Effect of intravenous infusion of amino acids on pancreatic secretion

BACKGROUND/AIMS: The effect of intravenous administration of amino acids on exocrine pancreatic secretion is controversial. Since amino acids are used in parenteral nutrition of patients with acute pancreatitis or other pancreatic diseases, it seemed useful to establish whether or not they affect pancreatic secretion. METHODOLOGY: Four patients having an external transduodenal drainage of the main pancreatic duct performed after sphincteroplasty for common bile duct stones were studied. Two of them had undergone a Billroth II gastrectomy in the past. Pancreatic secretion was stimulated with low doses of secretin (0.1 CU/kg/h) and cerulein (10 ng/kg/h); after 75 min of stimulation, when pancreatic secretion was stable, a solution of L-amino acids (Freamine III 8.5%) was infused intravenously at a rate of 150 mL/h, for two hours. The volume of pancreatic secretion, bicarbonate and total protein was measured. RESULTS: The infusion of amino acids did not cause significant changes in pancreatic secretion. However, considering the results individually, they caused a clear increase of pancreatic secretion, mainly of bicarbonates (mean increase of 36%) in the two subjects who had not undergone previous surgical procedures and no increase in the two who had had a Billroth II gastrectomy. CONCLUSIONS: The results suggest that intravenous administration of amino acids stimulates exocrine pancreatic secretion in normal subjects but not in those who underwent previous gastrectomy. This stimulatory effect could be mediated by stimulation of gastric acid. This effect should be taken into consideration when amino acids are used in patients with acute pancreatitis or other pancreatic disorders.     

Metabolism of 131I-labelled human pancreatic cationic trypsin after intraduodenal administration

Human pancreatic cationic trypsin labelled with 131I was administered into the duodenum in 9 healthy individuals. Five had earlier been proctocolectomized and had ileostomies. Radioactivity was measured in plasma, urine, ileostomy content and feces for a period of 72 h. Radioactivity was present in plasma 15 min after administration. The total recovery of radioactivity was 78-98%, the largest amount being observed in urine during the first 24-hour period. About 20% of the administered radioactive dose was recovered in ileostomy content and 10% in feces. The recovered radioactivity in plasma, urine and extracts of ileostomy content and feces was characterized with dialysis and gel filtration. All radioactivity in plasma and urine corresponded to free 131I, whereas in the extracts radioactivity corresponding to intact enzyme and degradation products as well as a small amount of free 131I was observed. It is concluded that pancreatic trypsin is degraded during intestinal passage as with other proteins. Due to a deiodinating mechanism in the intestine, only free 131I is absorbed into the circulation. This deiodination does not take place in duodenal juice. The absence of high molecular weight radioactivity in plasma argues against an enteropancreatic circulation.     

Neural reflex of the canine pylorus to intraduodenal acid infusion

In 29 chloralose-urethane anesthetized dogs, a manometric assembly was inserted through a gastrostomy to monitor pressure of the pyloric region with a sleeve sensor. Antral and duodenal contractions were monitored with both manometric sideholes and serosal strain gauges. An additional tube channel allowed intraduodenal infusions 1-2 cm aborad from the pylorus. Intraluminal infusion of hydrochloric acid (0.1 N, 0.92 ml/min, for 2 min) reproducibly caused activation of motor activity in the pyloric region and peristaltic duodenal activity. Proximal duodenal activity probably contributed to the total phasic response recorded in the pylorus region. Excitatory responses could also be elicited by infusion of phenyl-biguanide (stimulant of sensory nerve endings), but not by control infusions with diluent (Krebs' buffer or saline). The motor response of the pyloric region to intraduodenal acid was blocked by intraduodenal application of 2% xylocaine. Atropine (30 micrograms/kg i.v. and 100 micrograms i.a.) or hexamethonium (10 mg/kg and 1 mg i.a.) markedly reduced or blocked the acid-induced pyloric motor response of this region but propranolol (1.0 mg/kg i.v. and 100 micrograms i.a.), phentolamine (1.5 mg/kg i.v. and 100 micrograms i.a.), or naloxone (200 micrograms/kg and 20 micrograms i.a.) had no effect. We believe these observations show the existence of a reflex from the duodenum to the pylorus in response to intraluminal stimuli mediated by a chain of cholinergic nerves. In the dog, endogenous opioid peptides do not contribute to the excitatory reflex pathway activated by intraduodenal acid or phenyl-biguanide. As intraluminal acid in the duodenum activates this reflex, it may play a role in the physiologic and pathophysiologic role of gastric emptying in this species.     

Sidechain torsional potentials and motion of amino acids in porteins: bovine pancreatic trypsin inhibitor.

Conformational potentials of sidechains in the bovine pancreatic trypsin inhibitor have been studied with an empirical energy function. Calculated minimumenergy positions are in excellent agreement with the x-ray structure for sidechains in the core or at the surface of the protein; as expected, angles for sidechains that are directed out into the solvent do not agree with the calculated values. The contributions to the potentials are analyzed and compared with the potentials for the free amino acid. Although there is a large restriction in the available conformational space due to nonbonded interactions, the minimum energy positions in the protein are close to those of the free amino acid; the significance of this result is discussed. To estimate the effective barriers for rotation of the aromatic rings (tyrosine and phenylalanine), calculations are done in which the protein is permitted to relax as a function of the ring orientation. Thr resulting barriers, which are much lowere than the rigid rotation barriers, are used to evaluate the rotation rates; comparison is made with the available nuclear magnetic resonance data.     

Bile acids in bile during long-term chenodeoxycholic acid treatment.

Relative concentrations of conjugated and sulfated bile acids in duodenal bile were measured in 5 patients before and during treatment with 0.50-0.75 g of chenodeoxycholic acid per day for 3-4 months. Lithocholic acid constituted 0.8-3.3% (mean 1.8%) of total conjugated and sulfated bile acids before and 0-5.4% (mean 2.6%) during treatment. Lithocholic acid was the predominant bile acid in the sulfate fraction in three patients and chenodeoxycholic acid in two. Sulfated bile acids constituted less than 1% of total bile acids and did not increase during treatment. Ursodeoxycholic acid, the other major metabolite of chenodeoxycholic acid, was found in higher amounts during therapy. The unsaturated bile acid 3beta-hydroxy-delta5-cholenic acid, which was found exclusively as its sulfate ester, showed a slight fall. The average G/T conjugation ratio rose from 2.2 to 4.5.     

Serum amino acids in hepatic encephalopathy--effects of branched chain amino acid infusion on serum aminogram

Encephalopathic patients with cirrhosis of the liver consistently showed elevated levels of the aromatic amino acids, phenylalanine, tyrosine and free tryptophan as well as methionine in serum, whereas levels of the branched chain amino acids, valine, leucine and isoleucine, were depressed. Comatose patients with fulminant hepatitis had markedly elevated levels of all amino acids, the results being greatly different from those of cirrhotic patients. Molar ratios of (valine + leucine + isoleucine)/(phenylalanine + tyrosine) decreased both in cirrhotics with and without encephalopathy and in cases with fulminant hepatitis. Infusion of a commercially available L-amino acid solution in a cirrhotic patient induced a strikingly abnormal aminogram documented in hepatic encephalopathy. Therefore, effects of branched chain amino acid infusion on the deranged amino acid pattern were primarily studied for the purpose of improvement in hepatic encephalopathy by normalization of serum amino acid patterns. Elevated levels of the aromatic amino acids and methionine could be apparently depressed in a cirrhotic patient by this type of infusion but not in a case of fulminant hepatitis probably because of the poor utilization of these amino acids in severely impaired liver.     

Regulatory effects on the pancreas of intraduodenal pancreatic juice and trypsin in the Syrian golden hamster

The effect of intraduodenal trypsin activity on pancreatic exocrine secretion was studied in conscious Syrian golden hamsters provided with bile-pancreatic fistulae. The secretion (secretory volume, amylase and protein output) was stable during a collection period of 14 h without any duodenal infusions. Infusion into the duodenum of bicarbonate or bile did not affect the secretion. When, however, bile-pancreatic juice or trypsin was administered intraduodenally, a marked depression of amylase and protein output was found. After addition of trypsin inhibitor--in a dose sufficient to eliminate all trypsin activity--to either of the two infusates the secretion was restored to the initial values. In a long-term experiment (10 days) repeated subcutaneous injections of cholecystokinin caused a significant increase of pancreatic protein and amylase content in the hamster. Oral trypsin inhibitor administration for 10 days had similar, although not so pronounced effects. Subcutaneous secretin administration was without effect in this respect. The results show that pancreatic enzyme secretion in the Syrian golden hamster is controlled by a negative feedback regulation exerted by intraluminal trypsin. The findings also suggest that both cholecystokinin and orally administered trypsin inhibitor exert trophic effects on the pancreas.     

十二指肠灌注生大黄对SD大鼠胰腺外分泌的影响

目的:观察十二指肠灌注生大黄对SD大鼠胰腺外分泌的影响.方法:取体质量250-300 g SD大鼠24只,随机分为2组白=12).麻醉后在大鼠幽门下5 mm和十二指肠、空肠交界处分别置直径2 mm的塑料管并固定;从十二指肠乳头Oddi括约肌处留置直径0.7 mm的塑料留置管.稳定30min后,每隔15 min收集1次胆胰混合液,测定体积后留取100 μL胆胰混合液用双蒸水稀释以测定蛋白质含量,剩余的胆胰混合液在下一收集时间内灌入十二指肠.收集5管基础状态胆胰混合液后实验组以3 mL/h的速度向十二指肠内灌注生大黄2 h,并收集8管胆胰混合液进行体积和蛋白质测定.对照组不进行十二指肠灌注.结果:十二指肠灌注生大黄后胆胰混合液体积较基础状态增加30.95%,与对照组比较,差别有统计学意义(P＜0.01);蛋白质分泌量较基础状态增加5.02%,但与对照组比较,其差别无统计学意义(P＞0.05).结论:对大鼠进行十二指肠灌注生大黄后单位时间内胆胰混合液分泌的体积增加,但蛋白质分泌量无明显增加.     

Effect of CCK-OP and intraduodenal administration of essential amino acids on intraluminal pressures of sigmoid and rectum in patients with Chagasic megacolon

The motility of the sigmoid colon and rectum was studied by manometry in patients with Chagasic megacolon and in control individuals using two different experimental procedures: (1) intravenous infusion of saline, followed by intravenous infusion of cholecystokinin octapeptide (OP-CCK) at the dose of 20 ng/kg/hr; and (2) intraduodenal instillation of saline followed by a solution of essential amino acids at a flow of 10 ml/min. CCK-OP induced an increase in motility index in the sigmoid colon (P less than 0.05) and rectum (P less than 0.05) in the controls, whereas intraduodenal infusion of amino acids produced a significant increase in motility index exclusively in the sigmoid colon (P less than 0.005). A significant increase (P less than 0.05) in sigmoid colon motility also occurred in the control group after duodenal saline infusion was interrupted. The release of other substances in addition to CCK must have been responsible for the different behavior of sigmoid colon and rectum in response to the stimuli used. Neither procedure caused significant changes in the motility of the sigmoid colon or the rectum of the Chagasic patients. The extensive intramural denervation occurring in Chagasic megacolon probably destroys the neural pathway through which OP-CCK and the substances released by the duodenum by the infusion of essential amino acids activate the motor cells of the human terminal intestine.     

Effect of intravenous omeprazole on intragastric pH during intravenous infusion of amino acids

Intravenous amino acids stimulate gastric acid secretion by an unknown mechanism. In patients on parenteral nutrition, this amino acid-induced gastric acid secretion might contribute to the failure of H₂-receptor antagonists to raise intragastric pH above 4.0, a level thought to be needed to prevent stress ulceration. Therefore we studied the effect of single and repeated doses of the H⁺/K⁺-ATPase blocker omeprazole on the intragastric pH during a 3-hr infusion of amino acids in 10 healthy volunteers; 5% glucose was used as a control infusion. Amino acids significantly decreased intragastric pH when compared to glucose infusion (P <0.05). After intravenous administration of 40 mg, 80 mg and 2 × 40 mg omeprazole, this amino acid-induced fall in pH was significantly inhibited (P < 0.01). No advantage of the 80-mg dose over the 40-mg dose could be demonstrated. The repeated dose of 40 mg showed a tendency to higher pH values compared to the single-dose experiments, which reached significance in the amino acid experiments only (P <0.05). Neither during the infusion of amino acids nor the glucose infusion omeprazole was able to continuously raise intragastric pH above 4.0. In conclusion, this study shows that intravenous omeprazole prevents gastric acid stimulation by intravenous amino acids but fails to continuously raise intragastric pH above 4.     

Physiological control of cholecystokinin release and pancreatic enzyme secretion by intraduodenal bile acids.

BACKGROUND: The physiological relevance of duodenal bile acids in the control of cholecystokinin release and pancreatic enzyme secretion is still unknown. AIMS: To provide a near physiological situation by perfusing a bile acid mixture mimicking the individual endogenous bile acid composition of the person under investigation. For maximal reduction of endogenous bile output the CCK-A receptor antagonist loxiglumide was infused intravenously. SUBJECTS AND METHODS: Seven healthy volunteers were studied on four different days by a duodenal marker perfusion technique. The individual bile acid composition in duodenal juice and test meal stimulated bile acid output was assessed on day 1. Bile acids were perfused at an amount of 30 or 100% as determined on day 1 in combination with the test meal in the presence or absence of loxiglumide. Pancreatic enzymes, bilirubin, and bile acid output were determined in duodenal juice. Plasma cholecystokinin (CCK) and plasma pancreatic polypeptide (PP) were measured radioimmunologically. RESULTS: Bile acid perfusion did not significantly alter stimulated pancreatic enzyme, bilirubin or bile acid output or plasma CCK. Loxiglumide did not alter basal CCK release but increased test meal stimulated CCK output fourfold (p < 0.05). The addition of bile acids to the test meal at a dose resembling 30% of bile acid output as determined on day 1 prevented this increase. Plasma PP concentration remained unchanged by bile acids and were mostly undetectable during loxiglumide infusion. CONCLUSIONS: The CCK producing cell is under constant suppression by intraduodenal bile acids which cannot be further enhanced by a physiological bile acid mixture. However, removal of duodenal bile acids by inhibition of gall bladder contraction unmasks this suppression leading to a dramatic increase in plasma CCK levels. As little as one third of postprandially released bile acids completely reverse this effect. Bile acids are the most important luminal regulator of CCK release in humans.     

Selective release of gastric inhibitory polypeptide by intraduodenal amino acid perfusion in man

Intraduodenal amino acids are known to stimulate the release of gastric inhibitory polypeptide and cholecystokinin. In order to separate and quantitate gastric inhibitory polypeptide secretion selectively, 12 normal subjects received an intraduodenal perfusion of a mixed amino acid solution (158 mM) containing either methionine, phenylalanine, tryptophan, and valine (perfusate 1), or an amino acid solution containing arginine, histidine, isoleucine, leucine, lysine, and threonine (perfusate 2). Serum concentrations of gastric inhibitory polypeptide and insulin were significantly greater in the group receiving perfusate 2 (P less than 0.001). In contrast, after administration of amino acid perfusate 1, there was only a slight increase in serum gastric inhibitory polypeptide concentration and insulin secretion increased only slightly. Mean trypsin and bilirubin outputs in the group receiving perfusate 1 were nearly 3 times greater than the outputs of the group receiving the other amino acid mixture. This study expands the importance of intraduodenal amino acid mixtures in stimulating secretion of gastric inhibitory polypeptide and insulin and quantitatively separates gastric inhibitory polypeptide release from release of hormones that stimulate pancreatic enzyme secretion, such as cholecystokinin.     

Only two amino acids are essential for cytolytic toxin recognition of cholesterol at the membrane surface

The recognition and binding of cholesterol is an important feature of many eukaryotic, viral, and prokaryotic proteins, but the molecular details of such interactions are understood only for a few proteins. The pore-forming cholesterol-dependent cytolysins (CDCs) contribute to the pathogenic mechanisms of a large number of Gram-positive bacteria. Cholesterol dependence of the CDC mechanism is a hallmark of these toxins, yet the identity of the CDC cholesterol recognition motif has remained elusive. A detailed analysis of membrane interactive structures at the tip of perfringolysin O (PFO) domain 4 reveals that a threonine-leucine pair mediates CDC recognition of and binding to membrane cholesterol. This motif is conserved in all known CDCs and conservative changes in its sequence or order are not well tolerated. Thus, the Thr-Leu pair constitutes a common structural basis for mediating CDC-cholesterol recognition and binding, and defines a unique paradigm for membrane cholesterol recognition by surface-binding proteins.     

Effect of atropine on responses of exocrine pancreas and plasma cholecystokinin to intraduodenal amino acids in dogs

The effect of atropine on responses of exocrine pancreas and plasma cholecystokinin (CCK) to intraduodenal mixed amino acids has been studied in conscious dogs with Thomas gastric and duodenal fistulae. Intraduodenal amino acids provoked significant increase of pancreatic protein output and of plasma CCK concentration. Atropine significantly reduced protein output only in the initial peak after amino acid administration. Atropine had no significant effect on plasma CCK. It is indicated that cholinergic nerves predominate in the early pancreatic protein response to intraduodenal amino acids and CCK prevails in the later phase, though these two factors do not seem to be the only factors responsible for the secretion.     

Decrease of plasma sulfur amino acids in essential hypertension

In order to evaluate the correlation between sulfur amino acids (derived mainly form animal protein in the diet) and blood pressure, free amino acids, including sulfur amino acids such as taurine and methionine, were determined in the plasma and cerebrospinal fluid (CSF) of twelve normotensive subjects and twelve patients with essential hypertension under nutritional control after at least 10 days of standard hospital diet (total calorie and protein content: 2100-2300 Cal per day and 78-83 g per day, respectively). The results obtained were as follows: plasma taurine, serine, methionine and threonine were significantly lower in patients with essential hypertension than in normotensive patients. The levels of plasma taurine, serine, methionine and total sulfur amino acids in individuals correlated inversely to systolic blood pressure. No difference was observed in the CSF levels of free amino acids in normotensive and hypertensive patients. As taurine, methionine and serine are involved in the metabolism of sulfur amino acids, these observations support the view that the decrease in plasma sulfur amino acids may be a factor contributing to elevated blood pressure.