S. Domschke

Influence of enkephalin on K+-evoked efflux of putative neurotransmitters in rat brain

SummaryIn rat brain slices preincubated with various radiolabelled putative neurotransmitters, methionine-enkephalin diminished the potassium-evoked release of dopamine and acetylcholine. The effect was antagonised by naloxone. The potassium-induced efflux of three other neurotransmitters, histamine, 5-hydroxytryptamine and γ-aminobutyric acid, were unaffected by methionine-enkephalin. A probable physiological function for the endogenous ligands in specifically affecting the catecholaminergic and cholinergic transmission is suggested.

Bicarbonate and Cyclic Amp Content of Pure Human Pancreatic Juice in Response to Graded Doses of Synthetic Secretin

In seven healthy volunteers pure pancreatic juice was obtained by endoscopic cannulation of the papilla of Vater. Synthetic secretin was intravenously infused in doses doubled every 20 min. The volume of pancreatic juice was proportional to the log of the secretin dose. A significant rise (P less than 0.05) in pancreatic juice flow was elicited at a dose as low as 8.05 ng per kg per hr. Maximum flow rate approximating 250 mul per 5 min per kg of body weight was attained during infusion of 129 ng per kg per hr. At the same dose maximal bicarbonate outputs averaging 383 muEq per hr per kg of body weight were obtained, whereas bicarbonate ion concentration approached peak values (135 +/- 9 muEq per ml) at 32.2 ng per kg per hr. Bicarbonate concentrations showed a tendency to fall at supramaximal doses. The effect of increasing secretin doses on bicarbonate and cyclic AMP concentrations was remarkably similar (rs = 0.635, P less than 0.001) suggesting the participation of cyclic AMP in human pancreatic bicarbonate secretion.

RELEASE OF MOTILIN AFTER DUODENAL ACIDIFICATION

The physiological stimulus leading to motilin release in man has not yet been determined. Six healthy volunteers had 3-minute intraduodenal infusions of acid, alkali, or saline solutions. After infusing acid, plasma-motilin rose by 90% at 4 min and was still significantly raised at 45 min, whereas there was an insignificant fall in plasma-motilin after alkali and no change after saline solution. Release of motilin after duodenal acidification may be an important factor in inhibiting gastric emptying.

Exocrine pancreatic function in juvenile diabetics.

In 11 juvenile diabetics and 13 control subjects, the secretin-pancreozymin test was performed. Doudenal-volume losses were corrected by use of radioactive vitamin B12 as marker substance. As compared to normal subjects, juvenile diabetics had significantly decreased pancreatic outputs of amylase, trypsin, chymotrypsin, and to a lesser degree, of bicarbonate. Clinical evidence of disease of the exocrine pancreas was missing. There was no discernible relationship between the abnormality of external pancreatic function and the duration of diabetes mellitus or the dose of insulin required. Possible factors that may be responsible for the exocrine deficiency of the pancreas in juvenile diabetics are discussed.

Decrease in plasma amino acid level after secretin and pancreozymin as an indicator of exocrine pancreatic function

Total plasma amino acids were determined by the ninhydrin method in 37 controls and 30 patients with chronic pancreatitis and normal (n = 7) pancreatic enzyme output or mildly (n = 6), moderately (n = 8), and severely (n = 9) reduced pancreatic enzyme output. Intravenous injection of synthetic secretin did not change plasma amino acid levels. During a combined intravenous infusion of secretin (1 CU/kg X h) and pancreozymin (1 Ivy dog unit/kg X h), amino acid concentrations decreased maximally by 31% +/- 19% (mean +/- SD) in controls, but only by 6.3% +/- 4.7% in patients with exocrine pancreatic insufficiency (p less than 0.001 vs. controls). At a cutoff limit of less than or equal to 12% for the decrease in total amino acids, mild exocrine insufficiency (20%-40% of mean normal chymotrypsin output) was identified with a sensitivity of 67%, whereas moderately to severely impaired function was detected in every case (overall sensitivity 91%). Pancreatic function, as assessed by duodenal intubation and the tubeless amino acid test, was significantly correlated (e.g., rs = 0.73 for chymotrypsin output, p much less than 0.001). In 15 controls and 13 patients with mildly (n = 5) to severely impaired pancreatic function, individual amino acids were estimated. Plasma serine kinetics completely distinguished both groups. Kinetics of serine, valine, isoleucine, and histidine correlated even better with pancreatic function than those of total amino acids.

Comparison of CA 72–4 with CA 19–9 and Carcinoembryonic Antigen in the Serodiagnostics of Gastrointestinal Malignancies

Serum levels of the new tumor-associated marker CA 72-4 were measured in healthy controls (n = 64) and patients with benign (n = 410) or malignant (n = 199) gastrointestinal diseases. A cut-off limit of 4 U/ml was established. Tumor-indicating sensitivity was compared with that of the conventional markers carcinoembryonic antigen (CEA) and CA 19-9. In serodiagnostic evaluations CA 72-4 was clearly inferior to CA 19-9 in pancreatic carcinomas (22% versus 82%; all stages) and to CEA in colorectal cancer (32% versus 58%; all stages), with no appreciable diagnostic gain from combined determination. However, in gastric carcinoma CA 72-4 identified 59% of all patients (CA 19-9, 52%; CEA, 25%), and a combination of CA 72-4 and CA 19-9 detected as many as 70%. Positive results correlated roughly with tumor size. Compared with the other two tumor markers, CA 72-4 had a very high specificity (98%) in benign diseases of the gastrointestinal tract, including inflammatory processes, so that elevated serum levels of CA 72-4 should always be taken seriously.

Pharmacokinetics of Motilin in Man

The study provides pharmacokinetic data for exogenous synthetic and endogenous natural motilin in man. Synthetic 13-norleucine-motilin was infused into 6 healthy volunteers at a dose of 0.6 and 2.4 (pmoles per kg) per min over 60 min and plasma motilin was measured by radioimmunoassay. During the infusions mean plasma levels of 124.8 +/- 14.8 and 360 +/- 19.6 pmoles per liter, respectively, were achieved. Disappearance half-time on stopping the infusion was 4.36 min. The apparent volume of distribution was calculated to be 49.4 +/- 3.3 ml per kg, and the metabolic clearance rate was 7.8 +/- 0.5 (ml per kg) per min. To measure the decay of endogenous motilin somatostatin was used in the same 6 subjects. A bolus of 100 mug and a subsequent 15-min infusion of 15 mug per min of somatostatin suppressed the fasting motilin level by 50%. The disappearance half-time was 4.56 min. It is concluded that both synthetic and endogenous motilin are eliminated by first order kinetics with very similar half-times. Our data also suggest that the previously reported motilin infusions at these dose levels gave plasma concentrations within the physiological range and that the effects noted may thus have reflected the physiological actions of motilin.

Some Properties of Mucus in Patients with Gastric Ulcer Effect of Treatment with Carbenoxolone Sodium

In gastric ulcer patients the free, bound, and total N-acetylneuraminic acid (NANA) fractions of gastric juice were shown to be reduced significantly as compared to control subjects. During four weeks of treatment with carbenoxolone sodium, NANA contents increased above normal values. As sialic acids are known to be essential constituents of gastric glycoproteins which serve as a protective coat, it is suggested that the stimulative effect of carbenoxolone on NANA production may contribute to the increased rate of healing of peptic ulcer in patients treated with the drug. In the present study no statistically relevant evidence was obtained of carben-oxolone-induced changes in Alcian blue binding capacity, acid production, peptic activity, or protein content of gastric juice.

Inhibition by somatostatin of gastrin release and gastric acid responses to meals and to pentagastrin in man.

The inhibitory actions of intravenous somatostatin on the gastric secretory responses to pentagastrin (1.5 microng/kg-h i.v.) and to a meal (10% peptone, pH 5.5) were studied in six healthy subjects. Meal-induced gastric acid output was estimated by means of a modified Fordtran and Walsh method of intragastric titration. Somatostatin (5 microng/kg-h; cyclic form) significantly inhibited the total 1-hour acid response to pentagastrin by about 70% (inhibition of pepsin secretion: about 70%) and that to a test meal by about 75%. During the last 30 min of somatostatin infusion the pentagastrin-stimulated secretion of acid was significantly reduced by about 90% (inhibition of pepsin output: about 85%) while the corresponding figure in the test with meal-induced secretion was about 95%. Serum gastric--elevated in response to the test meal--was found to be merely lowered by about 30% during somatostatin infusion. Consequently, it is tempting to assume that inhibition of human gastric acid secretion by exogenous somatostatin largely results from a direct antisecretory effect upon parietal cells and, only to a minor extent, from an indirect action via reduction of gastrin release.

Cyclic-AMP and Pancreatic Bicarbonate Secretion in Response to Secretin in Dogs

Summary In anesthetized dogs given secretin intravenously in doses doubling every 60 min and ranging from 0.5 to 8 units per kg body weight per hr, cyclic-AMP levels in pancreatic tissue rose continuously, whereas DNA concentrations were slightly decreased. Bicarbonate concentrations and bicarbonate outputs, cyclic-AMP tissue concentrations and bicarbonate outputs, as well as cyclic-AMP tissue concentrations and juice outputs, were significantly correlated. In conscious pancreatic fistula dogs, there was also a significant correlation between cyclic-AMP and bicarbonate concentrations and outputs in the pancreatic juice after stimulation by exogenous secretin. Accordingly, enhanced release of endogenous secretin achieved by intraduodenal acidification led to a dose-dependent increase in bicarbonate and cyclic-AMP outputs in both conscious and anesthetized dogs. Phosphodiesterase inhibitors (aminophylline, caffeine, and papaverine) given alone to the conscious dogs did not initiate pancreatic bicarbonate secretion, but they potentiated bicarbonate responses to exogenous secretin. These data suggest that cyclic-AMP plays a part in secretin-stimulated pancreatic secretion.