Jorge E. Valenzuela

Dopamine as A Possible Neurotransmitter in Gastric Relaxation

In dogs with gastric fistulas, intragastric pressure was measured with a flaccid ballon containing 500 ml of water. Graded doses of dopamine caused graded decreases in intragastric pressure. The effect was blocked by pimozide or by metoclopramide but was not significantly affected by phenoxybenzamine, propranolol, guanethidine, or FLA-63 (a beta-hydroxylase inhibitor). Pretreatment with metoclopramide or with pimozide shifted the volume-pressure diagram of the stomach to the left; that is, at any given volume the pressure was greater after than before these drugs. In dogs with vagally innervated gastric pouches and gastric fistulas, feeding for 1 min (while allowing the food to leave the stomach through the gastric fistula) caused a prompt decrease in pressure in the pouch that lasted for about 5 min. Pretreatment with metoclopramide decreased the magnitude and duration of this receptive relaxation. It is concluded that these findings are consistent with (but do not establish) the hypothesis that dopamine is the neurotransmitter for receptive relaxation of the stomach, because dopamine mimics receptive relaxation, and dopamine antagonists partially block reflexly induced receptive relaxation.

Double-contrast barium meal and upper gastrointestinal endoscopy. A comparative study.

One hundred randomly selected inpatients were examined with both double-contrast barium meal and endoscopy in a blinded prospective fashion. All studies were done by staff personnel, with equal clinical information available to both the radiologist and endoscopist. The final diagnosis was made by a review committee of participating radiologists and endoscopists. Endoscopy was more sensitive (92% versus 54%, p less than 0.001) and specific (100% versus 91%, p less than 0.05) than the double-contrast barium meal. Both procedures significantly affected the clinical outcome of the patient, the effect of endoscopy being significantly greater than that of the double-contrast barium meal. Although errors with the barium study related predominantly to an inability to show subtle lesions, poor patient cooperation and perceptual and technical failures were additional significant factors. Endoscopy is recommended for certain groups of patients.

Cholecystokinin-Octapeptidelike Immunoreactivity in Human Plasma

A method for concentration and measurement of cholecystokininlike immunoreactivity in human plasma was developed and used to measure and to characterize the circulating forms of this hormone. Immunoreactive cholecystokinin was concentrated from 20–50-ml volumes of plasma by affinity chromatography and characterized by gel filtration and by radioimmunoassay with two antibodies that differed markedly in specificity for cholecystokinin and gastrin. About two-thirds of immunoreactive cholecystokinin eluted from G50 superfine columns in the same region as synthetic cholecystokinin-octapeptide and the remainder eluted between 33-peptide cholecystokinin and minigastrin. Measurable cholecystokininlike immunoreactivity was below the detection limit of 0.2 pmol/L in most fasting subjects, but 45 min after ingestion of a mixed meal mean plasma cholecystokinin-octapeptidelike immunoreactivity was increased significantly in normal subjects to 1.1 pmol/L and in patients with previous Billroth I gastrectomy and vagotomy to 2.9 pmol/L. Significantly higher mean plasma cholecystokinin-octapeptidelike immunoreactivity values (6.2 pmol/L) were found in normal subjects immediately after duodenal perfusion with 10.5 mmol sodium oleate for 30 min. In the same subjects, exogenous cholecystokinin-octapeptide was administered intravenously at three doses along with a low dose of secretion, 41 pmol·kg−1·h−1. Threshhold stimulation of pancreatic enzyme secretion was found when circulating cholecystokinin-octapeptide concentrations were 4–5 pmol/L and approximately half-maximal responses were found with cholecystokinin-octapeptide concentrations of about 10 pmol/L. Increases in plasma cholecystokinin-octapeptidelike immunoreactivity after duodenal fat were sufficient to account for substantial stimulation of pancreatic enzyme secretion but cholecystokinin-octapeptidelike immunoreactivity concentrations after ingestion of a meal were below the threshold for stimulation by exogenous cholecystokinin-octapeptide. It is likely that low concentrations of cholecystokinin peptides in the circulation interact with other factors such as enteropancreatic reflexes to produce normal postprandial stimulation of pancreatic enzyme secretion.

Urinary trypsinogen activation peptide (TAP) predicts severity in patients with acute pancreatitis.

SummaryConclusionsUrinary TAP obtained within the first 48 h of the onset of symptoms can distinguish patients with severe acute pancreatitis.BackgroundUrinary trypsinogen activation peptide (TAP) has recently been described as an early marker of severity in acute pancreatitis.MethodsIn a multicenter study, urine samples were collected for TAP concentration at 6–12, 24, and 48 h after admission from 139 patients with acute pancreatitis (99 with mild disease, 40 with severe disease) and from 50 control patients. Severity of acute pancreatitis was defined by the presence of organ failure and/or pancreatic necrosis on dynamic contrast-enhanced computed tomography.ResultsMedian urinary TAP in the 139 patients with acute pancreatitis compared to the 50 control patients was significantly higher at admission, 4.6 vs 0.8 ng/mL (p<0.001), and 6–12 h, 1.9 vs 0.55 ng/mL (p=0.04). Among patients who presented within 48h of the onset of symptoms, the median urinary TAP for severe pancreatitis (9 patients) compared to mild pancreatitis (40 patients) was significantly higher at admission, 29.6 vs. 3.6 ng/mL (p=0.001). Also, when obtained within 48h of the onset of symptoms, all patients with severe pancreatitis had an admission urinary TAP level>10 ng/mL. The sensitivity and specificity of an admission urinary TAP≥10 for severe pancreatitis was 100 and 85%, respectively. Given a cutoff of 10 ng/mL for an admission urinary TAP obtained within 48h of the onset of symptoms, the negative predictive value was 100% for mild pancreatitis.

Variability of migrating motor complex in humans

Fasting gastrointestinal motility in the human is characterized by the regular cycling activity of the migrating motor complex (MMC). Our purpose was to define the variability of the MMC within and between a group of six healthy subjects studied for 6–9 hr over six separate days with a perfused catheter system. A total of 88 phase III events was observed during 255 hr of recording in this group. The mean MMC cycling time varied significantly between subjects (range 113–230 min,P<0.001), and variation within subjects also was wide (sd range 58–70 min). Seventy-one percent of phase III events commenced in the gastric antrum, 18% in the proximal duodenum, 10% in the distal duodenum, and 1% in the proximal jejunum. For each subject, the velocity of propagation of phase III decreased significantly (P<0.001), and phase III duration increased significantly (P<0.001), with increasing distance from the os. In the antrum, phase I was predominant, and significant (P<0.006) variation between subjects was noted for percentage of MMC cycle occupied by phase I (overall mean ±sd 55±23%). Phase II was predominant in both duodenum and jejunum (mean range 70–80%), and no significant variation was noted between subjects for percentage of MMC occupied by phase II. We conclude that human MMC activity varies widely between individuals and within the same individual when studied on separate days.

Studies of Pure Pancreatic Secretions in Chronic Alcoholic Subjects without Pancreatic Insufficiency

To determine the role alcohol might play in altering pancreatic function, we have examined pure pancreatic juice, obtained by endoscopic cannulation of the pancreatic duct, from a group of 10 chronic alcoholic subjects without history or clinical or laboratory evidence of pancreatic disease and compared the results with those obtained from 15 healthy, non-alcoholic subjects. These findings confirm observations in experimental animals made by others and support the hypothesis that chronic alcohol abuse may damage the pancreas via a sequence of events involving protein hypersecretion. Increase in concentration was not uniform for all proteins measured. Unexpectedly, chronic alcoholics exhibited a highly significant elevation (two- to three-fold over normal) in trypsinogen, in contrast to statistically insignificant increases of other zymogens and trypsin inhibitor. The strikingly increased ratio of trypsinogen to trypsin inhibitor observed in all our alcoholic patients may indicate a weakening of the defence mechanism provided by the trypsin inhibitor against premature intraductal activation of zymogens and explain the predisposition of these patients to pancreatitis.

Esophageal dysfunction in patients with mixed connective tissue diseases and systemic lupus erythematosus.

We sought to correlate esophageal symptoins with esophaged motility abnormality in 17 patients with mixed connective tissue disease (MCTD) and in 14 patients with systemic lupus erythematosus (SLE). Heartburn and regurgitation were common symptoms (11/17) in patients with MCTD, and most of them (10/11) exhibited significant manometric abnormalities. Additionally, impairment of esophageal peristalsis was found in four of the remaining asymptomatic patiens. Severe esophageal aperistalsis was noted in nine MCTD patients. Patients with SLE also frequently reported esophageal symptoms (8/14), but significant motility abnormalities were seen in only three cases. In both patient groups good correlation between Raynauds phenomenon and esophageal aperistalsis was found. Our results reveal that, although esophageal symptoms are commonly present in patients with both MCTD and SLE, severe esophageal motility abnormalities are more often found in patients with MCTD than in those with SLE.

Abnormalities of the Migrating Motor Complex in Diabetics with Autonomic Neuropathy and Diarrhea

Diarrhea is a common symptom in long-standing diabetes. The pathogenesis of this diarrhea remains obscure, although it appears to be related to the development of autonomic neuropathy, which may cause several abnormalities including altered gut motility. We studied fasting gastrointestinal motility for a mean of 210 min in a group of 12 type-II diabetics with diarrhea. All patients had peripheral neuropathy and symptoms of autonomic neuropathy. Their motor activity was compared with that of a group of six normal volunteers. In addition, gastrointestinal transit time was assessed by the hydrogen breath test. The presence of bacterial overgrowth was assessed by the hydrogen breath test and culture of jejunal secretions. The diabetics showed grossly disordered motor activity. There was a complete absence of phase-III activity in two patients. Most phase IIIs commenced in the distal duodenum or jejunum. The phase-III component was often of short duration at each recording site. There was increased velocity of propagation between sites. Continuous phase-II activity was noted in some patients. Antral activity was absent or reduced during phase II. Gastrointestinal transit time was significantly prolonged in the diabetics. Bacterial overgrowth was demonstrated in three diabetic subjects. These motility abnormalities are nonspecific and are unlikely to play a major role in the pathogenesis of diabetic diarrhea.

Inhibition of Gastric Emptying in Humans by Secretin, the Octapeptide of Cholecystokinin, and Intraduodenal Fat

Intraduodenal fat is a potent inhibitor of gastric emptying. Neural and hormonal mechanisms are probably involved. Secretin and cholecystokinin are among the hormones known to be released by fat in the intestine. In this study we investigated the effect of the octapeptide of cholecystokinin, secretin, and intraduodenal oleate on the inhibition of gastric emptying of liquids in humans. On different days the gastric emptying of a 250-ml saline meal was studied in 6 healthy volunteers under the following conditions: (a) during graded doses of the cholecystokinin-octapeptide alone; (b) during graded doses of secretin; (c) during graded doses of secretin with a background of the cholecystokinin-octapeptide; and (d) during intraduodenal oleate perfusion. All the subjects were also studied for pancreatic enzyme secretion in response to the hormones and intraduodenal oieate. With a secretin background, the octapeptide of cholecystokinin was a potent stimulant of pancreatic secretion; while alone, only the highest dose significantly delayed gastric emptying. Secretin at doses of 2.5 pmol kg -1 · h -1 and higher significantly inhibited gastric emptying (p

Impaired exocrine pancreatic function in diabetics with diarrhea and peripheral neuropathy

Exocrine pancreatic insufficiency has been observed in some diabetics with peripheral neuropathy and diarrhea. Several mechanisms may be responsible for this insufficiency: (1) pancreatic atrophy, (2) disruption of the cholinergic enteropancreatic reflexes, or (3) elevated serum levels of peptides such as glucagon and pancreatic polypeptide which are known to inhibit pancreatic exocrine secretion. To clarify the mechanism(s) involved in this exocrine pancreatic impairment, we studied 10 diabetics with diarrhea and peripheral neuropathy. Their results were compared to those of eight normal volunteers. Each subject underwent a standardized pancreatic function study which assessed nonstimulated secretion, the response to intrajejunal infusion of a mixture of amino acids, and the output following intravenous administration of secretin and cholecystokinin (CCK). In separate studies, the effect of a background infusion of bethanechol and secretin on the pancreatic response to CCK was assessed in six patients and six normal controls. Compared to normals, all diabetics exhibited a significant reduction in both enzyme and bicarbonate secretion to all stimuli. This reduction was not corrected by administering bethanechol. Plasma glucagon and pancreatic polypeptide levels in diabetics were not significantly higher than those in controls. We conclude that diabetics with diarrhea and peripheral neuropathy exhibit impairment of their exocrine pancreatic secretion and possible mechanisms for this are discussed.