In rat gastroduodenal mucosa the cytoprotective effect of sulfhydryl drugs is not mediated via endogenous prostacyclin.
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Biomedical subjects
Publications and source records attributed to V Varró.
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An open, intraindividually controlled study with two doses of Creon (5 X 2 and 5 X 3 capsules/day) was performed in 15 patients suffering from severe pancreatic steatorrhea. A diet containing 70 g of fat/day was offered and the means of 3-day fat loss of daily collected stools were measured in the last 3 days of 5-day equilibration periods with and without replacement therapy. After these short-term periods, patients were treated with 5 X 2 capsules of Creon for 3 months at home, and fat loss was then measured as previously on a 70 g fat/day diet. Stool weight and stool frequency significantly decreased already during the short-term periods. The fat loss decreased dose-dependently during the short periods, more after 5 X 3 capsules/day than after 5 X 2 capsules/day. However, after 3-month replacement therapy the effect of 5 X 2 capsules of Creon was similar (16.5%), possibly because of improved intes-tinal function. Weight increases and patients' appraisal were also favorable. The excellent results with Creon treatment were attributed to a better lipase/trypsin ratio of the pancreatin pre-aration which, together with the favorable galenic properties, can diminish proteolytic inactivation of lipase during passage through the gastrointestinal tract.
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In both ulcer models investigated, except the 240-min IND and 8-hr STR cAMP values in the antrum, the cyclic nucleotides showed a significant decrease in the gastric mucosa, which is most probably a sign of cellular exhaustion.
It seems that the mucosal CaM content does not play a significant role in the pathomechanism or the regeneration of (experimental) gastric ulcers of rat.
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The effect of gastric secretory inhibitors, vasoactive agents and gastrointestinal peptide hormones were investigated on gastric mucosal blood flow (MBF) and HCl secretion in 197 subjects. Changes in MBF were estimated by a new clearance substance, 99mTc-4-methyl-aminophenazone originally described by the authors. The procedure seemed to be suitable for characterizing changes in MBF without any toxic side effect or considerable radioactive loading of the patient or its surroundings. The studies were performed after a secretory steady state had been achieved by continuous pentagastrin infusion. Some experiments were done in the fasting stomach instilled with 0.160 N HCl. Secretory inhibition following atropine, pirenzepine, ranitidine and somatostatin was a primary effect of these substances, the observed MBF decrease being a secondary one. In contrast, vasopressin caused a fall in mucosal blood supply through vasoconstriction, the concomitant secretory inhibition being a secondary phenomenon. Certain doses of dopamine and terbutaline increased MBF without influencing HCl secretion. Glucagon in the dose used did not influence either mucosal blood flow or acid secretion. Synthetic secretin in the fasting stomach increased MBF without affecting HCl production; during pentagastrin stimulation it inhibited acid production while MBF remained unchanged. Cholecystokinin-octapeptide proved to be a direct vasodilating agent with a slight acid output increasing effect. Divergent effects of some drugs on mucosal blood flow and HCl production may be important in the pathology of hypoxic ulcerative damage and in the reparative processes of gastric ulceration. The 99mTc-4-methyl-aminophenazone clearance technique proved to be a reliable method for screening of drugs possessing vasoactive or secretion influencing properties.
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Using specific radioimmunoassay it seems that Prostacyclin has a strong effect on the cyclic nucleotide-content of the rat gastric antral mucosa. Shortly (1 min) after an intragastric application of 100 micrograms/kg Prostacyclin the cAMP and the cGMP-content showed a significant decrease. Investigating the antral and fundic mucosal calmodulin-levels, it seems that 15-30 mins after Prostacyclin application both tend to increase. It seems very probable that the primary intracellular effect of Prostacyclin in the gastric mucosa is directed to the so-called 'second messenger system' but later Prostacyclin activates the calmodulin-system too.
It seems that the gastric antral mucosa either in normal, physiological circumstances, or in IND or STR induced gastric ulcer models, contains significantly more endogenous PG-I2 than that of gastric fundic mucosa, while the duodenal mucosa contains significantly lower endogenous PG-I2-level compared to the gastric antral or fundic level. Either in gastric or in duodenal ulceration the endogenous PG-I2 level basically decreased proportionally to the degree of ulceration - therefore it is tempting to speculate that the endogenous PG-I2 is most probably one of the natural protective substances in the gastrointestinal mucosa.
In our opinion the endogenous prostacyclin (PGI2) is one of the most important natural protective substances in the gastric mucosa. We have, therefore checked in experimental circumstances in rats, as well as in clinical observations in humans, the possible effect of smoking on endogenous gastroduodenal mucosal PGI2 level. The animal experiments seem to verify that cigarette smoke really has an unwanted effect on the gastric mucosa. The target of this action is the endogenous PGI2 content of the mucosa. According to our observations in humans there is a definite tendency toward decreased endogenous PGI2 production in the gastroduodenal mucosa of smokers too.
In anesthetized rats, a marked decrease in CCK-OP activity and, to a far lesser extent, in the pancreatic secretory effect of CCK-33 were found after portal administration, compared to the femoral route. Changes in the biological activity of CCK-OP were further investigated after 30 min incubation with different subcellular liver fractions (1000 X g, 12,000 X g, microsomal fraction with or without NADPH). All the subcellular liver fractions caused an approximately 70% decrease in the CCK-effect, as calculated from dose-response relationships. The inactivation of CCK-OP after incubation with microsomal fractions of thioacetamide (TAA)-induced cirrhotic liver did not differ from that of control rats. The CCK-OP dose-response curves were similar in cirrhotic and control rats, but the pancreatic secretion was sustained to a greater extent and the inhibitory effect of supramaximal stimulation was delayed in cirrhotic rats. It was concluded that CCK-OP can be inactivated by liver proteins present in microsomal fractions, by a NADPH-independent mechanism. This inactivation did not diminish in liver cirrhosis. There were no changes in CCK-OP elimination in cirrhotic rats in vivo, thus pancreatic hypertrophy in experimental cirrhosis must be explained by other mechanisms.
Capsaicin injected into the lumen of the small intestine produced marked changes in mesenteric blood flow in anesthetized dogs. In the majority of cases capsaicin evoked a significant increase in mesenteric blood flow, the time-course of which indicated it was of a reflex nature. The response to capsaicin was completely abolished by a previous intraluminal application of the local anesthetic lidocaine, and was inhibited by an intraarterial injection of somatostatin. The present findings suggest that the effects of capsaicin may be related to a release of vasoactive peptides from afferent nerves associated with the vascular system of the gastrointestinal tract. It is concluded that capsaicin-sensitive mucosal afferent nerves, possibly provided with an axon reflex arrangement, may play a role in the regulation of local intestinal blood flow.
The effects of somatostatin on pancreatic secretion were studied in conscious rats during diversion and recirculation of pancreatic juice. Pancreatic secretion was significantly inhibited by low doses (2 micrograms/kg/h) of somatostatin during diversion of pancreatic juice. The inhibitory effect was more marked on bicarbonate and protein output than on volume, while in bicarbonate and protein output a rebound effect was observed. These data suggest a combined inhibitory effect of somatostatin on endogenous CCK release and cholinergic mechanisms. During recirculation of pancreatic juice there was no rebound effect, thus only the inhibition of cholinergic mechanisms seems to be involved in the inhibitory effect of somatostatin. During recirculation, CCK-OP-stimulated bicarbonate and protein secretion was strongly inhibited by somatostatin. Even water secretion not stimulated by CCK-OP was significantly inhibited demonstrating a supplementary inhibitory effect on basal cholinergic mechanisms. Somatostatin decreased only slightly the synthetic secretin-stimulated water and bicarbonate secretion. The more effective inhibition of protein output was explained by an additive effect of somatostatin on basal cholinergic tone.
The diagnostic efficacy of some tubeless screening tests was examined in chronic pancreatitis patients with different degrees of pancreatic insufficiency. Results of the Pancreolauryl and Lipiodol tests were equal in the same patients. Sensitivity of the Lipiodol test, starch tolerance test and PABA test was 80%, 90% and 57%, respectively. Specificities were 48%, 57% and 100%. Sensitivity increased considerably when two tubeless tests were used in combination: 99% and 90% of patients had at last one abnormal result with starch tolerance + Lipiodol and PABA + Lipiodol tests, respectively. The specificity did not change significantly. Combination of tubeless tests seems to be useful for screening of mild and moderate pancreatic diseases because false negative results of single tests caused possibly by non-parallel enzyme secretion can be avoided.