Serum gastrin responses to bombesin and food in patients with hypergastrinemia

Serum gastrin responses to bombesin and to food wer studied in patients with hypergastrinemia. Nine unoperated patients with hypergastrinemia of antral origin (seven achlorhydria and two idiopathic G-cell hyperfunction) had significantly higher serum gastrin responses to bombesin (P<0.001) and to food (P<0.001) than eight unoperated patients with Zollinger-Ellison syndrome. Three gastrectomized Zollinger-Ellison patients showed large serum gastrin responses to bombesin, and two of them had large postprandial increases in serum gastrin. Serum gastrin in a single patient with retained excluded antrum in the duodenal stump after partial gastrectomy with Billroth II anastomosis responded to bombesin but not to food. In nonoperated patients with hypergastrinemia of antral origin, the serum gastrin responses to bombesin and to food were significantly correlated (r=0.786;P<0.02) while in unoperated Zollinger-Ellison patients no such correlation was found (r=0.095;P>0.10). It is concluded that determination of the serum gastrin response to bombesin does not provide more information than measurement of postprandial serum gastrin concentrations in the differential diagnosis of patients with basal hypergastrinemia.     

Effect of bombesin on glucose-induced insulin release in humans

The effect of bombesin on basal and glucose-stimulated insulin release was studied in male healthy volunteers. Glucose was administered by oral, intravenous or intraduodenal route during saline or bombesin infusion (5 ng/kg/min for 60 min). The peptide had no significant effect on basal levels of glucose and insulin. However, during its administration, the insulin response and the expected rise in blood glucose after oral glucose load (50 g) were strongly inhibited, and the gastric emptying of liquids was significantly delayed. On the contrary, the insulin response to intravenous glucose (20 g) was significantly increased by bombesin without changes in plasma glucose levels. Finally, when glucose was infused into the duodenum, thus bypassing the stomach, the insulin response was significantly increased by the peptide. In this case, too, plasma glucose levels after glucose load were virtually identical during either bombesin or saline infusion. These data clearly demonstrate that the direct effect of bombesin on insulin release is stimulatory and suggest that the inhibitory effect observed after oral glucose is connected with the action of the peptide on gastric emptying, the delay of which slows the entry of glucose into the small bowel.     

Opposite effects of cholestyramine and loxiglumide on gallbladder dynamics in humans.

The aim of this study was to conduct dose-response studies of the effect of cholestyramine, alone or in combination with a test meal, on gallbladder emptying studied by ultrasonography in 31 healthy volunteers. The role of cholecystokinin in mediating the effects of cholestyramine was studied using the cholecystokinin-receptor antagonist loxiglumide. In the absence of a test meal, cholestyramine produced a dose-dependent decrease in gallbladder volume; minimal residual volumes were 30% (2 g), 55% (4 g), and 110% (12 g) of the minimal volume produced by a test meal alone. Gallbladder volume was still only 50% of the initial volume, 24 hours after ingestion of 12 g cholestyramine. Cholestyramine also enhanced gallbladder emptying in response to the test meal (n = 7). Oral loxiglumide strongly inhibited gallbladder evacuation in response to either test meal (n = 6) or cholestyramine alone (n = 6) but partially blocked gallbladder emptying when the resin was added to the test meal (n = 12). It is concluded that (a) cholestyramine alone or in combination with a test meal produces a marked decrease in gallbladder volume and (b) the action of the resin itself on gallbladder motor function appears to be mainly, but not solely, mediated by cholecystokinin through the disinhibition of the luminal feedback mechanism between bile salts and the endogenous release of cholecystokinin.     

Serum gastrin response to food stimulation in male azotemic patients.

In 37 patients with hypertension and/or renal disease, blood from a peripheral and a renal vein was drawn during renal vein catheterization. The serum gastrin concentrations were determined and found by paired comparison to be statistically significantly (p less than 0.05) higher in the peripheral than in the renal vein. A test meal was given to 9 male controls and 7 male azotemic patients, and the serum gastrin concentration response determined. The mean fasting serum gastrin values were 173 +/- 22 pg/ml in the group of patients versus 42 +/- 5.5 pg/ml in the controls. The serum gastrin response was significantly higher and of longer duration in the azotemic patients than in the controls. The pentagastrin-stimulated gastric acid secretion was, however, equal in the two groups.     

Opposite effects of enalapril and nitrendipine on natriuretic response to atrial natriuretic factor. Renal function evaluated with clearance studies in humans

In clearance studies, we analyzed the effect of Ca2+ entry blockade with nitrendipine treatment (20 mg b.i.d. for 4 days) and of converting enzyme inhibition with enalapril treatment (20 mg b.i.d. for 4 days) on renal response to atrial natriuretic factor (ANF) (25 micrograms bolus followed by an infusion of 0.03 microgram/kg/min for 90 minutes) in six healthy volunteers who were taking 300 mmol sodium daily. In a control study ANF was administered without Ca2+ entry blockade or converting enzyme inhibition. Natriuresis rose from 239 +/- 38 to 605 +/- 137 mumol/min in the control study (p less than 0.05), from 330 +/- 53 to 943 +/- 152 mumol/min with Ca2+ entry blockade (p less than 0.05), and from 236 +/- 22 to 344 +/- 39 mumol/min with converting enzyme inhibition (NS). ANF induced a rise in maximal free water clearance, inulin clearance, and in the excretion of multiple electrolytes except potassium. Fractional lithium reabsorption fell. In general, these effects were stronger during Ca2+ entry blockade and blunted during converting enzyme inhibition. p-Aminohippurate clearance tended to decrease during the control study (NS), remained constant during Ca2+ entry blockade, and decreased significantly when ANF was infused during converting enzyme inhibition (p less than 0.05 vs. control and vs. Ca2+ entry blockade study). Blood pressure was lowered by Ca2+ entry blockade and, to a somewhat greater extent, by converting enzyme inhibition, but ANF administration induced no additional fall except for a short-term drop during Ca2+ entry blockade.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of bombesin on extragastric gastrin in man

The effect of a protein test meal and a bombesin infusion on extragastric gastrin levels was studied in patients with truncal vagotomy, antrectomy, and gastroduodenostomy or gastrojejunostomy and in patients with total gastrectomy. In patients with vagotomy, antrectomy, and gastroduodenostomy and in patients with total gastrectomy the gastrin levels were raised by 33% and 35%, respectively, from basal after test meal, while during BBS infusion gastrin values decreased by 25% and 30%, respectively, from basal. In patients with vagotomy, antrectomy, and gastrojejunostomy, test meal and BBS infusion did not significantly alter basal gastrin values. It is concluded that BBS does not stimulate extragastric gastrin.     

Regulatory mechanism of bombesin on gastrin release

Bombesin has been demonstrated to stimulate gastrin release by an atropine-resistant mechanism. In the present study, the effects of truncal vagotomy and chemical sympathectomy on the gastrin release by exogenous and endogenous bombesin using rat antral mucosa in tissue culture were studied. Exogenous bombesin 10^-8 mol/l significantly stimulated gastrin release. The stimulation of gastrin release by bombesin was abolished by truncal vagotomy, but not altered by chemical sympathectomy. Bombesin antiserum inhibited gastrin release by blocking the effect of endogenous bombesin. The inhibition of gastrin release by bombesin antiserum was abolished by truncal vagotomy, but not altered by chemical sympathectomy. In addition, the concentrations of bombesin-like immunoreactivity in antral mucosa were not altered by truncal vagotomy. These results suggest that the mechanism of gastrin release by bombesin is influenced by non-cholinergic local nerves under vagal control.     

Long-term changes in gastrin, cholecystokinin and insulin in response to oxytocin treatment

The present study was designed to investigate how repeated injections of oxytocin influence plasma levels of vagally controlled hormones such as gastrin, cholecystokinin (CCK), insulin and somatostatin, as well as of endogenous oxytocin and glucose. Since oxytocin may enhance the activity of centrally located alpha2-adrenoreceptors, a second aim of this study was to explore whether these receptors are involved in the effects. For this purpose, oxytocin (1.0 mg/kg) or NaCl was given subcutaneously (s.c.) once a day during 5 days to male rats. Rats were decapitated 1, 3 and 10 days after the last injection, blood was collected and hormone levels were radioimmunoassayed. The oxytocin treatment caused an elevation of plasma levels of oxytocin 1 day (p < 0.05) but not 3 and 10 days after treatment. Gastrin levels were decreased on day 1, 3 and 10 (ANOVA; p < 0.01). In addition, both insulin and CCK levels were decreased in response to the oxytocin treatment when measured 3 and 10 days after the last injection (ANOVA; insulin p < 0.01, CCK p < 0.05). When the alpha2-adrenoreceptor agonist clonidine (2.5 microgram/kg intracerebroventricularly) was administered 3 days after the 5-day treatment period with oxytocin or saline, plasma levels of insulin and CCK increased significantly (p < 0.05) in the oxytocin-treated rats, when compared to saline-treated controls receiving clonidine only. No change in glucose or somatostatin levels was found in response to the oxytocin treatment. In conclusion, these results show that oxytocin induces long-lasting changes in plasma levels of gastrin, CCK and insulin, without affecting somatostatin or glucose levels. These effects may be mediated by changes in vagal nerve activity.     

Serum gastrin response to food stimulation and gastric acid secretion in male patients with ileal resection.

Gastric acid secretion before and after stimulation with pentagastrin and serum gastrin response to a test meal were recorded in 9 male controls and in 7 male patients from whom more than 50 cm of the terminal ileum had been resected because of Crohn's disease. The mean gastric acid secretion before and after stimulation was not found to be significantly different in the two groups. The mean fasting serum gastrin concentration and the serum gastrin response in absolute values were not different in the two groups. The MAO-BAO/'integrated gastrin response' was higher (p less than 0.05), and the gastrin response in relation to fasting level was lower in the patients than in the controls (p less than 0.05). The results indicate that an increased parietal cell sensitivity to gastrin is present after ileal resection. The negative acid feed back mechanism, however, seems to be at work. Under physiological conditions, therefore, the increased sensitivity may not result in acid hypersecretion.     

Effect of bombesin on esophageal motility in humans

We have investigated the effect of bombesin on esophageal motility and explored the mechanism of action of bombesin. Eight healthy subjects were studied in random order during intravenous administration of (1) bombesin, (2) bombesin + vagal cholinergic receptor blockade with atropine and (3) bombesin + somatostatin. Lower esophageal sphincter pressure (LESP) and esophageal body motility were recorded continuously by Dent-sleeve manometry. Bombesin significantly (p < 0.01) increased LESP from 20 +/- 2 mmHg to 43 +/- 6 mmHg. Neither atropine nor somatostatin significantly reduced the bombesin-induced increases in LESP. Bombesin significantly (p<0.05) increased peristaltic wave amplitude (from 61 +/- 4 to 105 +/- 9 mmHg) and duration (from 2.9 +/- 0.2 to 4.8 +/- 0.3 s) in the mid and distal part of the esophagus. Neither atropine nor somatostatin significantly reduced the esophageal body motor response to bombesin. In conclusion (1) bombesin significantly increases LESP and affects esophageal body motility by increasing peristaltic wave amplitude and duration and (2) the effect of bombesin on esophageal motility is not dependent on vagal cholinergic mechanisms and is not mediated by the action of gastrointestinal hormones released by bombesin.     

Peripheral insulin in response to the sight and smell of food

Twenty-five obese and 23 reference women were compared with respect to their peripheral insulin concentrations in response to the sight and smell of food. An additional 21 obese women were examined for different control purposes. The women were examined after fasting for approximately 16 hr. Venous blood samples for determination of glucose and insulin were drawn 20, 10, and 1 min prior to the demonstration of food for 5 min. After the food had been presented to the subjects, samples were drawn at 1, 2, 3, 4, 5, 6, 10, 15, and 20 min. The response was calculated in two different ways: method I--the difference between meal basal insulin values and mean insulin values during and/or after stimulation, and method II--the "insulin area" over the mean basal concentration was calculated for 0-20 min after start of food presentation. Both methods resulted in significantly higher insulin responses in obese as compared to reference subjects. However, when performing duplicate experiments in the same subjects only method II resulted in reproducible results and even with this method the error was as high as 60%-90%. The high error of the method was partly expected since the insulin elevation is most likely not only a function of controlled external cues but also dependent on unknown sensorimotor and cognitive-affective alterations. No insulin response was observed when obese women were exposed to an external cue that was not food related. Atropine completely blocked the insulin elevation in response to food related external stimuli indicating that this insulin response is mediated via vagus.     

Effect of parietal cell vagotomy on acid secretory responsiveness to circulating gastrin in humans. Relationship to postprandial serum gastrin concentration

To study the relationship between gastric acid secretion and serum gastrin concentration after vagotomy, gastric acid output and serum gastrin concentration were measured simultaneously during intravenous infusion of graded doses of human gastrin heptadecapeptide (G-17) in duodenal ulcer patients with parietal cell vagotomy and in unoperated patients with duodenal ulcer disease (controls). The curve relating serum gastrin concentration to gastric acid output was shifted downward and to the right after vagotomy; the peak acid output to G-17 was reduced by 50% (p less than 0.001). The serum gastrin concentration that produced half of peak acid output (EC50%) averaged 185.5 pg/ml after vagotomy and 74.1 pg/ml in controls (p less than 0.01). Mean basal and postprandial serum gastrin concentrations were twofold to threefold higher in vagotomy patients than in controls (p less than 0.005). However, when peak postprandial serum gastrin concentrations were used to predict acid secretion from curves relating serum gastrin to acid output, predicted acid secretion was only 12.6 mmol/h in vagotomy patients compared to 24.4 mmol/h in controls. Parietal cell vagotomy decreases "functional" parietal cell mass, as reflected by a 50% decrease in peak acid output, and also reduces the responsiveness of "functional" parietal cells to gastrin to such an extent that acid secretion is reduced after vagotomy despite basal and postprandial hypergastrinemia.     

Antagonism of receptors for bombesin, gastrin and cholecystokinin in pancreatic secretion and growth.

The effects of bombesin, gastrin and cholecystokinin (CCK) on amylase secretion from the isolated rat pancreatic acini and on DNA synthesis (as biochemical indicator of trophic action) in the pancreas have been examined in 48-hour fasted and 16-hour refed rats with and without administration of specific receptor antagonists for bombesin, gastrin and CCK. Studies on the isolated rat acini revealed that bombesin, gastrin and CCK-8 all showed the same efficacy in their ability to stimulate amylase release. RC-3095, bombesin pseudo-peptide antagonizing bombesin receptors, was effective only in suppressing the amylase response to bombesin but not to gastrin or CCK. Benzodiazepine receptor antagonists for gastrin (L-365,260) and for CCK (L-364,718) showed higher efficacy in the inhibition of amylase release induced by pentagastrin and CCK, respectively, but failed to affect that induced by bombesin. These peptides administered 3 times daily for 48 h in fasted rats increased the rate of DNA synthesis as measured by the incorporation of [3H]thymidine into DNA. The blockade of bombesin receptors abolished the DNA synthesis induced only by bombesin but not by gastrin or CCK. The blockade of gastrin receptors by L-365,260 suppressed the DNA synthesis induced by gastrin while the antagonism of CCK receptors by L-364,718 was effective only against CCK. Refeeding of 48-hour fasting rats strongly enhanced DNA synthesis which was significantly reduced by blocking only the CCK receptors (with L-364,718), but not the bombesin (with RC-3095) or gastrin receptors (with L-365,260).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of press stimulation applied to back skin on gastric emptying and serum gastrin response to solid food

We studied the effect of press stimulation applied to the back skin on gastric emptying and serum gastrin response to solid food in healthy subjects. Although gastric emptying and serum gastrin response were significantly suppressed by press stimulation of T6-9 dermatomes corresponding to the spinal levels which sympathetic outflow to the stomach arise, they were not affected by press stimulation of T10-L1 dermatomes. Plasma levels of ACTH, epinephrine and norepinephrine, which usually increase by stresses acting on the brain, did not change by press stimulation of T6-10 dermatomes. These results suggest that press stimulation applied to the back skin of T6-9 dermatomes suppress gastric emptying and gastrin response to solid food mainly through the spinal cord.     

Leptin response to insulin in humans is related to the lipolytic state of abdominal subcutaneous fat.

Insulin-induced leptinemia in humans appears to be blunted by insulin resistance. We therefore examined the relationship between insulin action and plasma leptin by monitoring regional and whole body lipolysis and plasma leptin levels in 15 premenopausal women (body fat range, 14-59%) during a two-stage euglycemic clamp (insulin was infused 90 min each at 6-10 and 12-20 mU/m2 x min). Microdialysis probes were placed in abdominal and femoral sc adipose tissue. Subjects were given a primed, constant infusion of a stable isotope tracer (2H5-glycerol), and plasma glycerol isotope enrichments were analyzed by mass spectrometry to determine glycerol kinetics. Although there was no mean change in plasma leptin during the clamp (baseline, 16.6 +/- 4.5 ng/mL; final, 16.3 +/- 4.3 ng/mL), there was large interindividual variability in the changes in plasma leptin (range, -18% to +19%). Changes in plasma leptin during the clamp stages were correlated with abdominal dialysate glycerol concentrations (r = -0.44; P < 0.05), but not femoral dialysate glycerol concentrations (r = -0.15), the rate of appearance of glycerol in plasma (r = 0.005), or plasma insulin levels (r = 0.16). The results suggest that insulin-induced changes in plasma leptin are more related to the lipolytic state (i.e. low leptin response when lipolysis is high) of abdominal sc adipose tissue than that of other fat depots.     

Opposite effects of short- and long-term fatty acid infusion on insulin secretion in healthy subjects

Summary Our study investigates short- and long-term effects of infusion of non-esterified fatty acids (NEFA) on insulin secretion in healthy subjects. Twelve healthy individuals underwent a 24-h Intralipid (10% triglyceride emulsion) infusion at a rate of 0.4 ml/min with a simultaneous infusion of heparin (a bolus of 200 U followed by 0.2 U/min per kg body weight). After an overnight fast (baseline), at 6 and at 24 h of Intralipid infusion and 24 h after Intralipid discontinuation (recovery test), all subjects underwent an intravenous glucose tolerance test (iv-GTT) (25 g of glucose/min). Intralipid infusion caused a threefold rise in plasma NEFA concentrations with no difference between the 6- and the 24-h concentrations. Compared to baseline acute insulin response (AIR) (AIR=63±8 mU/l), short-term (6-h) Intralipid infusion was associated with a significant increase in AIR (86±12 mU/l p<0.01); in contrast, long-term (24-h) Intralipid delivery was associated with inhibition of AIR (31±5 mU/l) compared to baseline (p<0.001) and to the 6-h (p<0.03) triglyceride emulsion infusion. Intralipid infusion was associated with a progressive and significant decline in respiratory quotient (RQ). A positive correlation between changes in fasting plasma NEFA concentrations and AIR at the 6-h infusion (r=0.89 p<0.001) was found. In contrast, at the end of the Intralipid infusion period, changes in plasma NEFA concentrations and AIR were negatively correlated (r=–0.87 p<0.001). The recovery test showed that fasting plasma NEFA concentrations, RQ and AIR had returned to baseline values. In the control study (n=8) 0.9% NaCl infusion did not mimick the effect of Intralipid. In conclusion, our study demonstrates that short- and long-term exposures of beta cells to high plasma NEFA concentrations have opposite effects on glucose-induced insulin secretion.Abbreviations NEFA Non-esterified fatty acids - ivGTT intravenous glucose tolerance test - AIR acute insulin response - NIDDM non-insulin-dependent diabetes mellitus     

The effect of beta-adrenergic blockade upon basal and pentagastrin-stimulated gastric acid secretion and upon gastrin response to food.

Beta-adrenergic blockade with 10 mg of propanolol had no significant effect upon the spontaneous gastric acid secretion, while the maximum (pentagastrin) acid secretion was depressed in healthy subjects and patients with duodenal ulcer. The gastrin response to food was significantly higher during beta-adrenergic blockade. It is suggested that a minor part of the maximum acid secretion may be due to activation of beta-receptors, while the gastrin response to food is probably not related to activation of beta-receptors.