastritis. In 202 patients treated with omeprazole for at least 330 days, the incidence of micronodular hyperplasia increased from 2.5% at the first biopsy to 10.4% at the final biopsy, while the incidence of chronic atrophic gastritis increased from 1.0% to 13.0%. The present and parallel studies suggest that progression of gastritis is inherent in the natural history of acid-related diseases, while endocrine cell changes are mostly secondary to gastritis-related gland atrophy and have no tumorigenic potential.

Prevention of relapse of reflux esophagitis after endoscopic healing: the efficacy and safety of omeprazole compared with ranitidine.

Ninety-eight patients with erosive and/or ulcerative esophagitis unhealed after at least 3 months' treatment with standard doses of cimetidine (greater than or equal to 1200 mg daily) or ranitidine (greater than or equal to 300 mg daily) were primarily included in an acute healing phase study, and 51 were allocated to 40 mg omeprazole once daily and 47 to 300 mg ranitidine twice daily. After 12 weeks of treatment, 46 (90%) patients given omeprazole were healed, compared with 22 (47%) allocated to ranitidine. Healed patients were then given maintenance treatment with either 20 mg omeprazole once daily or 150 mg ranitidine twice daily for 12 months. Plasma gastrin was determined and gastric mucosal biopsy specimens were obtained during the entire study to assess the structure of the exocrine and endocrine cell populations of the oxyntic mucosa. Sixty-seven per cent of the total number of patients randomized to omeprazole were maintained in clinical and endoscopic remission throughout the 12-month study period as compared with only 10% among those given ranitidine (p less than 0.0001). After 4 weeks of omeprazole treatment basal gastrin levels were slightly increased, with a 95% confidence interval for the change of from 8.6 to 16.9 pmol/l. No further increase in basal gastrin levels was observed during the ensuing study months. No significant histopathologic lesion was found in the oxyntic gland mucosa. In conclusion, omeprazole was far superior to ranitidine in preventing recurrence, a goal achieved without adverse events and significant abnormalities in the oxyntic mucosal exocrine or endocrine cells but with a moderate increase in basal gastrin levels.

Partial gastric corpectomy results in hypergastrinemia and development of gastric enterochromaffinlike-cell carcinoids in the rat.

Studies in the rat have shown that partial gastric corpectomy, in which about 75% of the acid-producing oxyntic mucosa was removed, leads to markedly reduced acid secretion and a feedback increase in the plasma gastrin levels. Ten weeks after operation, the gastric enterochromaffin (ECL)-like cell density in the remaining part of the oxyntic mucosa had increased significantly. In the present study, the effects on the gastric ECL cells of lifelong persistent hypergastrinemia induced by partial (75%) corpectomy have been investigated. Seventy-five partially corpectomized rats and 40 control rats were investigated for plasma gastrin and oxyntic mucosal changes in a 124-week study. The partially corpectomized rats showed increased plasma gastrin levels after the operation; the mean increase compared with the controls was almost 10-fold during the entire study. The remaining oxyntic mucosa of the partially corpectomized rats differed from that of control rats in two respects, showing first general hypertrophy and second a marked hyperplasia of argyrophil ECL cells. The degree and incidence of these changes increased towards the end of the study, i.e., in the aging rats. An age-related increase in ECL-cell density occurred spontaneously also in the control rats but to a lesser extent than in the partially corpectomized group. ECL-cell carcinoids were found in the oxyntic mucosa of 26 of the 75 partially corpectomized rats. The first carcinoid was found 78 weeks after the beginning of the study. Six rats with carcinoids (23%) were found before week 104 (2 years) and the remainder, 20 (77%), were discovered later. No carcinoid tumor was found in the control rats. It is concluded that lifelong hypergastrinemia induced by partial corpectomy leads to the development of ECL-cell carcinoids in the oxyntic mucosa of some rats towards the end of their life span. This observation strongly supports the hypothesis that the gastric ECL-cell carcinoids found in rats treated with antisecretory drugs are caused by long-standing hypergastrinemia developing secondary to inhibition of gastric acid secretion.

Argyrophil cell hyperplasia associated with chronic corpus gastritis in gastric ulcer disease.

Argyrophil cell (AC) hyperplasia in corpus mucosa was investigated in 53 patients with chronic gastric ulcer disease not previously treated with antisecretory drugs. Mucosal biopsies were taken stepwise from the posterior wall in the corpus area of the stomach. Of 117 biopsy sites, 28 showed gastritis without atrophy, 85 showed chronic atrophic gastritis of varying degrees while 4 biopsies showed a normal mucosa. About one third (38%) showed a normal AC pattern. Of the remaining two thirds (62%), 45% had simple AC hyperplasia, 18% had linear and 37% had micronodular AC hyperplasia. A strong association was found between focal (linear/micronodular) AC hyperplasia and chronic atrophic gastritis. It is concluded that focal AC hyperplasia is a common phenomenon in gastric ulcer patients and is inherently related to the spontaneous development of atrophy in the corpus mucosa of these patients.

The intracellular distribution of cobalt in exposed and unexposed rat myocardium.

The intracellular distribution of cobalt was analysed in the myocardium of exposed and unexposed rats. The exposed rats were given a dietary cobalt supplementation of 40 mg CoSO4.7 H2O/kg body weight for 8 weeks. The mitochondrial fraction showed the greatest relative increase in cobalt: 0.09 ng/mg protein in the unexposed rats to 8.43 ng/mg protein in the exposed rats. In the exposed rats the submitochondrial particles had the highest levels of cobalt: 19.43 ng/mg protein, followed by the sarcoplasmatic reticulum: 12.3 ng/mg protein. The microsomal 44,000 g supernatant also showed an increase, although the levels remained low (0.51 ng/mg protein in the exposed animals). Apparently the calcium-storing organelles had the highest levels of cobalt. This could affect calcium flux in myocardial cells and, secondarily, tension development in cardiac muscle.

The effect of cobalt on mitochondrial ATP-production in the rat myocardium and skeletal muscle.

Cobalt has been shown to accumulate in the myocardium of uraemic patients and has been suggested as a myocardial toxin inhibiting mitochondrial respiration. In order to study the cellular effects of cobalt exposure three groups of rats (n = 12 per group) were fed a diet containing 12% protein without supplementation or with 20 mg and 40 mg CoSO4 7 H2O/kg body weight/day respectively. After 8 weeks the hearts and soleus muscles were removed. Cobalt in tissues and in four cell fractions were analysed with neutron-activation analysis (ng/g wet weight and ng/mg protein respectively). Mitochondrial respiration was analysed as ATP-production rate using pyruvate + malate and palmitoyl-carnitine + malate as substrate. The ATP-production from pyruvate + malate was unchanged in both heart and skeletal muscle in the exposed animals. With palmitate as substrate, the heart muscle showed a slightly lower ATP-production rate (p less than 0.05) after the 20 mg cobalt dose, but the rate was unchanged in the group with higher cobalt intake. No changes in ATP-production rate from palmitate was observed in soleus muscle. The microsomal (100,000 g) fraction in the myocardial cells contained significantly higher cobalt concentrations compared to the mitochondrial fraction in both the unexposed (1.4 ng/mg protein vs 0.19, p less than 0.05) and exposed rats (53.4 ng/mg protein vs 13.2, p less than 0.005). In conclusion, cobalt showed a large accumulation in myocardial cells, without significant effects on mitochondrial ATP-formation rate from oxidation of pyruvate or palmitate and with the highest cobalt content contained in the microsomal (100,000 g) fraction.