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E Carlsson

Publications and source records attributed to E Carlsson.

At least 55 records · Page 3Linked to original sources
PubMed1989

A review of the effects of long-term acid inhibition in animals.

Studies with H2-receptor antagonists have revealed a trophic effect on the gastric mucosa - an effect which has been ascribed to hypergastrinaemia secondary to acid inhibition. Such hyperplasia of oxyntic mucosal cells has also been demonstrated in chronic toxicity studies following profound, long-standing inhibition of gastric acid secretion with omeprazole. The central role of gastrin in this effect was clearly demonstrated in the omeprazole studies, as antrectomy prevented this effect in both rats and dogs. The hyperplasia was fully reversible in both species. The close correlation between serum gastrin and hyperplasia of enterochromaffin-like (ECL) cells in the rat oxyntic mucosa has been demonstrated in a large number of experiments using different means to induce hypergastrinaemia, including administration of exogenous gastrin, treatment with antisecretory drugs and partial fundectomy. The hyperplasia of ECL cells was fully reversible even after 1 year of sustained gastric acid inhibition following treatment with a high dose of omeprazole. Marked long-standing hypergastrinaemia explains the findings of gastric ECL cell carcinoids in the life-long rat toxicity studies with both omeprazole and other inhibitors of gastric acid secretion.

Animals↗
PubMed1989

Correlation between inhibition of gastric acid secretion, plasma gastrin, and oxyntic mucosal histidine decarboxylase activity in the rat.

Female rats were treated for 1 week with ranitidine (125-1700 mumol/kg.day, given subcutaneously by means of osmotic minipumps), the proton pump inhibitor omeprazole (10-400 mumol/kg.day orally), or vehicle. Acid secretion, plasma gastrin levels, and oxyntic mucosal histidine decarboxylase (HDC) activity were determined. Both compounds dose-dependently inhibited maximally stimulated gastric acid secretion and caused a parallel increase in plasma gastrin levels. There was very good correlation between plasma gastrin levels and HDC activity for both compounds, although higher oxyntic mucosal HDC activity was found during ranitidine treatment. The higher HDC activity in the ranitidine-treated rats indicated the presence of a histamine H2-receptor on the ECL cells. It is concluded that, regardless of what kind of antisecretory agent is used, a dose-dependent inhibition of gastric acid secretion results in a parallel increase in plasma levels of gastrin, and as a consequence the HDC activity in the rat oxyntic mucosa is increased.

Animals↗
PubMed1988

Time-course of development and reversal of gastric endocrine cell hyperplasia after inhibition of acid secretion. Studies with omeprazole and ranitidine in intact and antrectomized rats.

In intact rats plasma gastrin levels were increased during a 20-wk treatment course with either omeprazole or ranitidine. Although plasma gastrin levels were the same during treatment, the enterochromaffinlike (ECL) cell density increased approximately linearly with time at a rate correlated to the plasma gastrin level. Antrectomy prevented the ECL cell hyperplasia seen in omeprazole-treated rats, suggesting that it was not caused by omeprazole per se. Changes in ECL cell density roughly paralleled changes in oxyntic mucosal histidine carboxylase activity and histamine concentration. Treatment with omeprazole also raised stomach weight and antral gastrin and gastrin cell density, reduced antral somatostatin cell density, but did not affect enterochromaffin cell density. Within 19 days of cessation of a 10-wk treatment course, plasma gastrin levels, oxyntic mucosal histidine decarboxylase activity, and antral gastrin and somatostatin cell densities had returned to control levels. The stomach weight was normal within 5-10 wk, antral gastrin concentration within 10 wk, and oxyntic mucosal ECL cell density and histamine concentration within 20 wk. After renewed treatment with omeprazole for 10 wk starting 10 wk after completion of the first omeprazole treatment period, changes in all parameters were of similar magnitude in animals previously treated with omeprazole and those previously treated with vehicle. The results suggest that the effects described are reversible and that gastrin cells turn over more rapidly than ECL cells.

Animals↗
PubMed1988

Effects of thoracic epidural analgesia with morphine or bupivacaine on lower oesophageal motility--an experimental study in man.

Lower oesophageal peristalsis and lower oesophageal sphincter (LOS) pressure during thoracic epidural analgesia (TEA) were studied in 20 healthy volunteers. After oesophageal manometric baseline recordings, 10 volunteers received 4 mg epidural morphine. The other ten received 0.5% bupivacaine epidurally in sufficient amounts to block the sympathetic innervation of the oesophagus. Thereafter oesophageal manometry was repeated. During epidural morphine oesophageal peristalsis, resting LOS pressure and the contraction of LOS after swallowing did not change, but the relaxation of the LOS in response to swallowing decreased significantly (P less than 0.01). Following TEA with bupivacaine, neither distal oesophageal peristalsis nor LOS pressure changed.

Adult↗
PubMed1988

Rat parietal cell function after prolonged inhibition of gastric acid secretion.

Female rats were treated orally for 3 mo with omeprazole (40 and 400 mumol/kg). Both doses caused total inhibition of gastric acid secretion and recovery was parallel to that of H+-K+-ATPase activity (30-50 and 60-80% inhibition 24 h after doses, respectively). The H+-K+-ATPase activity returned to control levels within 1 wk after the last dose. Plasma gastrin levels were dose-dependently increased during treatment but reversed to control levels within 9 days after the last dose. Parallel with a general increase in corpus mucosal mass, both pepsinogen and H+-K+-ATPase total content increased. However, their tissue concentrations did not differ from control values, suggesting that neither parietal nor chief cell density are changed by omeprazole treatment and also that their growth is parallel to the general hyperplasia. In contrast, the oxyntic mucosal histamine concentration was increased, indicating an increase in the enterochromaffin-like (ECL) cell density. Maximal capacity of the mucosa to secrete acid increased in parallel with the increase in mucosal mass and total H+-K+-ATPase content. However, basal acid secretion did not differ between treatment groups. Increased capacity slowly declined toward control levels over the 70-day recovery period after withdrawal of omeprazole. These results suggest that hypergastrinemia, induced in the rat by pharmacological inhibition of gastric acid secretion, causes a hyperplasia of oxyntic mucosal cells, ECL cells growing faster than the others. The hyperplastic mucosa has an increased capacity to produce acid and is functionally normal.

Adenosine Triphosphatases↗
PubMed1988

Effects of omeprazole and ranitidine on gastric acid secretion, blood gastrin levels and [3H]-thymidine incorporation in the oxyntic mucosa from dogs and rats.

Dogs provided with a gastric fistula were treated orally for 1 week either with the H+, K+-ATPase inhibitor omeprazole, 80 mumol/kg once daily, or with the histamine H2 receptor antagonist ranitidine, 85-175 mumol/kg every 8 h. Acid secretion, serum gastrin levels and [3H]-thymidine incorporation in the corpus mucosa were determined before, during and after the treatment period. In order to examine differences between species, plasma gastrin levels and [3H]-thymidine incorporation in the oxyntic mucosa were also determined in female rats treated up to 1 week with omeprazole, 400 mumol/kg orally once daily. Histamine-stimulated gastric acid secretion in dogs treated with omeprazole or ranitidine was almost completely inhibited during the whole treatment period. As a consequence of that, the meal-stimulated gastrin levels were increased (7-fold) during treatment by both compounds. [3H]-thymidine incorporation in the dog corpus mucosa was increased approximately 4 times on day 5 both with omeprazole and ranitidine. After the treatment was stopped, gastric acid secretion, serum levels of gastrin and the rate of [3H]-thymidine incorporation were back to control level in both groups within 11 days. In the rats, the plasma gastrin levels increased 10-fold and the rate of [3H]-thymidine incorporation in the corpus mucosa increased 3-fold during treatment with omeprazole. In conclusion, a pronounced suppression of gastric acid secretion over the day with antisecretagogues results in hypergastrinemia in both dogs and rats. As a consequence of the trophic effect of gastrin, the incorporation of [3H]-thymidine in the oxyntic mucosa is increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Omeprazole: its influence on gastric acid secretion, gastrin and ECL cells.

The H+,K+-ATPase inhibitor omeprazole is a highly effective gastric antisecretory agent, both in animals and man, with a long duration of action. These properties are shared by a number of recently described histamine H2-receptor antagonists. In life-long oncogenicity studies of these H2-receptor antagonists, as well as with the H+,K+-ATPase inhibitor omeprazole, gastric enterochromaffin-like cell (ECL cell) hyperplasia and carcinoids have been found. The purpose of this paper is to summarize available evidence for the "Gastrin Hypothesis" to explain the development of ECL-cell hyperplasia. The hypothesis may be outlined as follows: 1) Inhibition of gastric acid secretion leads to elevated antral pH and, secondarily, to release of gastrin from the antral gastrin cells into the blood stream. 2) Gastrin causes both general hypertrophy of the oxyntic mucosa and hyperplasia of the ECL cells in the oxyntic mucosa. That this sequence of events occurs not only with omeprazole but also with other effective gastric antisecretory agents has been verified in the rat by giving the H2-receptor antagonist ranitidine as a continuous infusion. Ranitidine caused a hypergastrinemia of a similar magnitude as that seen after omeprazole, provided that the acid secretion was inhibited to a similar degree. At similar gastrin levels, ECL-cell hyperplasia of the same magnitude developed during both ranitidine and omeprazole treatment. Antrectomy prevented the development of ECL-cell hyperplasia during omeprazole treatment, indicating that the hyperplasia was not due to the drug treatment per se, but rather to the hypergastrinemia. Both the hypergastrinemia and the ECL-cell hyperplasia were found to be reversible.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Gastric acid antisecretory effect of two different dosage forms of omeprazole during prolonged oral treatment in the gastric fistula dog.

Two series of experiments have been performed in gastric fistula dogs to test the antisecretory effect of two different oral dosage forms of omeprazole: 2 mumol x kg-1 x day-1 as a methylcellulose suspension for 8 weeks and 0.5 mumol x kg-1 x day-1 in enteric-coated granules (ECG) for 3 weeks. There was an increasing inhibitory effect during the first days of repeated administration of omeprazole, which is in accordance with its long duration of action. The steady-state inhibitory level was reached after five doses. During the 8-week treatment with the omeprazole suspension (2 mumol x kg-1) the mean maximal inhibitory level (3 h after dose) was 82%, and the mean minimal inhibitory level (24 h after dose) was 35%. With omeprazole in ECG (0.5 mumol x kg-1) the steady-state maximal inhibition (4th h) was 60%, whereas 40% inhibition remained after 24 h. Thus, a more even inhibitory level over day and night seems to be obtained with the ECG formulation than with the suspension. Basal and food-stimulated plasma gastrin levels were not significantly affected by the treatment with 0.5 mumol x kg-1, whereas food-stimulated gastrin levels were slightly increased during treatment with 2 mumol x kg-1. Control levels of acid secretion were reached within 4 days of stopping treatment. In the present studies, in which the inhibition of acid secretion varied over 24 h between approximately 80% and 35% (maximum and minimum), no rebound effects could be detected as measured up to 1 month after cessation of treatment.

Animals↗
PubMed1987

Diversification of the myofibrillar M-band in rat skeletal muscle during postnatal development.

The fine structure of the M-band in soleus (SOL) and extensor digitorum longus (EDL) muscles in newborn and four-week-old rats was studied using electron-microscopic techniques. In newborn rats, all myotubes and fibres in both muscles had an identical myofibrillar appearance. A five-line M-band pattern was seen in longitudinal sections and distinct M-bridges in cross-sections. The Z-discs were of medium width. On the other hand, in four-week-old rats, different muscle fibre types were observed on the basis of their myofibrillar pattern. In SOL two fibre types were distinguished in longitudinal sections. One had a four-line M-band pattern and very broad Z-discs, whereas the other type had five lines in the M-band and broad Z-discs. In EDL, three different myofibrillar patterns were observed. The M-bands were composed of three, four or five lines. Fibres had either thin, broad or medium Z-disc widths, respectively. In cross-sections of the SOL muscle one group of fibres showed indistinct M-bridges, whereas distinct M-bridges were seen in the other fibres and in all observed EDL muscle fibres. We conclude that initially there seems to be a single intrinsic program for M-band genesis; this program becomes modified upon the induction of functionally differentiated fibres.

Aging↗
PubMed1987

Myofibrillar M-band structure and composition of physiologically defined rat motor units.

The isometric contraction time of 19 fast and slow rat motor units in the soleus and the anterior tibial muscles were recorded. The motor unit fibers, subsequently distinguished by glycogen depletion, were histochemically differentiated into fiber types and analyzed immunohistochemically for high molecular weight M-band proteins, as well as ultrastructurally for M-band fine structure, Z-disc width, and volume density of mitochondria. All fibers belonging to slow-twitch motor units in both the anterior tibialis and soleus muscles were histochemically classed as type 1. They lacked the Mr 165,000 M-protein, showed ultrastructurally a four-line M-band pattern, and had broad Z-discs, whereas the volume density of the mitochondria varied considerably. Muscle fibers belonging to the fast-twitch motor units were histochemically classed as types 2A and 2B in anterior tibialis and type 2A in soleus. They contained a three- or a five-line M-band pattern and medium-to-thin Z-discs in the anterior tibialis and a five-line M-band pattern and broad Z-discs in the soleus. Furthermore, the volume density of mitochondria showed considerable variation within and in between soleus and anterior tibialis type 2 fibers. As the differences in M-band composition and structure between fiber types overrode the intragroup variability in contraction times of slow and fast units within and between the two muscles, it is concluded that the M-band composition and structure is fundamentally related to whether the fiber is innervated by a slow or fast motor neuron, whereas other parameters such as contraction time, Z-disc width, and mitochondrial content of fibers of fast and slow units are relative and vary between muscles. Thus the M-band appearance can be used as a reliable marker to distinguish between fibers of slow- and fast-twitch motor units in rat leg muscles.

Animals↗
PubMed1987

Quantification of effect of pericardium on LV diastolic PV relation in dogs.

The aim of the present study was to quantify the effect of the pericardium on the left ventricular (LV) diastolic pressure-volume relation. The experiments were done in 10 anesthetized closed-chest dogs. Pericardial and cardiac volumes were determined by computed tomography. Pericardial effusion (n = 5) and volume loading (6% dextran iv; n = 5) were used to increase pericardial volume. Volumes were normalized as multiples of the LV volume measured when LV transmural pressure was 6 mmHg (VLV6). Using the data from the pericardial effusion experiments, we calculated the best-fit exponential equations for the pericardial pressure-volume relations. From these equations we calculated that the changes in pericardial volume necessary to shift the LV diastolic pressure-volume curve upward by 2, 5, 10, and 20 mmHg were 0.6 +/- 0.1, 1.1 +/- 0.2, 1.6 +/- 0.2, and 2.2 +/- 0.3 times VLV6, respectively. Using the data from the volume loading experiments, we also calculated the degree of upward shift of the LV pressure-volume relation caused by volume loading, which increased LV mean diastolic pressure by 12 mmHg. (The upward shift is that increment in pericardial pressure caused by the total increase in volume of the extra-LV contents of the pericardium, i.e., the atria, the right ventricle, and any pericardial effusion.) This volume loading increased the total volume of the right ventricle and the atria by 1.0 +/- 0.1 VLV6, which, in itself, increased pericardial pressure by 3.6 +/- 0.8 mmHg. We conclude that in situations in which heart or pericardial volume increases acutely, the pericardium shifts the diastolic pressure-volume relation of the LV upward by a significant amount.

Animals↗
PubMed1986

Effect of inhibition of acid secretion on the regulatory peptides in the rat stomach.

The effect of inhibiting acid secretion by pharmacologic agents on the gastric content of regulatory peptides has been determined by radioimmunoassay and immunocytochemistry. Plasma, antral, and fundic concentrations of gastrin were elevated in rats rendered virtually achlorhydric by treatment with high-dose omeprazole (400 mumol/kg daily for 10 wk). This was associated with an increase in the number and staining intensity of gastrin immunoreactive cells. A clear reciprocal relationship was observed between antral gastrin and somatostatin as assessed by both quantitative and qualitative methods. These changes had disappeared 10 wk after treatment was stopped. No alteration was found in the concentrations of other regulatory peptides proposed as important in control of acid secretion. Plasma and antral gastrin concentrations were elevated in rats treated with high-dose ranitidine (700 mumol/kg daily), but to a lesser extent than during omeprazole therapy, and somatostatin concentrations were unchanged.

Animals↗
PubMed1986

Plasma gastrin and gastric enterochromaffinlike cell activation and proliferation. Studies with omeprazole and ranitidine in intact and antrectomized rats.

Unoperated female rats were subjected to daily oral treatment with omeprazole (10 or 400 mumol/kg body wt), ranitidine (175 + 175 + 350 mumol/kg body wt), or vehicle and antrectomized rats were treated with omeprazole (400 mumol/kg body wt) or vehicle. After 10 wk of treatment, plasma gastrin levels were high in unoperated rats treated with the high omeprazole dose and with ranitidine, and low in antrectomized controls. Plasma gastrin levels were slightly higher in the low-dose omeprazole group than in the intact controls. In antrectomized rats treated with the high dose of omeprazole, the plasma gastrin level was in the same range as in intact control rats. A close correlation (r = 0.89, p less than 0.0001) was found between the plasma gastrin level and the oxyntic mucosal enterochromaffinlike cell density (as well as the tissue levels of histidine decarboxylase and histamine in the oxyntic mucosa) in all groups. The somatostatin cell density in the oxyntic mucosa was not altered by the various treatments. During a recovery period of 10 wk after the 10-wk treatment, the enterochromaffinlike cell density and histamine concentration decreased by 30%-40% in the rats treated with the high dose of omeprazole, whereas the corresponding values increased by 50% and 40%, respectively, in the control rats. The difference between the two groups, however, was still statistically significant. Plasma gastrin levels and gastric histidine decarboxylase activity returned to control values during recovery. The results suggest that the observed changes in enterochromaffinlike cell density are related to the plasma gastrin levels and that they are reversible. it is concluded that neither omeprazole nor ranitidine per se is likely to induce proliferation of enterochromaffinlike cells.

Animals↗
PubMed1986

Hypergastrinaemia produces trophic effects in stomach but not in pancreas and intestines.

Hypo- or anacidity, caused by antisecretagogues, stimulates gastrin release and leads to hypergastrinaemia. If drug treatment is maintained over a period of time, the hypergastrinaemia can be expected to give rise to trophic effects. We examined the trophic consequences of the very marked hypergastrinaemia produced by long-term treatment (16-20 weeks) of rats with large doses of the substituted benzimidazole, omeprazole, a potent and long-acting blocker of acid secretion. The weight of the stomach and the oxyntic mucosal thickness were increased, whereas the weight of the pancreas and the intestines and the thickness of the mucosa of the antrum and small and large intestine were unaffected. The number of exocrine cells (parietal, zymogen and mucous cells) were uniformly increased by 25-30%. The density of parietal and zymogen cells, expressed as number of cell nuclei per mm2 epithelium, was unchanged. The volume density of parietal cells, expressed as % of epithelial volume, was also unchanged, implying that the volume of the individual parietal cell had not increased. The density of endocrine ECL cells in the stomach increased 5-fold. Thus, the findings demonstrate a growth-promoting effect of the hypergastrinaemia on the oxyntic mucosa, the ECL cells in particular, and the lack of such an effect on the antrum, pancreas and intestines.

Animals↗
PubMed1986

Hypergastrinemia after blockade of acid secretion in the rat: trophic effects.

The availability of potent and long-acting blockers of acid secretion, such as omeprazole, has paved the way for experimental studies on the long-term effects of permanently raised levels of circulating gastrin without the complication of surgical intervention. We have examined rats given high doses of the antisecretagogues omeprazole and ranitidine during 10 or 20 weeks for general trophic effects on the gastrointestinal tract and pancreas and for the effects on endocrine cells such as the somatostatin cells and the enterochromaffin-like (ECL) cells, which are present in the oxyntic mucosa. The ECL cells, which in the rat produce and store histamine (in addition to an as yet unidentified peptide hormone), are known to be activated by gastrin. In rats given high doses of omeprazole, the serum gastrin levels rose about 10-fold. General trophic effects were restricted to the stomach; the weight was increased, as was the thickness of the oxyntic mucosa. Omeprazole treatment resulted in a 3- to 5-fold increase in the ECL cell density. A close correlation was found between plasma gastrin levels and the ECL cell density as well as the levels of histidine decarboxylase and histamine in the oxyntic mucosa. The somatostatin cell density was unaffected by the hypergastrinemia. During a 10-week recovery period after discontinuation of the omeprazole treatment, the ECL cell density diminished, but was still significantly higher than in age-matched control rats. Plasma gastrin levels and gastric histidine decarboxylase activity rapidly returned to control values. The results suggest that the observed general trophic effects on the oxyntic mucosa and on the ECL cells are related to the plasma gastrin levels and not to an action of the antisecretagogues per se.

Animals↗
PubMed1986

Gastric regulatory peptides in rats with reduced acid secretion.

Gastric acid secretion is known to be controlled by a complex system of interacting factors. Amongst these, regulatory peptides make a significant contribution. In the present study, immunocytochemistry and radioimmunoassay were used to investigate gastric regulatory peptides in animals with pharmacologically reduced gastric acid secretion. Increased numbers of densely immunostained antral gastrin-immunoreactive (G) cells were seen in rats which had been rendered virtually achlorhydric by administration of high-dose (400 mumol/kg daily) omeprazole over a 10-week period. These morphological changes were accompanied by increases in the plasma, antral and fundic concentrations of gastrin, as measured by radioimmunoassay. In contrast, antral somatostatin-containing cells were reduced, and there was a corresponding fall in the tissue content of the peptide. Ten weeks after treatment had ceased, the peptide profiles had returned to normal. No other regulatory peptide, whether endocrine or neural, appeared to alter during treatment with high-dose omeprazole. Treatment with high-dose (700 mumol/kg daily) ranitidine also caused an elevation in the G cell population and the antral and plasma content of gastrin, but to a lesser extent than that observed during omeprazole treatment. Somatostatin cells and tissue levels did not alter in these animals, and no other morphological changes could be detected. Radioimmunoassay, however, measured reduced quantities of vasoactive intestinal peptide, peptide histidine isoleucine and calcitonin gene-related peptide. Achlorhydria, induced by omeprazole at a dosage of 250-500 times that required for effective acid inhibition in man and animals, therefore resulted in reciprocal changes in gastrin and somatostatin cells. These changes are support for the postulated roles of these peptides in the control of gastric acid secretion.

Achlorhydria↗
PubMed1986

Pharmacology and toxicology of omeprazole--with special reference to the effects on the gastric mucosa.

Omeprazole is a long acting inhibitor of gastric acid secretion in different species including rat and dog. Due to the long duration of action, steady state inhibition at repeated once daily administration is reaches within 4-5 days in dogs and in about 3 days in rats. Daily dosing at high dose levels results in virtually complete 24-hour inhibition of acid secretion in experimental animals. The elimination of the inhibitory feedback effect of acid on gastrin secretion leads to hypergastrinaemia. Because gastrin has a trophic effect on the oxyntic mucosa, the hypergastrinaemia results in a reversible hypertrophy of the oxyntic mucosa and an increased capacity to produce acid following maximal stimulation with exogenous secretagogues after discontinuing treatment. Despite the increased capacity to produce acid, basal acid secretion seems to be unchanged. The pronounced hypergastrinaemia which occurs during long-term treatment with high doses rapidly normalizes after discontinuing treatment. The hyperplasia of the oxyntic endocrine ECL cells, and the eventual development of gastric ECL cell carcinoids after lifelong treatment of rats with high doses, can also be attributed to the hypergastrinaemia developing after almost complete elimination of gastric acid secretion in these animals.

Animals↗