O. B. Schaffalitzky de Muckadell

Vagal, Cholinergic Regulation of Pancreatic Polypeptide Secretion

THE EFFECT OF EFFERENT, PARASYMPATHETIC STIMULATION UPON PANCREATIC POLYPEPTIDE (PP) SECRETION WAS STUDIED IN THREE WAYS: (a) Plasma PP concentrations increased in response to insulin-induced hypoglycemia in both normal subjects, from 11 pM (9.5-12.5) to 136 pM (118-147), n = 8 (median and interquartile range) and in duodenal ulcer patients, from 33 pM (21-52) to 213 pM (157-233), n = 7. The PP response to hypoglycemia was diminished by atropine in normal subjects (P < 0.005) and completely abolished by vagotomy in the duodenal ulcer patients. (b) Electrical stimulation, 8 Hz, of the vagal nerves in anesthetized pigs induced an increase in portal PP concentrations within 30 s from 32 pM (28-39) to 285 pM (248-294), n = 12. Minimal stimulatory frequency was 0.5 Hz and maximal stimulatory frequency 8-12 Hz. Atropine inhibited the PP response to electrical stimulation. Median inhibition with 0.5 mg of atropine/kg body wt was 74%, range 31-90%, n = 6. The response was eliminated by hexamethonium. Adrenergic alpha and beta blockade did not influence the release of PP in response to vagal stimulation. (c) Acetylcholine stimulated, in a dose-dependent manner, the secretion of PP from the isolated perfused porcine pancreas, half-maximal effective dose being 0.19 muM; maximal PP output in response to 5 min stimulation was 228 pmol, range 140-342 pmol, n = 5. Atropine completely abolished this response.The results of the present study together with the previously demonstrated poor PP response to food in vagotomized patients, indicate that vagal, cholinergic stimulation is a major regulator of PP secretion.

Radioimmunoassay of Vasoactive Intestinal Polypeptide (VIP) in Plasma

Abstract A sensitive and specific radioimmunoassay for vasoactive intestinal polypeptide (VIP) has been developed, which can detect 3.3 pmol × L −1 of the peptide in plasma. Antisera to highly purified porcine VIP coupled to albumin were raised in eight rabbits. The final dilution, the avidity, and the specificity of each antiserum were determined. 125 I-VIP served as label, and highly purified porcine VIP was used as standard. Separation of antibody-bound and free VIP was achieved by plasma-coated charcoal. Nonspecific interference with the assay system was excluded by extraction of plasma samples with ethanol. The reliability of the assay was investigated by recovery experiments, by serial dilution of plasma samples with high concentration of endogenous VIP, and by immunosorption. The within-and between assay reproducibility at a concentration of 18.3 pmol × L −1 was 1.6 and 2.3 pmol × L −1 (1 S.D.), respectively. Median fasting concentration of VIP in plasma from 74 normal subjects was 7.3 pmol × L −1 (range: 0–20.0 pmol × L −1 ).

Influence of the autonomic nervous system on the release of vasoactive intestinal polypeptide from the porcine gastrointestinal tract.

1. The release of vasoactive intestinal polypeptide from the gastrointestinal tract in response to stimulation of the vagus nerves, the splanchnic nerves and to intra‐arterial infusion of acetylcholine (ACh) was examined in pigs. 2. Stimulation of the vagus nerves caused an abrupt increase in the release of vasoactive intestinal polypeptide. The amount of the peptide released depended on the frequency at which the nerves were stimulated. Maximum release was obtained at 8 Hz. 3. Atropine and beta‐adrenergic blocking agents failed to diminish the vagally induced release of vasoactive intestinal polypeptide, while the response was completely blocked by hexamethonium and increased after alpha‐adrenergic blockade and after splanchnicotomy. 4. Intra‐arterial infusion of ACh closely imitated the response to vagal stimulation, but the release of vasoactive intestinal polypeptide induced by ACh was abolished by atropine. 5. Stimulation of the splanchnic nerves caused a decrease in the release of vasoactive intestinal polypeptide, an action which was annulled by alpha‐adrenergic blockade, but still present after the adrenal glands were isolated from the circulation. The inhibitory effect of splanchnic stimulation significantly diminished the vagally induced release of vasoactive intestinal polypeptide. 6. The results demonstrate a dual innervation with opposing effects on the neurones containing vasoactive intestinal polypeptides. The possible physiologic implication of this finding is discussed.

The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease

Background: Mutations in the PRSS1 gene explain most occurrences of hereditary pancreatitis (HP) but many HP families have no PRSS1 mutation. Recently, an association between the mutation N34S in the pancreatic secretory trypsin inhibitor (SPINK1 or PSTI) gene and idiopathic chronic pancreatitis (ICP) was reported. It is unclear whether the N34S mutation is a cause of pancreatitis per se, whether it modifies the disease, or whether it is a marker of the disease. Patients and methods: A total of 327 individuals from 217 families affected by pancreatitis were tested: 152 from families with HP, 108 from families with ICP, and 67 with alcohol related CP (ACP). Seven patients with ICP had a family history of pancreatitis but no evidence of autosomal dominant disease (f-ICP) compared with 87 patients with true ICP (t-ICP). Two hundred controls were also tested for the N34S mutation. The findings were related to clinical outcome. Results: The N34S mutation was carried by five controls (2.5%; allele frequency 1.25%), 11/87 (13%) t-ICP patients (p=0.0013 v controls), and 6/7 (86%) affected (p<0.0001 v controls) and 1/9 (11%) unaffected f-ICP cases. N34S was found in 4/108 affected HP patients (p=0.724 v controls), in 3/27 (11%) with wild-type and in 1/81 (1%) with mutant PRSS1, and 4/67 ACP patients (all p>0.05 v controls). The presence of the N34S mutation was not associated with early disease onset or disease severity. Conclusions: The prevalence of the N34S mutation was increased in patients with ICP and was greatest in f-ICP cases. Segregation of the N34S mutation in families with pancreatitis is unexplained and points to a complex association between N34S and another putative pancreatitis related gene.

Effect of Omeprazole on the Outcome of Endoscopically Treated Bleeding Peptic Ulcers Randomized Double-Blind Placebo-Controlled Multicentre Study

Background: Haemostasis is highly pH-dependent and severely impaired at low pH. However, there is no clear evidence that acid-suppressing drugs have beneficial effects in peptic ulcer haemorrhage. Endoscopic haemostatic treatment provides important reduction in morbidity and may be more efficient when a neutral intragastric pH is maintained. Methods: We conducted a double-blind, placebo-controlled multicentre study of intravenous infusion of omeprazole (80 mg as bolus, followed by 8 mg/h) or placebo for 72 h. All patients received 20 mg omeprazole orally from day 3 until follow-up on day 21. Only patients with ulcer haemorrhage, endoscoped within 12 h after admission, and with a history or signs of circulatory failure and spurting bleeding, oozing bleeding, visible vessel, or clot, were included. Endoscopic intervention was aimed at when spurting bleeding, oozing bleeding, or a visible vessel was observed. The primary efficacy measure was the worst ranking on an overall outcome scale (5 = death, 4 = surge...

Occurrence of nerves containing vasoactive intestinal polypeptide immunoreactivity in the male genital tract

Abstract Immunocytochemistry and radioimmunochemistry demonstrates the occurrence of numerous nerves containing the vasoactive intestinal polypeptide (VIP) in the male genital tract. The nerves occur in association with arteries and smooth musculature of the organs. Available evidence suggests VIP to be a new neurotransmittor possibly involved in the regulation of blood flow and muscle contractility of the male genital organs.

Development of vasoactive intestinal polypeptide (VIP) containing neurones in the rat brain

The development of VIP-containing neurones in the rat CNS and duodenum has been studied using a specific radioimmunoassay and immunohistochemistry. In the brain, VIP immunoreactivity appears entirely postnatally, while VIP in peripheral neurones in the duodenum was present before birth. The developmental changes observed in cerebral cortex appear to represent the maturation of a population of intrinsic cortical interneurones which contain VIP. These neurones develop entirely after birth. They are first seen in deep cortical layers, but later spread out into all cortical layers, particularly layers II--IV. Changes in the intensity of VIP cell body fluorescence can be correlated with changes in VIP content in the cortex measured by radioimmunoassay. Thus VIP forms a unique chemical marker for studying the maturation of a cortical neurone.

Release of Vasoactive Intestinal Polypeptide (VIP) by Intraduodenal Stimuli

The effect of intraduodenal infusion of amino acids, glucose, fat, HCl, ethanol, or saline on plasma VIP concentration was investigated in 7 normal subjects, 5 post-vagotomy patients, and 12 anaesthetized pigs. Furthermore, the concentrations of VIP in plasma after ingestion of a mixed meal were measured in 6 normal subjects. In normal subjects the median peripheral concentration of VIP in the basal state was 4.3 pmol X I-1 (range 0--12.0). No significant changes occurred after amino acids, glucose, saline, or ingestion of a meal. In contrast infusion of HCl, fat, or ethanol resulted in a rise in plasma VIP concentration in all the subjects studied. The peak values (medians and ranges) after HCl, fat, or ethanol were 9.8 (5.9--12.6), 7.5 (2.4--10.2), and 12.6 (7.8--16.8)pmol X I-1, respectively. Truncal vagotomy did not change the response of HCl. The results from measurements in portal plasma of pigs confirmed the findings in peripheral plasma of normal subjects and showed that the levels of VIP in portal plasma are 1.6--2.9 times higher than the levels of VIP in arterial plasma. The pH threshold to release of VIP was pH 1.1--2.1, and the effect of HCl was not abolished by ganglionic blockade.

Secretion pattern of secretin in man: regulation by gastric acid.

Median concentration of plasma secretin in the fasting state in 11 achlorhydria patients, 17 normal subjects, eight duodenal ulcer patients, and 11 Zollinger-Ellison patients was 0.3, 1.2, 2.5, and 5.9 pmol x 1(-1), respectively. Aspiration of gastric acid normal subjects and duodenal ulcer patients was followed by a significant lowering of the plasma secretin concentration. In normal subjects insulin-induced hypoglycaemia resulted in increased secretin levels when gastric acid was allowed to enter the duodenum, whereas no changes were observed when gastric acid was aspirated. Simultaneous measurements of intraduodenal pH and plasma secretin concentration in the fasting state and in response to a meal showed that rapid falls in intraduodenal pH were followed by short-lived increments in plasma secretin concentration. These changes in pH and in secretin levels were diminished after cimetidine. It is concluded that gastric acid in man does trigger release of secretin and that secretin is secreted intermittently both in the fasting state and in response to a meal when boluses of acid enter the duodenum.

Release of vasoactive intestinal polypeptide (VIP) by electric stimulation of the vagal nerves.

The concentration of immunoreactive VIP was measured in portal venous and peripheral arterial plasma in anesthetized pigs. Following electric stimulation of the vagal nerves the median concentration of VIP in portal plasma rose from 21 to 58 pmol l-1 and a simultaneous increase was found in arterial plasma. Atropine did not abolish this effect of vagal stimulation. The response is interpreted as increased release of VIP.