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Biomedical subjects

I M Modlin

Publications and source records attributed to I M Modlin.

At least 253 records · Page 14Linked to original sources

The diagnosis and management of gastrinoma.

Initial reports of patients with Zollinger-Ellison syndrome were characterized by a long history of recurrent peptic ulcer and multiple operations. Diagnosis was usually made by a combination of clinical history and roentgenograms of the upper aspect of the gastrointestinal tract. Diagnosis was confirmed by the demonstration of elevated basal plasma gastrin levels. The management of the disease included either tumor excision or gastric resection, but more often it included a total gastrectomy. The mortality was high, often because of late recognition of the disease or operative problems related to inadequate control of the hypersecretion of acid. This review is a brief synopsis of the evolution and status of the different diagnostic and therapeutic techniques involved in the contemporary management of patients with gastrinomas. The diagnostic emphasis has shifted away from gastrointestinal contrast studies. Techniques have been developed both for the biochemical diagnosis of the condition and for the topographic localization of the site of the lesion. The use of acid secretory data has declined in value with the development of more elegant techniques for the detection of elevated levels of plasma gastrin in the systemic circulation and the use of portal venous sampling for identifying the source. Thus, the results of sophisticated procedures such as percutaneous transhepatic portopancreatic venous sampling or selective angiography provide additional information. The biochemical diagnosis of gastrinoma is best supported by the evaluation of provocative testing with either calcium or secretin rather than measurement of the basal levels of plasma gastrin. The introduction of potent H2 receptor antagonists has produced support for more conservative management of the disease. The incidence of significant complications during such therapy limits its over-all efficacy. The use of these drugs has, however, facilitated both the conservative and the operative management of patients with extensive sequelae of acid hypersecretion due to a gastrin-secreting tumor. It is probably reasonable to surgically stage the disease of all patients with hypergastrinemia of neoplastic origin since a small percentage (10 per cent) may have a solitary benign lesion which is curable by resection. Total gastrectomy under elective circumstances still has considerable merit. Preliminary data have indicated that alternative, lesser surgical procedures, such as proximal gastric vagotomy, may be therapeutic options if the patient is compliant and sensitive to the appropriate dosage of H2 receptor antagonist.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

Cholinergic stimulation of pancreatic polypeptide release by a meal, bombesin, neurotensin, tetragastrin, cholecystokinin, and cerulein.

It has been demonstrated that pancreatic polypeptide (PP) release can be markedly impaired by vagotomy or anticholinergic drugs. The current studies examine the role of cholinomimetic stimulation on PP release in dogs. Eight conscious animals underwent a series of tests: (1) a test meal (10 g/kg Alpo); (2) tetragastrin infusion (4 micrograms/kg/hr); (3) bombesin infusion (1.0 microgram/kg/hr); (4) cerulein infusion (100 ng/kg/hr); (5) cholecystokinin octapeptide (CCK-OP) infusion (100 ng/kg/hr); (6) neurotensin infusion (3 ng/kg/hr). All the studies were repeated individually with intravenous bethanecol (100 micrograms/kg/hr) as the background stimulant. The mean increment of PP released by a meal (160 +/- 32 fmol/ml) was significantly increased by bethanecol infusion (316 +/- 49 fmol/ml) (P less than 0.05). Each individual peptide released a significant amount of PP; tetragastrin: 53 +/- 11; neurotensin: 58 +/- 14; CCK-OP: 42 +/- 9; cerulein: 42 +/- 12; bombesin: 118 +/- 24 (P less than 0.05). Bethanecol did not significantly augment PP release by any of the individual peptides (P greater than 0.05). This study indicates that PP release by a meal is sensitive to cholinomimetic stimulation and that the peptide involved is neither gastrin, neurotensin, CCK, bombesin, nor cerulein. These data support the possibility of the existence of a cholinergic stimulatable mechanism, possibly a peptide responsible for the release of PP.

Animals↗

Cholinergic component in the human pancreatic secretory response to intraintestinal oleate.

To determine the role of cholinergic reflexes on pancreatic secretory response to food, we studied the effect of atropine on amylase secretion in response to the octapeptide of cholecystokinin (CCK8) and to intraintestinal oleate. Four studies were done in six healthy volunteers. The duodenal content was aspirated by a double lumen tube while synthetic secretin (41 pmol/kg/h) was infused as a background in all the studies. Graded doses of CCK8 IV or 0.42 M oleate pH 9.4 at 25 ml/h into the intestine with and without atropine 1.8 mg were given on different days. CCK-like immunoreactivity (LI) in the plasma was measured by RIA during the intraintestinal oleate studies. CCK8 stimulated pancreatic enzyme secretion in a dose related fashion, an effect that was not modified by atropine. Intraintestinal oleate also stimulated pancreatic secretion and increased the CCK-LI in the plasma. Atropine significantly (p less than 0.05) decreased the pancreatic enzyme secretion before and during intraintestinal oleate, without effect on the CCK-LI levels. We conclude: (1) that the effect of exogenous CCK on pancreatic secretion of enzymes is not affected by atropine; (2) intraintestinal oleate stimulates pancreatic enzyme secretion significantly by an atropine-sensitive mechanism; (3) probably the atropine effect is a blockade of a cholinergic enteropancreatic reflex.

Adult↗

Bombesin and insulin-stimulated pancreatic polypeptide release as a discriminator of vagal integrity.

Intact vagi after ulcer operations are often implicated in the cause of recurrent ulcer. The stimulation of gastric acid by insulin hypoglycemia is dangerous and the measurement of acid secretion after gastrectomy unreliable. This study was undertaken to assess and compare PP release by bombesin or insulin as an indicator of vagal integrity. Eight dogs with a chronic gastric fistula were tested with bombesin (100 nanograms per kilogram) and insulin (0.1 unit per kilogram) intravenous bolus after unilateral and, then, bilateral truncal vagotomy. Each study was 120 minutes, and blood was taken at one, three, five, seven and then ten minute intervals. Gastric acid was measured by autobiuret titration. Plasma was stored at minus 20 degrees C. until assayed for PP by radioimmunoassay. Bombesin-stimulated gastric acid secretion was not significantly altered by vagotomy (p greater than 0.05), whereas that stimulated by insulin was significantly inhibited by bilateral truncal vagotomy (p less than 0.05). Bilateral and right hemivagotomy significantly inhibited PP release by bombesin (p less than 0.05), however, only bilateral truncal vagotomy significantly inhibited PP release by insulin (p less than 0.05). These results suggest that the measurement of PP release by insulin or bombesin is a sensitive index of vagal integrity and that bombesin-released PP may specifically delineate the integrity of the right vagus. Since the measurement of gastric acid secretion after operation is both uncomfortable and often difficult to interpret, the value of a simple blood test to determine vagal integrity may be of considerable clinical relevance.

Animals↗

Cholinergic modulation of substance P release.

This study was initiated to evaluate mechanisms of release of immunoreactive substance P into the peripheral circulation and to determine whether these mechanisms are subject to cholinergic modulation. In conscious dogs, a high-protein meal significantly increased plasma concentrations of immunoreactive substance P from basal levels of 13.7 +/- 1.8 pg/ml to a peak of 20.1 +/- 2.8 pg/ml after which they returned to baseline. Prior atropinization (200 mg/kg) abolished this response and lowered the plasma levels to a nadir of 2.2 pg/ml at 20 min. Similarly, infusion of bombesin (17 ng/kg/min) increased peripheral venous substance P levels by 768 +/- 155 pg-min/ml for 120 min, whereas after prior treatment with atropine, bombesin released no significant amounts of this peptide (-10 +/- 134 pg-min/ml). The data support the concept that substance P release is under cholinergic control.

Animals↗

Effect of methionine-enkephalin and naloxone on bombesin-stimulated gastric acid secretion, gastrin, and pancreatic polypeptide release in the dog.

In four dogs with chronic gastric fistulae, bombesin infusion was used to stimulate the release of gastrin and pancreatic polypeptide (PP) as well as rates of gastric acid secretion. Neither methionine-enkephalin (met-enkephalin) nor naloxone alone or the combination of these agents altered bombesin-stimulated gastrin release. met-enkephalin alone (but not naloxone) significantly inhibited the gastric secretory response to bombesin, but this inhibitory effect was not influenced by the simultaneous infusion of naloxone; the data suggested that the effect of met-enkephalin was indirect, and perhaps modulated by another inhibitory mechanism. Whereas PP release induced by bombesin was not affected by naloxone, it was significantly suppressed by met-enkaphalin; since this inhibition was virtually totally reversed by naloxone, the data suggested that the effect of opiate peptides on the release of pancreatic polypeptide was direct and mediated by a specific opiate receptor.

Animals↗

The early diagnosis of gastrinoma.

Despite the increasing awareness of gastrinoma and its lethal peptic ulcer sequelae, the diagnosis is often initially missed or made as a terminal event. The authors screened all patients with peptic ulcer symptoms serious enough to warrant hospital admission or those associated with diarrhea, nephrolithiasis, hypercalcemia, or pituitary abnormality. In a one-year period (1979-1980) nine (of 14 suspected) new gastrinoma patients were identified using a sensitive and specific gastrin radioimmunoassay in combination with provocative tests including IV secretin, calcium, and food. Conventional upper GI series, CAT scan, arteriography, and endoscopy provided no additional information other than to confirm the presence of ulcer disease. Basal plasma gastrin levels were more than 200 pmol L-1 in only three of the nine (normal fasting plasma gastrin levels are less than 25 pmol L-1). Three patients presented with acute ulcer perforation, and the diagnosis of gastrinoma was suspected because of multiple ulcers and pancreatic masses. In three other patients, previous duodenal ulcer surgery had failed. One patient with dyspepsia, high basal plasma gastrin, negative secretin and calcium infusion studies, and a positive meal test was diagnosed as having G-cell hyperplasia; this was confirmed by biopsy and antral gastrin extraction. Antrectomy alone resulted in cure. In all patients tested, a positive calcium infusion or secretin bolus (greater than 100% rise over basal) strongly suggested the diagnosis of gastrinoma, which was confirmed at surgery. In the acute perforations, initial management with omental patch and cimetidine therapy allowed survival of two patients, while emergency total gastrectomy in the third resulted in death due to esophagojejunal leak. Elective patients were treated with cimetidine initially for at least two weeks before total gastrectomy. In this group there were no operative mortalities, and postoperative morbidity was minimal. This series illustrates three important points: (1) careful screening of an ulcer population using gastrin radioimmunoassay and provocative tests has enabled a high yield of gastrinomas while conventional investigations are of minimal values; (2) a high index of suspicion in appropriate cases is necessary; and (3) total gastrectomy performed under elective circumstances is safe and allows the patients to resume a normal and healthy life without the sequelae of aggressive peptic ulceration or daily drug administration.

Adult↗

Effect of xenopsin on blood flow, hormone release, and acid secretion.

We investigated the effects of the neurotensin analogue xenopsin on regional blood flow, central hemodynamics, and stimulated acid secretion in awake conscious dogs. Organ blood flow, estimated using the radioactive microsphere technique, was significantly increased during the xenopsin infusion to the adrenals, pancreas, and ileum. There was no change in mean arterial pressure or cardiac output (measured by thermodilution). Along with changes in blood flow, there was a significant increase in the hormone output from the pancreas. These included rises in plasma pancreatic polypeptide, insulin, and glucagon. There also was a rise in plasma cortisol levels during the infusion. Substance P levels rose slowly but significantly during the xenospin infusion. There was no change in plasma gastrin levels. Xenopsin produced a significant inhibition of tetragastrin-stimulated gastric acid output. Thus, xenopsin appears to have region-specific influence on blood flow that correlates with region-specific hormonal secretion. In addition, xenopsin, like its mammalian analogue neurotensin, is an inhibitor of stimulated gastric acid secretion. A mammalian xenopsinlike peptide may well be involved in the modulation of gastrointestinal function.

Adrenal Glands↗

Opiate modulation of pancreatic polypeptide release by a meal in the dog.

It has been reported that morphine abolished the plasma pancreatic polypeptide (PP) response to a meal in man, but the mechanism of this action is unclear. This study was designed to investigate the effect of low doses of the endogenous opiate peptide. Met-enkephalin and naloxone on basal- and meal-stimulated PP release in order to examine the role of opioid modulation in the release of this hormone. Four gastric fistula dogs underwent a series of six studies, a test meal alone. Met-enkephalin infusion (40 microgram/kg/hr), naloxone infusion, meal plus naloxone infusion and meal plus Met-enkephalin plus naloxone. Gastrin and PP were measured by radioimmunoassay. Basal PP levels averaged 35.1 +/- 3.0 fmol/ml. Although Met-enkephalin had no effect on basal PP levels, it significantly (P less than 0.05) inhibited the mean peak increment of PP stimulated by a meal (control, 331 +/- 39 fmol/ml; Met-enkephalin, 145 +/- 49 fmol/ml; P less than 0.05). This inhibition was completely abolished by naloxone. Naloxone alone did not alter basal- or meal-stimulated plasma PP levels. Neither Met-enkephalin nor naloxone altered basal or stimulated plasma gastrin levels. This study demonstrated that opiate peptides play a role in the regulation of the release of PP by a meal; it thus suggests the possibility of an opioid modulatory mechanism for the release of this hormone.

Animals↗

Evidence for an intestinal mechanism of pancreatic polypeptide release.

The purpose of this study was to define the existence of an intestinal phase of pancreatic polypeptide (PP) release and to assess whether it was mediated by a cholinergic-sensitive mechanism. Four conscious dogs with 20-cm upper intestinal Thiry-Vella loops and chronic gastric fistulas were used. The Thiry-Vella (T-V) loops were perfused with 10% liver extract or 0.154 M NaCl at a rate of 1 ml/min for 120 min. In a separate experiment, 240 ml of 10% liver extract was infused over a 5-min period into the stomach via the gastric fistula. Basal PP levels were 29 +/- 4 fmol/ml. The gastric infusion of liver extract caused a significant increase of plasma PP levels to a peak of 215 +/- 29 fmol/ml (P less than 0.05). The perfusion of the T-V loop with liver extract significantly increased plasma PP levels over basal to a peak of 73 +/- 14 fmol/ml (P less than 0.05). This value was significantly less than that released by gastric infusion of liver extract (P less than 0.05). Perfusion of the loop with NaCl did not significantly alter basal plasma PP levels (P greater than 0.05). PP release by perfusion of the T-V loop with liver extract was abolished by atropine intravenous bolus (0.2 mg/kg). Although the combination of bethanechol (100 microgram/kg/hr intravenous) and liver extract consistently increased the plasma levels of PP, the values did not attain statistical significance when compared to liver extract alone (P greater than 0.05). The data presented are thus consistent with the hypothesis that there is an enteric phase of pancreatic polypeptide release and that this enteropancreatic reflex is mediated by a cholinergic-sensitive mechanism which might be hormonal or neural.

Animals↗

Bombesin: a vagally independent stimulator of gastrin release.

In this study we demonstrate that bombesin is a potent stimulant of canine gastrin and gastric acid secretion. Bombesin was shown to release almost fourfold more gastrin than a meal by a mechanism which is independent of vagal integrity. An exogenously administered cholinomimetic agent released only minimal amounts of gastrin after vagotomy and virtually none in the intact canine model. The combination of bombesin and bethanechol caused a significant increase in acid secretion compared with bombesin alone and was associated with a marked inhibition of gastrin release both before and after vagotomy. Gastric acid secretion in response to bombesin was not significantly altered by vagotomy. We interpret these data to reflect the sensitivity of bombesin-stimulated gastrin release to gastric luminal pH, although they also suggest the existence of a cholinergic inhibitory mechanism for gastrin release. The data provided by this study are consistent with the hypothesis that bombesin might function as a paracrine neuromodulator of gastrin release. in view of its presence in the nerves and mucosa of human stomach and its potent actions on gastrin release and gastric acid secretion, bombesin may play a role in gastric physiology.

Animals↗

Stimulation of canine pancreatic polypeptide, gastrin, and gastric acid secretion by ranatensin, litorin, bombesin nonapeptide and substance P.

Four dogs with chronic gastric fistulas were give intravenous bombesin nonapeptide (B9), ranatensin, and litorin by constant infusion for 90 min at 1.2 micrograms x kg-1 on separate days. A dose response study with substance P (1.5, 3.0, 60, 18 and 54 micrograms x kg-1 x h-1) was also carried out and all tests compared to a standard protein meal (10g x kg-1). Plasma gastrin and PP were measured by radioimmunoassay and gastric acid by autobiuret titration. Substance P failed to stimulate gastric acid secretion or release either pancreatic polypeptide (PP) or gastrin. Basal gastrin levels were 8 +/-2 fmol/ml. The peak increment of gastrin released by bombesin was 95 +/- 16, ranatensin 22 +/- 6, litorin 18 +/- 4, and meal 39 +/- 5 fmol/ml. Bombesin caused significantly greater release of gastrin than a meal, litorin or ranatensin (P less than 0.01). Basal gastric secretion was 23 +/- 4 microequiv./min. B9 produced a peak acid secretion of 356 +/- 124 muequiv./min. There was no significant difference between the bombesin-like peptides (P less than 0.01). Basal plasma PP was 38 +/- 12 fmol/ml. B9 produced a peak PP increment of 600 +/- 50, litorin 137 +/- 36, ranatensin 98 +/- 11, and a meal 305 +/- 58 fmol/ml. B9 released significantly more PP than either litorin of ranatensin (P less than 0.01). The different amino acid sequences of the peptides are probably responsible for their potency. The substitution of a penultimate phenylalanine residue in litorin and ranatensin for leucine in bombesin does not prevent PP or gastrin release by bombesin-like peptides. Since bombesin-like peptides are widely distributed in the gastrointestinal tract of man and stimulate both acid and gut hormone secretion, it is possible that they might play a physiological role in the modulation of gastrointestinal function.

Animals↗

High potency of bombesin for stimulation of human gastrin release and gastric acid secretion.

Dose-response studies were performed in 6 human volunteer subjects to determine the threshold and optimal doses of intravenous bombesin for stimulation of gastric acid secretion and gastrin release. A significant stimulation of both acid and gastrin was obtained with a very low dose, 3 pmol x kg-1 x h-1. Peak stimulation of acid secretion (67% of pentagastrin PAO) was obtained at 12.5 pmol x kg-1 x h-1. Serum gastrin response to this dose of bombesin was similar to that obtained after a high protein meal. Higher doses of bombesin caused further increases in serum gastrin but not in acid secretion. Since very low doses of bombesin, too small to produce detectable increases in immunoreactive serum bombesin, caused parallel increases in gastrin and acid secretion, it is possible that the bombesin-like peptides present in human gastrointestinal tissues contribute to regulation of human gastric secretion.

Adult↗

The effect of somatostatin and 16,16-dimethyl-prostaglandin E2 on bombesin-stimulated canine gastric acid, plasma gastrin and pancreatic polypeptide secretion.

We studied the effect of the intravenous infusion of 16,16-dimethylprostaglandin E2 methyl ester (di-M-PGE2) and somatostatin on bombesin-stimulated gastric acid secretion, plasma gastrin and plasma pancreatic polypeptide in four chronic gastric fistula dogs. Bombesin-stimulated gastric acid secretion was significantly inhibited by somatostatin and virtually abolished by di-M-PGE2. Both agents caused significant, but indistinguishable inhibition of gastrin release (P less than 0.05). Bombesin-stimulated pancreatic polypeptide release was also significantly inhibited by both somatostatin and di-M-PGE2; the inhibitory effect of somatostatin was significantly greater than that of di-M-PGE2 (P less than 0.05). This study provides further evidence in support of the complex interrelationships between agents responsible for the modulation of gastrointestinal physiology.

16,16-Dimethylprostaglandin E2↗

Variable effect of lithium on canine pancreatic polypeptide and gastrin release by a meal or bombesin.

Lithium is a cation which has central nervous system effects and is able to interfere with both the release and action of polypeptide hormones. We examined its effect on basal and stimulated plasma gastrin and pancreatic polypeptide (PP) levels in 4 dogs with chronic gastric fistulas. Gastrin and PP release were stimulated by a meal or bombesin nonapeptide infusion (1.2 microgram kg-1h-1). The studies were repeated 24h and 14 days after lithium administration (600 mg/12 h) orally. Basal plasma lithium values were undetectable and rose to 0.9 /+- 0.2 mmol l-1 in the acute and 1.0 +/- 0.2 mmol l-1 in the chronically treated animals. The dogs did not have any discernible side effects. Basal plasma gastrin was 14 +/- 4 fmol ml -1 and was not significantly altered by either 1 or 14 days Li+( p greater than 0.05). Gastrin release stimulated by either a meal or bombesin was not significantly decreased by acute or chronic Li+ administration . Acute lithium administration produced a slight but significant increase in meal-stimulated gastrin (p less than 0.01). Neither acute nor chronic lithium administration altered bombesin stimulated gastric acid secretin (p greater than 0.05). Basal PP levels were 24 +/- 7 fmol ml-1 and not significantly altered by 1 or 14 days Li+ administration. Both acute and chronic Li+ inhibited PP release by bombesin in the first 30-min period of the study (p less than 0.01). 14 days Li+ significantly inhibited both first and second hour PP responses to a meal (p less than 0.01). The mechanism of the cationic modification of the release of pancreatic polypeptide requires further elucidation.

Animals↗