Effects of thyrotrophin-releasing hormone, and methionine-enkephalin on gastric acid and pepsin secretion in the cat

1 The effect of intravenous administration of thyrotrophin-releasing hormone (TRH) and methionine-enkephalin on gastric acid and pepsin secretions was investigated in conscious cats prepared with chronic gastric fistulae.

2 TRH, 20 μg kg^-1 h^-1, did not influence unstimulated gastric acid secretion, nor gastric acid secretion stimulated by submaximal doses of pentagastrin or histamine. Pepsin secretion stimulated by pentagastrin was not influenced by TRH.

3 TRH, 20 μg kg^-1 h^-1, significantly reduced the gastric acid and pepsin responses to intravenous infusion of insulin. TRH also significantly reduced the degree of hypoglycaemia seen in response to insulin. TRH, 20 μg kg^-1 h^-1, but not 5 μg kg^-1 h^-1, infused alone resulted in a significant hyperglycaemia.

4 It is concluded that the reduction of insulin-stimulated gastric secretion by TRH is not dependent on the hyperglycaemic action of the peptide. The mechanism of action of TRH on insulin-stimulated secretion is discussed with respect to its site of action.

5 Methionine-enkephalin or the potent analogue, D-Ala², Met-enkephalinamide were without effect on unstimulated gastric secretion, or secretion stimulated by pentagastrin, histamine, and insulin. The opiate receptor antagonist, naloxone, did not significantly alter the gastric acid or pepsin response to insulin.

6 It is concluded that there is no evidence that opiates stimulate oxyntic glands directly, nor that the oxyntic cells may possess high affinity binding sites for opiates, nor that endogenous opiates are involved in the control of gastric secretion.

     

Effect of enprostil on basal and meal-stimulated gastric acid and pepsin secretion, serum gastrin and gastric emptying in healthy persons

Ten healthy volunteers took part in a double-blind, randomized, cross-over study of the effect of single doses of enprostil (70 micrograms) and placebo on basal and meal-stimulated gastric acid, pepsin secretion and serum gastrin. Meal-stimulation was induced by modified sham feeding combined with repeated gastric instillation and withdrawal of meat soup. When studied between 1 and 2.5 hours after oral administration of the drug, enprostil decreased basal acid output by 92% (P less than 0.001) and stimulated acid output by 70% (P less than 0.001). Basal and stimulated volumes of gastric juice were decreased by 50% (P less than 0.02) and 35% (P less than 0.002), respectively. Enprostil decreased stimulated pepsin output by 34% (P less than 0.05), but had no effect on the concentration of pepsin. Neither basal nor stimulated serum gastrin concentrations were affected by enprostil. Percent recovery of the meal was measured by an unabsorbable marker, polyethylene glycol, instilled into the stomach mixed with the soup. Polyethylene glycol recovery decreased from 89% with placebo to 67% with enprostil (P less than 0.01), indicating an enhanced gastric emptying rate with enprostil.     

Correlation of biliary cholesterol, phospholipids and bile acid compositions and the development of cholesterol cholelithiasis in mice

A study was attempted to establish a screening method for detecting cholelitholytic ingredients from a wide variety of natural substances. Although mice were selected as a suitable pathological model of cholelithiasis to detect a small amount of the ingredients, all the conventional lithogenic diets caused unfavorable influence on the animals. Therefore, as the first step we formulated a new lithogenic diet consisting of butter, cholesterol, cholic acid, etc, which was adequate for mice. Subsequently, the pathological characteristics and persistence of cholelithiasis were examined in the animals; the changes in bile compositions including free and conjugated bile acids, cholesterol and phospholipids were observed before and at the onset of cholelithiasis. Following confirmation of the stone formation, a normal diet was substituted for the lithogenic diet to likewise assess the bile compositions 4 and 6 weeks later. An increasing tendency for deoxycholic acid, disappearance of chenodeoxycholic acid and decrease in ursodeoxycholic acid were seen under the condition of cholelithiasis. In addition, the cholic acid-glycine conjugate which should not exist in the normal state and the increase in free and tauring-conjugated cholic acid were noticed. The biliary cholesterol level in treated mice increased to about 4 times higher than that in untreated mice, while the biliary phospholipids and total bile acids levels increased to only about 1.5 and about 2 times the control levels, respectively. The incidence of stone formation rose sharply at an experimental period between 2 and 3 weeks after starting the lithogenic diet. Gallstones die not disappear even at the 6th week after substituting a normal diet for the lithogenic one. However, the cholic acid-glycine conjugate disappeared, and deoxycholic acid as well as chenodeoxycholic acid and ursodeoxycholic acid tended to recover to the normal levels in the bile.     

Effects of successive doses of nizatidine, cimetidine and ranitidine on serum gastrin level and gastric acid secretion.

Nizatidine (N-[2-[[[2-[(dimethylamino)methyl]- 4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine , CAS 76963-41-2) is a new histamine H2-receptor antagonist which shows suppression of gastric acid secretion and antiulcer activity. In the present experiment, the effects of single s.c. administration of nizatidine, cimetidine and ranitidine on serum gastrin levels were studied in fasted rats. Nizatidine at 100 mg/kg increased serum gastrin level 3 h after administration, which however, returned to basal level 6 h after administration. Cimetidine and ranitidine at respective doses of 250 and 100 mg/kg markedly increased serum gastrin levels 3 and 6 h after administration. In a previous study, the suppressive effect of nizatidine on basal gastric acid secretion was 82.8% at a dose of 100 mg/kg s.c. in rat pylrus-ligated model. On the basis of these findings, changes in basal gastric acid secretion and serum gastrin level after withdrawal of nizatidine, cimetidine and ranitidine administered for 14 consecutive days were studied. One day after withdrawal, nizatidine at 100 mg/kg showed a tendency to increase the basal gastric acid secretion. However, 3 and 7 days after administration, almost no changes were obtained. Cimetidine at 250 mg/kg showed a tendency to increase the basal gastric acid secretion 7 days after withdrawal of the drug. Ranitidine at 100 mg/kg induced no changes in basal gastric acid secretion after withdrawal. No obvious influences of all drugs on serum gastrin level after withdrawals were obtained. These results indicate that consecutive administration of nizatidine may cause only a transient increase of gastric acid secretion but no hypergastrinaemia after its withdrawal.     

Lipopolysaccharide-induced inhibition of gastric acid and pepsin secretion in rats

We used male Wistar rats to determine the effects of lipopolysaccharide (LPS) on gastric secretion. After pylorus ligation, 24-h fasted rats received i.p. injections of different doses of LPS dissolved in sterile saline. The amounts of gastric acid and pepsin secreted were determined 2, 4 or 8 h after injection. Small doses of LPS (10-1000 ng/rat) significantly inhibited the release of both gastric secretants as compared with control animals, and this inhibitory effect of LPS on gastric secretion was dose-related. The gastric antisecretory effect of LPS was still evident 8 h after injection, indicating that this action of LPS was long-lasting. These results suggest that LPS might be involved in the regulation of gastric secretion under certain pathophysiological conditions such as acute bacterial infections.     

Effect of short-term omeprazole administration of serum pepsinogens in relation to fasting serum gastrin and gastric acid secretion

Summary A study has been done in 10 male healthy volunteers of the effect of oral omeprazole 20 mg daily for 3 days on the serum concentrations of Pepsinogens A and C in relation to changes in fasting serum gastrin and basal and pentagastrin stimulated gastric acid output.The concentrations of Pepsinogens A and C showed concomitant and variable but significant increases, and the Pepsinogen A, C ratio did not change during the 3-day course of omeprazole. The increments were also significantly correlated with the increase in fasting serum gastrin and with the reduction in pentagastrin stimulated acid output. The correlations were mainly due to the marked inhibition of gastric acid secretion and the corresponding increases in serum gastrin and Pepsinogens A and C in two subjects, as in the other 8 subjects the changes were only modest. There appears to be a relationship, therefore, between the degree of inhibition of acid by omeprazole and the parallel increases in both serum pepsinogens and fasting gastrin.     

Comparison of two antimuscarinic drugs, pirenzepine and propantheline, on gastric acid secretion, serum gastrin concentration, salivary flow and heart rate in patients with duodenal ulcer disease

Effects of orally-administered pirenzepine and propantheline bromide on food-stimulated gastric acid secretion, serum gastrin concentration, salivary flow and heart rate were compared in 10 duodenal ulcer patients in a placebo-controlled, double-blind study. Pirenzepine inhibited acid secretion by 25, 36 and 44% at doses of 50, 100, and 150 mg, respectively, while propantheline inhibited acid secretion by 32 and 41% at doses of 15 and 45 mg, respectively. None of the doses of pirenzepine affected food-stimulated serum gastrin concentrations, whereas 45 mg propantheline increased serum gastrin concentration significantly above placebo control. Enhancement of gastrin release by propantheline was not due to its antisecretory effect since intragastric pH after the meal was held constant at 5.0 by intragastric titration in vivo. Pirenzepine had no significant effect on heart rate and little or no inhibitory effect on salivary volume, depending on the dose administered. By contrast, both doses of propantheline increased heart rate and reduced salivary volume significantly (P less than 0.05). Thus, pirenzepine and propantheline in the doses administered inhibited acid secretion to approximately the same extent but pirenzepine had fewer effects on other organs.     

Effects of tissue cultured ginseng on gastric secretion and pepsin activity]

Effects of the tissue cultured and cultivated ginseng on gastric secretion and pepsin activity were investigated. Fifty percent ethanol extracts of both cultured and cultivated ginsengs reduced gastric secretion and acid output in pylorus-ligated rats. They did not affect pepsin activity. The tissue cultured ginseng inhibited histamine and pentagastrin-induced acid secretion in rats, whereas the cultivated ginseng showed no such effect. They also suppressed acid secretion induced by 2-deoxy-D-glucose and baclofen [beta-(p-chlorophenyl)-gamma-aminobutyric acid], which are known to stimulate gastric acid secretion via the central nervous system. However, they had no effect on acid secretion induced by vagal stimulation. These results suggest that both tissue cultured and cultivated ginsengs may have an inhibitory effect on gastric secretion. The effect seems to be due to the inhibition of acid secretion via the central nervous system.     

Effect of potassium chloride on gastric acid secretion and gastrin release in humans

The effect of potassium chloride on gastric acid secretion and gastrin release was studied in 6 healthy human beings. On 3 separate days and in random order, subjects received an intragastric infusion of 0.5 L of a glucose-saline solution to which had been added 40 mmol KCl, 40 mmol NaCl, or no additional salts. All test solutions stimulated acid secretion and gastrin release to a similar degree. While potassium ions play a critical role in acid secretion by parietal cells (via the H+, K(+)-ATPase), KCl administered into the gastric lumen at a concentration of 80 mmol/L has no effect on acid secretion in man.     

Effect of sulpiride isomers on gastric acid and gastrin secretion in healthy man

The effects of the antidopaminergic drug sulpiride on gastric acid secretion and gastrin release have been evaluated in 42 healthy individuals. Basal and submaximal pentagastrin (0.5 micrograms/kg-h)-stimulated gastric acid secretion, as well as basal and meal-induced gastrin secretion, were studied after acute intramuscular administration of racemic sulpiride (100 mg) and its L-(50 mg) D-(50 mg) isomers. Racemic and L-sulpiride significantly decreased stimulated serum gastrin concentration, but they did not affect fasting serum gastrin or basal and stimulated gastric acidity. D-sulpiride significantly decreased gastric acid secretion, without affecting serum gastrin levels. While the effects of racemic and L-sulpiride are analogous to those of other antidopaminergic drugs, D-sulpiride mimics the action of dopamine, at least at gastric level. These data support the hypothesis that the D-isomer may possess agonist-antagonist activity at dopamine receptors. Since racemic sulpiride has been used with conflicting results in the therapy of patients with peptic ulcer, in the light of the present results it would be of interest to study separately the efficiency of the D- and L-isomers of the drug in healing peptic ulcer.     

Effect of nifedipine on gastric acid secretion and gastrin release in healthy man

Summary Nifedipine, a calcium-channel antagonist widely used in cardiovascular disease, has recently been reported to be effective in the treatment of oesophageal motor disorders. The effect of a single therapeutic dose of nifedipine (20 mg p.o.) has been evaluated on basal and submaximal pentagastrin-stimulated gastric secretion and meal-stimulated gastrin release in healthy man. In comparison with placebo, nifedipine significantly decreased both basal and stimulated gastric acidity and juice volume, whereas only a slight but insignificant reduction in meal-stimulated gastrin levels was observed after drug administration. The results are in agreement with previous reports that calcium is involved in stimulus-secretion coupling in the human parietal cell. They do not confirm the effect of calcium on G-cells, although it is likely that doses of nifedipine higher than those commonly used might be effective in the reduction of gastrin secretion.     

Hepatic uptake and biliary secretion of bile acids in the perfused rat liver.

Hepatic uptake and biliary secretion have been evaluated in the isolated perfused rat liver for cholic, chenodeoxycholic, ursodeoxycholic acid, both free and taurine-conjugated; the physicochemical properties of the bile acids have also been calculated and related to these experimental parameters. Cholic acid disappearance rate from the perfusate was the fastest, followed by that of ursodeoxycholic and chenodeoxycholic; it was also faster for taurine-conjugated bile acids than for their respective unconjugated forms. The recovery in bile was higher for conjugated than for unconjugated bile acids, and among each class, was higher for cholic than for chenodeoxycholic and ursodeoxycholic. The hepatic uptake correlated negatively (r = -0.99) with the bile acid lipophilicity, while the biliary secretion correlated with the solubility of the molecules. These results show the effect of the physicochemical properties of BA on their hepatic handling, at the physiological concentration of BA in the portal blood.     

Effect of high dose omeprazole on gastric pepsin secretion and serum pepsinogen levels in man

Summary To investigate the effect of omeprazole on serum and urinary pepsinogens and on gastric pepsin, 8 healthy male volunteers were studied before and after 9 days of treatment with omeprazole 60 mg/day p.o. Fasting serum samples and 24 h urine specimens were obtained, and gastric contents were aspirated at 15-min intervals, 4 prior to and 6 during pentagastrin 1.5 µg·kg^–1·h^–1 i.v. during intra-gastric perfusion with NaCl 0.9% and phenol red 3 mg·ml^–1 as an inert recovery marker.Basal and pentagastrin-stimulated volume and acid secretion were significantly decreased. The basal and pentagastrin stimulated pepsin output remained unchanged but pepsin concentration in gastric secretion was increased. Administration of omeprazole resulted in a significant increase in the serum PGA and PGC levels. The 24-h urinary excretion of PGA increased, but that of PGC remained unchanged, and so did the renal clearances of creatinine and pepsinogen A. The renal clearance of pepsinogen C decreased.It was concluded that omeprazole did not affect gastric pepsin output, but, due to the decreased volume output, the concentration of pepsin in the gastric secretion was increased. Omeprazole increased the serum levels of pepsinogen A and C because more pepsinogen was released into the systemic circulation. This might be due to greater back-diffusion of pepsinogen from the gastric mucosa into the systemic circulation as a result of the higher pepsinogen concentration in gastric secretion.     

熊去氧胆酸联合中药对胆囊结石家兔模型保胆取石术后胆汁酸 、胆固醇合成代谢的影响

目的 研究保胆取石术术后应用熊去氧胆酸联合中药对胆囊结石家兔模型术后胆汁酸、胆固醇合成代谢的影响.方法 选择雄性新西兰家兔60只为研究对象,建立胆囊结石模型后进行内镜下保胆取石术,根据术后处理方式不同分为3组,对照组给予普通饮食,模型组给予致石饮食,干预组给予致石饮食+熊去氧胆酸联合中药.检测3组家兔血清中胆固醇(TC)、总胆汁酸(TBA)、总胆红素(TBIL)含量以及胆固醇7-羟化酶(CYP7A1)和胆汁酸盐输出泵(BSEP)运输因子acbc11 mRNA含量.结果 干预后3周、5周时,模型组家兔血清中TC、TBIL含量高于对照组,TBA含量均低于对照组(t=3.571~24.374,P<0.05);干预组家兔血清中胆固醇TC、TBIL含量低于对照组,TBA含量均高于模型组(t=2.438~18.230,P<0.05);模型组家兔胆囊组织中CYP7A1和acbc11的mRNA含量低于对照组(t=11.369~20.096,P<0.05),干预组家兔胆囊组织中CYP7A1和acbc11的mRNA含量高于模型组(t=5.923~16.049,P<0.05).结论 熊去氧胆酸联合中药有助于修复受损胆固醇7-羟化酶和胆汁酸盐输出泵运输因子acbc11基因表达,调节胆汁酸、胆固醇、胆红素的代谢水平,预防保胆取石术后结石复发.     

Effect of alpha 2-adrenoceptor agonists on gastric pepsin and acid secretion in the rat.

1. The purpose of the present study was to analyze the effects of the alpha 2-adrenoceptor agonists clonidine, guanabenz, detomidine and medetomidine on pepsin secretion in conscious rats provided with gastric chronic fistula and to compare this with acid secretion. 2. Basal interdigestive gastric secretion, which is mainly neurally driven in the rat, and the secretion directly stimulated by the two main stimulants of chief cells, cholecystokinin octapeptide (CCK8) and methacholine, were studied. 3. Basal secretion of pepsin and acid was inhibited by all four drugs with comparable EC50S. 4. CCK-stimulated pepsin and acid secretion was less sensitive than basal pepsin and acid secretion to alpha 2-adrenoceptor inhibition. 5. Methacholine-stimulated pepsin and acid secretion was not changed by clonidine and guanabenz; methacholine-stimulated acid was even marginally increased by clonidine. 6. These results do not favour the presence of alpha 2-receptors on chief cells in the rat stomach. They rather suggest that pepsin inhibition by alpha 2-adrenoceptor agonists is indirect and due to central or peripheral inhibition of the discharge of nerve fibres activating pepsin secretion.     

The effects of 3,5,5-trimethylcyclohexanol on hepatic cholesterol synthesis, bile flow and biliary lipid secretion in the rat.

The chemical trimethylcyclohexanol (TMC) is closely related to menthol, the major component of a terpene preparation with known choleretic and cholelitholytic activity. Its effects on hepatic cholesterol synthesis and bile secretion were examined in the rat. In both acute and long-term dosing experiments TMC significantly inhibited hepatic S-3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase. TMC was a potent choleretic, with detectable effects on bile flow at low doses, which also reduced coupling of cholesterol secretion to bile salt secretion. Single large doses tended to lower biliary cholesterol output and caused significant reduction in cholesterol saturation index after biliary diversion for 1 h. TMC and its widely prescribed ester cyclandelate, which is rapidly degraded to TMC after ingestion, should be investigated further as potential cholelitholytic treatments in man.     

Quantitative relationship between bile acid structure and biliary lipid secretion in rats

A series of unconjugated and taurine conjugated bile acids (BAs) differing in water solubility (SWo), critical micellar concentration (CMC), and hydrophilicity (K') were infused iv to rats at a tracer dose and a dose of 6 mumol/min/kg over a 1-h period. Bile was collected for 3 h to evaluate the role of BA structure on cholesterol, phospholipids secretions, and bile flow. The BAs studied differ in the number (2-3), position (-3, -6, -7, -12), and orientation of the hydroxyls (alpha/beta); the side chain structure was modified by shortening (C-23, nor-BA) and by lengthening (C-25, homo-BA), while maintaining the same structure of nuclear hydroxyls (3 alpha 7 beta). At a "tracer" dose, all C-24 natural BAs are efficiently recovered in bile when administered in both unconjugated and taurine conjugated forms. At a "high dose", all taurine conjugated BAs are efficiently recovered in bile (80-100%). However, a variable recovery was observed among unconjugated BAs: trihydroxy BAs are efficiently recovered (85-100%), while dihydroxy BAs are only partially recovered (25-40%). The side chain-modified BAs [i.e., C-23 nor and C-25 homo analogs of ursodeoxycholic acid (UDCA)] are partially recovered at a tracer dose (20-30%), but less at a high dose (10-20%) when administered in the unconjugated form. In contrast, the corresponding taurine conjugates are more efficiently recovered in bile (60-80%). Conjugation with taurine increases total recovery of unconjugated BAs in bile by not more than 30-40%. Highly hydrophilic and water-soluble BAs, such as ursocholic acid (SWo = 1.67 mM) and cholic acid (SWo = 0.27 mM), can also be secreted as unconjugates, and this accounts for their complete recovery. The conjugation step is rate limiting for poorly soluble BAs such as ursodeoxycholic acid (SWo = 0.009 mM) when administered at a high dose, and critical for nor and homo analogs which are poorly soluble and whose side chain modification partially suppresses their conjugation with taurine or glycine and thereby induces alternative pathways such as glucuronidation or sulfation. The induced bile flow is directly related to the hydrophilicity of the natural C-24 bile acid.(ABSTRACT TRUNCATED AT 400 WORDS)