Effects of the prostaglandin E2 analogue enprostil on the carbon tetrachloride-induced necrosis of liver cells in mice.

Female mice, eight weeks old, were injected with carbon tetrachloride (CCl4) (10 mg subcutaneously). Groups of mice (n = 10-30) were then injected with enprostil (E) 2, 20 or 50 micrograms/kg body weight (bw) intraperitoneally 15 min and two h after, or E 100 micrograms/kg bw two h after the CCl4 injection. The mice were killed after 24, 48 or 72 h. Plasma activity concentrations of alanine aminotransferase (ALAT) were determined in blood specimens from the iliac veins. The extent of liver cell necrosis in histological sections was recorded on a 100 mm Visual Analogue Scale (VAS) and measured using the electronic Mini Mop method. In the group given the highest single dose of E (100 micrograms/kg) a significant lowering of the CCl4-induced liver cell necrosis was found after 24 h. No significant differences were found after 48 and 72 h. In the other groups injected with lower doses of E after CCl4, no significant differences were found compared to groups injected with CCl4 alone.

Liver cell necrosis and regeneration following injections of carbon tetrachloride. Effects of the thyrotropin-releasing hormone and somatostatin.

Mice were given 10 micrograms somatostatin or 25 micrograms TRH intraperitoneally 10 min before s.c. injection of 2 or 20 mg CCl4. The extent of liver cell necrosis and nuclear size were measured by the electronic Mini Mop method and the extent of necrosis and nuclear pleomorphism were estimated by a visual linear analogue scale of 100 mm, and compared to plasma concentrations of ASAT and ALAT. Pre-treatment with TRH or somatostatin resulted in significant reduction in the extent of necrosis 24 h after CCl4-injections (25%), with a lowering of ASAT from 13209 +/- 2955 U/l to 5144 +/- 924 after TRH and to 6186 +/- 966 after somatostatin, and of ALAT from 14343 +/- 3209 to 7718 +/- 1727 and 6494 +/- 1253 U/l, respectively. After 3 days the necroses were reduced from 16.5 +/- 1.7% by the Minimop method to 1.4 +/- 0.5% (90%) in mice given CCl4 alone, and from 12.3 +/- 1.7% to 3.8 +/- 1.2% in mice pretreated with TRH, and from 12.3 +/- 1.8% to 3.8 +/- 1.7% (70%) in mice pretreated with somatostatin. The plasma concentrations of ASAT and ALAT were reduced correspondingly. After 5 days no necroses were seen, and the plasma ASAT and ALAT were normal. After 6 months of weekly injections of TRH or somatostatin before 20 mg CCl4 the liver cell nuclear size (10.5 and 9.7 0.3 mu 2) was similar to that after CCl4 alone (9.7 0.3 mu 2), and twice that of controls (4.6-5.4 0.1 mu 2). Liver cell necrosis was not seen. The plasma concentrations of ASAT (131 8.6-162 11.3) and ALAT (98 8-104 9 Iu/l) were similarly 2-3 times those in controls. TRH and somatostatin thus reduced liver cell injury and delayed regeneration after single injections of CCl4. After 6 months of weekly injections no effects were observed.

Diminution of postprandial release of pancreatic polypeptide in myotonic dystrophy.

The meal-stimulated release of pancreatic polypeptide (PP), gastrin, somatostatin and glucagon was studied in nine patients with myotonic dystrophy (MD) and in 11 healthy controls. PP-release was significantly reduced in MD compared to controls. This reduction may be related to the abnormal gut motility demonstrated in MD. The release of gastrin, somatostatin and glucagon was not significantly different in the two groups.

The immediate effect of human renal transplantation on basal and meal-stimulated levels of gastrointestinal hormones.

Elevated serum levels of gastrin, pancreatic polypeptide, and glucagon were found in 10 uraemic patients, whereas gastric inhibitory polypeptide and somatostatin levels were normal. After renal transplantation there was a significant reduction in serum gastrin (median, 5 pmol/l; p = 0.05, n = 9), pancreatic polypeptide (145 pmol/l; p less than 0.01, n = 9), GIP (9.5 pmol/l; p = 0.02, n = 7), and glucagon (92 pg/l; p less than 0.02, n = 9), whereas no alteration was seen in the somatostatin level. Meal stimulation produced consistent increases in serum levels of all hormones, and the response appeared to be unchanged after renal transplantation.

Autopsy findings in three family members with a presumably acquired immunodeficiency syndrome of unknown etiology.

This paper presents clinical, immunological and post-mortem findings in three family members (husband, wife and daughter) who all died in 1976 after having had chronic and recurrent opportunistic infections for many years. In all of them a progressive, presumably acquired T-lymphocyte defect associated with B-lymphocyte dysfunction had been diagnosed several years before death. The clinical and immunological findings are compatible with those seen in acquired immunodeficiency syndrome (AIDS) caused by HTLV-III/LAV infection, but examinations of stored blood samples from the three patients were negative with regard to the presence of HTLV-III/LAV antibodies. This immunodeficiency may therefore have been caused by an infectious agent of unknown nature. The most remarkable finding on post-mortem examination was the presence of a granulomatous encephalomyelitis with multinucleated giant cells in the husband and his wife. In addition, the wife's CNS revealed scattered microglial nodules. No infectious agents could be demonstrated, and the etiology of this peculiar CNS affection therefore remains obscure.

The antisecretory effects of RP 40 749 in patients with previous duodenal ulcer.

Thirteen male patients with a history of duodenal ulcer were given 150 mg RP 40 749 or placebo tablets at bedtime in a double-blind crossover study. The medication was given for two periods of 10 days with an 11-day wash-out period between. pH and pepsin concentrations were determined each hour in aspirates of gastric juice for 24 h on day 1, 10, 22, 31, and a 2-h collection of gastric juice was examined in the middle of the treatment and wash-out periods. At defined hours blood samples were examined for gastrin, somatostatin, and pancreatic polypeptide (PP) by radioimmunological methods, and concentrations of RP 40 749 were determined in blood and gastric juice. Meals were served at fixed hours on days 1, 10, 22, and 31. After treatment with RP 40 749 a highly significant elevation of pH was found after the 1st day compared with placebo, most pronounced during night hours. The pepsin activity was slightly elevated. The serum concentrations of gastrin were increased and those of somatostatin and PP decreased during the first 3-4 h after medication, with a subsequent normalization. No side effects were observed.

Dopaminergic and adrenergic influence on gastric acid and pepsin secretion stimulated by food. The role of vagal innervation.

Dopaminergic and adrenergic mechanisms were studied in a dog model which made possible physiological stimulation by food and comparison of vagally innervated and denervated acid and pepsin response at the same time. Five dogs were equipped with two pouches separated from the stomach, and stimulation was done by a standard meal - a mixture of liver, heart and bonemeal , 10 g/kg. The meal was combined with different doses of dopamine 0.1 - 2.0 - 20.0 - 40.0 micrograms/kg/min and with single doses of phentolamine, propranolol and sulpiride separately and combined with dopamine. Acid and pepsin secretion were inhibited in dose-response manner by dopamine in innervated mucosa, but all other effects of the compounds were different in parietal cells and chief cells and in vagally innervated and denervated mucosa.

Pancreatic polypeptide release stimulated by food, secretin and cholecystokinin in chronic pancreatitis.

The pancreatic polypeptide (PP) release after a standard meal and the PP release and the pancreatic secretion of bicarbonate and amylase after stimulation by secretin GIH, 1 CU kg-1 intravenously, and by cholecystokinin (CCK), 1 Ivy dog unit kg-1 intravenously, have been investigated in 10 patients with chronic pancreatitis. Significant correlations were found between the integrated PP responses after food and hormonal stimulation (p less than 0.05), between the integrated PP response and the peak serum PP concentration after food (p less than 0.01) and after secretin/CCK (p less than 0.01), and between the peak serum PP concentrations obtained after food, secretin, and CCK (p less than 0.01). The pancreatic outputs of bicarbonate and amylase and the peak amylase concentration after hormonal stimulation were significantly correlated (p less than 0.01), but no significant correlation was found between any one of these variables of exocrine pancreatic function and the PP release. It is concluded that, in chronic pancreatitis, food, secretin, and CCK stimulate PP release similarly and that no correlation can be established between the PP release and the exocrine pancreatic secretion.

The effect of histamine, H1 and H2 agonists, and H1 and H2 antagonists on postprandial pancreatic polypeptide release in dogs.

The influence of histamine, H1 and H2 agonists (2-AETD and dimaprit), and H1 and H2 antagonists (mepyramine and cimetidine) on the postprandial release of pancreatic polypeptide (PP) was assessed in five Labrador retrievers. Infusions of histamine, 0.25 mumol kg-1 h-1; 2AETD, 4 mumol kg-1 h-1; and dimaprit, 1 mumol kg-1 h-1, enhanced postprandial release (131-189% of control values). The response to 2-AETD and dimaprit was significantly different from control values (p less than 0.05). An increase was observed even when 50 mg mepyramine and 400 mg cimetidine were injected as intravenous boluses (131-139% of control values (p less than 0.05]. The action of the antagonists may be explained by partial agonism or histamine release induced by these agents. It is concluded that postprandial PP release is stimulated by H1 and H2 receptors.

The release of human pancreatic polypeptide, gastrin, gastric inhibitory polypeptide, and somatostatin in celiac disease related to the histological appearance of jejunal mucosa before and 1 year after gluten withdrawal.

Jejunal biopsies and the postprandial response of pancreatic polypeptide (PP), gastrin, gastric inhibitory polypeptide (GIP), and somatostatin have been examined in nine patients with celiac disease before and 1 year after gluten withdrawal. All presented initially with total villous atrophy of the jejunal mucosa. After gluten withdrawal five showed marked mucosal regeneration on light microscopy examination (responders) and four only moderate or no regeneration (nonresponders). Before treatment the celiac patients had enhanced gastrin response and normal PP response compared with normal controls. After gluten withdrawal the integrated gastrin release was reduced to normal in the responders (275 versus 114; p less than 0.05) but remained elevated in the nonresponders (231 versus 204). Postprandial PP release was similar before and after treatment regardless of the degree of mucosal regeneration. In the responders the integrated release of GIP was increased (180 versus 241; p less than 0.05), and the somatostatin release was enhanced (-2.6 versus 8.4; p less than 0.05) after gluten withdrawal. We conclude that the postprandial release of GIP and somatostatin increases and that the release of gastrin decreases when the intestinal mucosa is regenerated in celiacs on a gluten-free diet. The release of PP after food is not influenced by mucosal regeneration.

Effects of dopamine and dopamine antagonists on postprandial release of pancreatic polypeptide in dogs and in healthy volunteers.

The effect of dopamine, 0.006, 0.12, 1.2, and 2.4 mg X kg-1 X h1, and the dopamine antagonist sulpiride on postprandial pancreatic polypeptide (PP) release has been studied in dogs. Dopamine reduced PP release, the reduction ranging between 28% and 97% of the integrated PP response after food. The inhibition obtained with dopamine, 0.12 and 2.4 mg X kg-1 X h-1, could be partly reversed (p less than 0.05) by sulpiride, 7.5 mg X kg-1. The concomitant administration of phentolamine, 1.0 mg X kg-1, and propranolol, 0.5 mg X kg -1, partly reversed the inhibition obtained with dopamine, 2.4 mg X kg-1 X h-1 (p less than 0.05). In healthy volunteers basal PP concentration and postprandial PP release were diminished by dopamine, 0.12 mg X kg-1 X h-1 (p less than 0.02). Sulpiride in dogs and haloperidol in volunteers reduced PP release when given without concomitant administration of dopamine. It is concluded that dopamine inhibits postprandial PP release via both dopaminergic and adrenergic receptors.

The effect of alpha- and beta-adrenergic agonists and blockers on postprandial pancreatic polypeptide release in dogs.

The influence of adrenergic agonists--phenylephrine (alpha), isoproterenol (beta), and salbutamol (beta 2)--and of adrenergic blockers--phentolamine (alpha), pranolol (beta), and practolol (beta 1)--on the postprandial pancreatic polypeptide (PP) release has been assessed in five Labrador retrievers. Infusions of phenylephrine, 0.12 mg kg-1h-1; isoproterenol, 3 micrograms kg-1h-1; salbutamol, 12 micrograms kg-1h-1, did not significantly affect PP release. Propranolol, 0.5 mg kg-1, and propranolol, 0.5 mg kg-1, + phentolamine, 1 mg kg-1, combined, given as intravenous boluses before the meal significantly reduce PP release (44% and 58% of controls, p less than 0.05), whereas phentolamine, 1 mg kg-1, and practolol, 1 mg kg-1, had no effect. Phenylephrine combined with phentolamine and isoproterenol combined with propranolol and practolol did not influence PP secretion. It is concluded that the postprandial PP release is stimulated by beta 2-adrenergic mechanisms.

Effect of cholinergic and adrenergic blockade on human pancreatic polypeptide secretion in healthy subjects.

The effect of cholinergic, alpha-adrenergic, and beta-adrenergic blockade on human pancreatic polypeptide (HPP) release has been tested in six normal subjects before and after a meal. The response to food was abolished by atropine and significantly enhanced by phentolamine and propranolol. The increase induced by phentolamine occurred during the primary phase 0-60 min after food, and that caused by propranolol was observed during the secondary phase 60-120 min postprandially. A radioimmunoassay for HPP, evaluated by accepted criteria of reliability, is described. Various fractions of the 125I-BPP tracer peak have been evaluated. Those of the central portion proved to be superior to the others because of the constant immunoreactivity and the constant incubation damage during the observation period. Serum and plasma samples were subject to different conditions of preservation before analysis of HPP. It is concluded that preservation with aprotinin heparin, collection in chilled tubes, or instant centrifugation and freezing does not improve the stability of HPP after sampling. The present study confirms a positive correlation between age and fasting HPP concentrations (R = 0.15, p = 0.05), but no difference in HPP levels between men and women has been demonstrated.