Gastric response to meat extract stimulation in patients with gastroduodenal ulcer and patients after vagotomy or antrectomy

Gastric acid secretion basally and in response to intragastric meat extract instillation or to tetragastrin, and circulating gastrin concentration basally and after meat extract stimulation were studied in 67 patients with gastroduodenal ulcer, 30 patients after highly selective vagotomy or selective vagotomy for duodenal ulcer, 12 patients after antrectomy for or gastric ulcer and 10 control subjects. Circulating gastrin concentration increased significantly after meat extract stimulation in control subjects, patients with ulceration and patients after highly selective vagotomy, and acid secretion in each group was increased significantly above basal level. In patients after selective vagotomy, significant increase of circulating gastrin concentration was observed, but it was not associated with significant increase of acid secretion. After antrectomy, neither gastrin nor acid secretion increased significantly after meat extract stimulation. In conclusion, present study suggested that (1) gastric acid secretion in response to intragastric meat extract is chiefly affected by the responsiveness of oxyntic cells and release of antral gastric and that (2) the presence of the antrum is almost essential for acid secretion after a test meal, and release of duodenal gastrin after antrectomy would not be so potent biologically as to result in an acid secretion.     

Gastric response to meat extract stimulation in patients with gastroduodenal ulcer and patients after vagotomy or antrectomy

Gastric acid secretion basally and in response to intragastric meat extract instillation or to tetragastrin, and circulating gastrin concentration basally and after meat extract stimulation were studied in 67 patients with gastroduodenal ulcer, 30 patients after highly selective vagotomy or selective vagotomy for duodenal ulcer, 12 patients after antrectomy for or gastric ulcer and 10 control subjects. Circulating gastrin concentration increased significantly after meat extract stimulation in control subjects, patients with ulceration and patients after highly selective vagotomy, and acid secretion in each group was increased significantly above basal level. In patients after selective vagotomy, significant increase of circulating gastrin concentration was observed, but it was not associated with significant increase of acid secretion. After antrectomy, neither gastrin nor acid secretion increased significantly after meat extract stimulation. In conclusion, present study suggested that (1) gastric acid secretion in response to intragastric meat extract is chiefly affected by the responsiveness of oxyntic cells and release of antral gastrin and that (2) the presence of the antrum is almost essential for acid secretion after a test meal, and release of duodenal gastrin after antrectomy would not be so potent biologically as to result in an acid secretion.     

Bombesin-induced gastroprotection

Bombesin is an endogenous gut peptide that is prominent in the stomach. In addition to its effects on modulating acid and gut peptide secretion, recent evidence indicates that bombesin is a potent gastroprotective agent. This review article examines the ability of bombesin to prevent gastric injury. Its protective actions appear to be mediated primarily via the release of endogenous gastrin, as gastroprotection is negated by blockade of gastrin receptors. Bombesin-induced gastroprotection and gastrin release are modified by somatostatin. Immunoneutralization of endogenous somatostatin increases the ability of bombesin to prevent gastric injury by increasing gastrin release. In mechanistic studies, ablation of capsaicin-sensitive afferent neurons abolishes bombesin-induced gastroprotection while cyclo-oxygenase inhibition partially reverses this effect. Nitric oxide synthase inhibition also negates bombesin-induced gastroprotection as well as the ability of bombesin to increase gastric mucosal blood flow. Taken together, the available evidence indicates that bombesin causes release of endogenous gastrin that activates sensory neurons located in the gastric mucosa. Activation of sensory neurons causes increased production of nitric oxide through activation of constitutive nitric oxide synthase, which leads to a resultant increase in gastric mucosal blood flow and renders the stomach less susceptible to damage from luminal irritants.     

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.     

Proximal gastric vagotomy interferes with a fundic inhibitory mechanism: A hypothesis for the high recurrence rate of peptic ulceration

The mucosa of the proximal stomach contains a powerful inhibitor of acid secretion and gastrin release. The release of this inhibitor is dependent on intact vagal innervation of the proximal stomach. Thus, proximal gastric vagotomy interferes with the release of the inhibitor. After proximal gastric vagotomy for peptic ulcer, recurrence rates increase over time. In addition, there is some recovery of acid secretion. Although nerve regeneration or sprouting has been suggested as the possible explanation for these events, we propose that interference with the inhibitory mechanism of the proximal stomach may be another possible explanation for the increasing ulcer recurrence rates after proximal gastric vagotomy. At present, this is only a hypothesis and is suggested only by indirect evidence. Direct testing of the hypothesis will require complete purification of the inhibitor and the development of a specific radioimmunoassay.     

Mechanisms of gastrin release by bombesin and food

Since bombesin is widely distributed in the gastrointestinal tract and releases gastrin, it may play a physiological role in gastric acid secretion. We compared the effects of an anticholinergic drug, atropine, and a cholinomimetic drug, bethanecol, on gastric release caused by bombesin and by a mixed meal in dogs. Atropine slightly enhanced the gastrin responses to both stimuli. Bethanecol had no effect on food-stimulated gastrin release, but markedly diminished the gastrin response to bombesin. Gastrin release by bombesin appeared to be inhibited by antral acidification. When food and bombesin were given together, the gastrin response was increased in an additive fashion with no evidence for potentiation. The present data provide no evidence for a role of bombesin in food-stimulated gastrin release. However, it could participate in the neural release of gastrin that has been shown previously to be enhanced by small doses of atropine in man.     

Vagal control of gastrin release in the dog: pathways for stimulation and inhibition

The vagus has a dual effect on gastrin: it both stimulates and inhibits its release. To determine the gastric vagal pathways for these opposing effects, plasma gastrin and acid responses to meal (intragastric titration of 15% liver extract, pH 5.5) and to insulin (0.5 U regular insulin intravenously) were studied in seven dogs in three consecutive stages: a control stage, after antral vagotomy (AV), and after subsequent proximal gastric vagotomy (PGV). AV abolished the plasma gastrin response to insulin but had no effect on either basal or meal-stimulated gastrin release. Subsequent PGV caused significant elevation in basal plasma gastrin concentration, no further change in the gastrin response to insulin, but a significant increase in meal-stimulated gastrin release. AV decreased acid response to insulin nonsignificantly and had no effect on meal-stimulated acid secretion. Subsequent PGV reduced by 90% the acid response to insulin, had negligible effect on the gastric fistula acid response to meal, but increased Heidenhain pouch response sixfold. These studies show that vagal stimulation of gastrin release is mediated along direct antral vagal pathways, while vagal inhibition requires intact vagal fibers to the proximal stomach. The mechanism by which the fundic vagal pathways exert an inhibitory influence on the G cell in the antrum is yet to be elucidated.     

The effect of chronic acidification of the canine duodenum on gastrin release from the antrum transplanted into the colon

Exogenous infusion of acid into the canine duodenum inhibits acid secretion stimulated by endogenously released and exogenously administered gastrin. The importance of this mechanism in normal acid homeostasis and in the inhibition of chronic endogenous acid hypersecretion is not established. In this study the classic Dragstedt model antral colonic transplant (ACT) was used to produce endogenous hypergastrinemia and acid hypersecretion. The effects of the ACT when the duodenum was retained in continuity with the stomach (gastroduodenostomy) were compared with those obtained when the duodenum was no longer in continuity with the stomach (gastrojejunostomy). The duodenum markedly suppressed gastrin release (p = 0.003) and gastric acid secretion (p = 0.005) in each of the four dogs. The dogs remained free of ulcers for 8 months after gastroduodenostomy and ACT. However, after conversion to gastrojejunostomy, large, chronic peptic ulcers developed after a mean of 3.5 months. The inhibitory effect of the duodenum on gastric release and gastric acid secretion protected the dog against ulceration for an extended period. The duodenum may be the major site of inhibitory control of acid secretion and endogenous gastrin release in dogs.     

Influence of vagus on mechanisms for stimulation and inhibition of gastrin release

In studies in dogs the gastrin response to food, to bombesin (1 micrgoram/kg-hr), and to somatostatin (2.5 and 5.0 microgram/kh-hr) plus food before and after truncal vagotomy was determined. Vagotomy caused an increase in basal levels of gastrin and in the release of gastrin after bombesin and food. Vagotomy augmented somatostatin suppression of food-stimulated gastrin release in a dose-dependent manner. We suggest that vagotomy causes a loss of both stimulatory and inhibitory vagal effects on gastrin release. Loss of vagal inhibition results in increased gastrin release to bombesin and food. Loss of vagal stimulation results in intensification of somatostatin-induced inhibition of postprandial gastrin release.     

Proximal gastric vagotomy and mucosal antrectomy: a comparative physiologic examination

Proximal gastric vagotomy-mucosal antrectomy (PGV-MA) was devised in an attempt to reduce the cephalic and hormonal phases of acid secretion without disturbing gastric emptying. The current study determines the effects of proximal gastric vagotomy (PGV), or PGV-MA on acid secretion, gastrin, and gastric emptying. Twelve dogs underwent measurement of gastric emptying, fasting and postcibal acid production, and fasting and postprandial gastrin levels. The animals then underwent either PGV or PGV-MA and the studies were repeated. PGV markedly decreased basal acid (P less than 0.001); however, there was still a large postprandial acid increase. In contrast, PGV-MA nearly abolished both fasting and postprandial acid secretion (difference from control and PGV significant at P less than 0.001). Gastric emptying was not significantly altered by either procedure. PGV was associated with increased fasting and postprandial gastrin levels, while PGV-MA produced lower gastrin levels at all intervals than either controls or PGV-MA. PGV-MA emulates the effects of truncal vagotomy and antrectomy on acid secretion, without affecting gastric emptying and deserves further investigation as a possible surgical alternative in the treatment of duodenal ulcer disease.     

Experimental studies on the effect of pyloroplasty on gastric emptying, serum gastrin and duodenogastric reflux in selective proximal vagotomy (SPV)

The influence of selective proximal vagotomy (SPV) and of an additional pyloroplasty (Heineke-Mikulicz) on gastric emptying, acid and gastrin secretion, and duodenogastric reflux was examined experimentally. After SPV, gastric emptying of fluids and a solid meal was significantly faster than before surgery. An additional pyloroplasty did not influence gastric emptying time significantly. Gastrin secretion after stimulation with a protein-rich meal increased significantly after SPV and did not change much after pyloroplasty was added. It can be concluded that increased gastrin secretion after SPV is not a result of delayed emptying. Pentagastrin-stimulated acid secretion was reduced by 70% after SPV and after additional pyloroplasty as well. The results show that reduced acid secretion after SPV causes the rise in serum gastrin levels. After SPV no duodenogastric reflux occurred. An additional pyloroplasty led to a significant rise of bromsulphaleine used as a marker for bile in gastric aspirate. Obviously destruction of the pylorus leads to a loss of its antireflux function. This leads to an antral gastritis which after 3 months is of chronic-atrophic type. A stimulation of gastrin output by bile could not be demonstrated. It can be concluded that after SPV gastric emptying is not delayed. A pyloroplasty does not affect gastrin release and acid secretion. Drainage procedures together with SPV should be avoided to prevent duodenogastric reflux and antral gastritis.     

Gastrin determinations in symptomatic patients before and after standard ulcer operations.

Whereas 67 patients with duodenal ulcer had fasting and 30-minute postprandial mean serum gastrin levels not substantially different from 32 normal subjects, they had substantially higher fasting and histamine-stimulated gastric acid secretion. The increased acid secretion found in patients with duodenal ulcer is not caused by increased serum gastrin levels. Ten patients with recurrent ulcer, after incomplete vagotomy and gastric resection, had high gastric acid secretion and normal serum gastrin levels. Three patients with recurrent ulcer following complete vagotomy and gastric resection, but with retained antrum, had both high gastric acid secretion and high fasting and postprandial secrum gastrin levels. Three patients with Zollinger-Ellison tumors had even higher basal acid outputs and serum gastrin levels. The combination of basic gastric acid secretory studies and serum gastrin determinations may identify three causes of recurrent ulcer: incomplete vagotomy, retained antrum, and Zollinger-Ellison tumor.     

Aberrations in Hollander test response after incomplete vagotomy. Compensating effect of antral resection in the dog.

Acid secretory and serum gastrin responses to 2-deoxy-D-glucose and insulin were compared in gastric fistula dogs before and after partial vagotomy and pyloroplasty or partial vagotomy and antrectomy. The acid response and serum gastrin curve were basically unaltered by partial vagotomy and pyloroplasty. Based on the data presented, the acid response to insulin hypoglycemia appears to be more dependent on the vagal release of antral gastrin than on direct vagal stimulation of the parietal cell. However, acid response to insulin was profoundly suppressed to only 4 per cent of control levels after partial vagotomy and antrectomy. Although acid response to 2-deoxy-D-glucose was also profoundly depressed to 33 per cent of control levels after partial vagotomy and antrectomy, it was seven times greater than that seen with insulin. Serum gastrin response was abolished after antrectomy to either insulin or 2-deoxy-D-glucose. Finally, the question to which we originally addressed ourselves appears to have been answered and, in terms of response to vagal stimulation, antrectomy appears to compensate for incomplete vagal denervation and may lead to aberrations and misinterpretations, raising serious questions as to the validity of the Hollander test in patients who have undergone distal gastric resection.     

Fasting and postprandial serum gastrin levels before and after highly selective gastric vagotomy, truncal vagotomy with pyloroplasty and truncal vagotomy with antrectomy: is there a cholinergic antral gastrin inhibitory and releasing mechanism?

Fasting serum gastrin levels and postprandial gastrin response were measured before and 1 month after highly selective vagotomy, truncal vagotomy with pyloroplasty and truncal vagotomy with antrectomy. The three groups of patients, 12 in each group, were closely matched for age, sex, maximum acid output and completeness of vagotomy. After highly selective and truncal vagotomy an identical and significant increase in fasting gastrin was observed, whereas after truncal vagotomy with antrectomy the pre- and postoperative fasting gastrin levels were not different. The net postprandial gastrin output over basal value was significantly increased after highly selective vagotomy, unchanged after truncal vagotomy and significantly lowered after truncal vagotomy with antrectomy. These results suggest the presence in the intact subject of a cholinergic inhibitory mechanism in the gastric body and fundus for the release of antral gastrin in the fasting and postprandial states and a possible cholinergic facilitatory mechanism for the release of antral gastrin after meals.     

Effect of selective proximal vagotomy and truncal vagotomy on gastric acid and serum gastrin responses to a meal in duodenal ulcer patients.

To assess the effectiveness of selective proximal vagotomy (SPV) in reducing the acid response to food, we have compared pre- and postoperative gastric acid and serum gastrin responses to a meal in 11 duodenal ulcer patients with intractable pain treated by SPV, with those of seven ulcer patients with gastric outlet obstruction treated by truncal vagotomy and drainage (TV + D). Acid secretion was measured by an intragastric titration method which measures acid response to food within the stomach (5% amino acid meal) adjusted to various pH levels (5.5, 2.5, and 1.5). Studies were performed before and two to six weeks after operation. The preoperative intragastric acid output (IGAO) was about 50% of maximal acid response to Histalog. The mean preoperative IGAO at pH 5.5 For 11 SPV patients was 17.4 +/- 3.1 mEq/hour; this was decreased by 72% to 4.3 +/- 1.1 mEq/hour after operation. The mean IGAO at pH 5.5 in nine patients treated by TV + D was 21.6 +/- 3.4 mEq/hour; this was decreased by 67% to 7.3 +/- 2.1 mEq/hour. Gastrin levels were significantly higher in postop than in preop SPV PATIENTS EVEN THOUGH PH values were constant. Gastrin levels were higher in postop TV + D patients than in postop SPV patients. This study demonstrates that acid reduction achieved by SPV is reliable and at least comparable with that achieved by turncal vagotomy. Postoperative elevation of gastrin in the SPV patients suggests that the vagus may release a humoral inhibitor of gastrin release from the gastric fundus; there may also be a further direct vagal inhibitor of antral gastrin release.     

Effect of intraduodenal acid on the pre- and postvagotomy basal gastric secretion and gastrin.

Acid instillation into the duodenum inhibits basal and stimulated gastric secretion. In man vagotomy suppresses this secretory inhibition. It is postulated that such inhibition responds to a dual mechanism: an hormonal one (enterogastrone) and a nervous one (vagus nerve). This study showed that preoperative duodenal acidification of duodenal ulcer patients results in a decrease in basal gastric secretion and in gastrin levels. On the contrary, in patients submitted to vagal denervation--either through truncal division or highly selective vagotomy--duodenal acidification does not inhibit gastric secretion; however, a drop occurs in basal gastrin levels. An intact gastric vagal innervation therefore, seems necessary for the preservation of the sensitivity of the parietal cell to the effect of hormonal inhibitors, it being immaterial whether duodenal innervation is present or not, as that duodenal acidification provokes a significant fall in serum gastrin levels as determined by radioimmunoassay. This hormonal decrease produced by duodenal acidification can be explained by the inhibition of gastrin release from the antrum. Agreement is expressed with the opinion of other authors that highly selective vagotomy does not appear to carry any advantage over truncal section of the vagus nerves from the standpoint of the inhibitory mechanism of gastric secretion from the duodenum.     

Effect of vagotomy with conservative stomach resection on the level of blood gastrin]

The concentration of gastrin in blood prior to and after vagotomy, associated with economic gastric resection, was determined radioimmunologically in patients with duodenal ulcerous disease. In patients with ulcerous disease of the duodenum insulin hypoglycemia resulted in an increased gastrin concentration in blood. Vagotomy associated with economic gastric resection has led to disappearance of this effect and to a decrease in the gastrin concentration in blood. There was stated the role of extragastric sources in the production of gastrin and the inhibitory effect of the vagus on the release of gastrin from these sources. Following vagotomy, associated with economic gastric resection, only gastrin produced by extragastric sources is circulating in blood. Vagotomy with economic gastric resection affecting both phases of gastric secretion is a high effective and pathogenetically grounded method of therapy for ulcerous disease of the duodenum.     

Parietal cell ultrastructure and acid secretory function before and after vagotomy

Vagotomy was performed in 238 consecutive patients with duodenal ulcer since 1977. Electron microscopy of parietal cells from gastric body mucosa, gastric acid secretory test, and serum gastrin evaluation were done in randomly selected 15 PCV and 13 SV+A cases before and after vagotomy. It was found that 2-6 weeks after the surgery, the ultrastructure of parietal cells presented the feature of secretory depression and gastric acid output was decreased. One to ten years after PCV, the ultrastructure gradually regained its preoperative morphology, serum gastrin level was also increased, though acid output remained on low level. During the same period, patients undergoing SV+A were characterized with the feature of depressed secretion in gastric mucosa ultrastructure, and constantly low level of gastric acid output and serum gastrin. These results, in the authors' belief, may explain low gastric acid output after vagotomy and provide theoretical basis for the application of vagotomy in surgical treatment of duodenal ulcer.     

A new intraoperative test for completeness of vagotomy: the PCP-GABA (beta-parachlorophenol-gamma-aminobutyric acid) test

PCP-GABA, an analogue of the neurotransmitter amino acid, GABA, is as effective a stimulant of vagal centers and acid secretion as sham feeding. Insulin hypoglycemia, a test hitherto widely used for the cephalic phase, is unsafe and nonspecific because it also stimulates catecholamine release which affects gastrin secretion. PCP-GABA, unlike insulin, causes no tachycardia or hypoglycemia; however, the major advantage of PCP-GABA is that it can be used safely intraoperatively to assess completeness of vagotomy. Its muscle relaxant action is an additional advantage in this regard. As an intraoperative test, PCP-GABA is given intravenously shortly after induction of anesthesia to stimulate acid secretion and to reduce gastric mucosal pH, which is measured by an intraluminal combination electrode. The electrode can be moved around through the intact gastric wall to take measurements from multiple sites. When vagotomy is complete, gastric mucosal pH increases to over 6. This test works well in the dog. We hope to assess its clinical use in the near future.     

The effects on gastrin and gastric secretion of five current operations for duodenal ulcer.

We have measured serum gastrin and gastric acid secretion in 66 duodenal ulcer patients before and after vagotomy and pyloroplasty (V + P--15 patients), selective proximal vagotomy without drainage (SPV - D--11 patients), and with drainage (SPV + D--19 patients), and vagotomy, antrectomy, and either gastroduodenostomy (V + BI--15 patients) or gastrojejunostomy (V + BII--6 patients). Basal and peak postprandial gastrin levels were increased in postoperative V + P, SPV - D, and SPV + D patients. Basal and peak postprandial levels of gastrin were unchanged after V + BII, indicative of duodenal release of gastrin. Gastrin response to food was abolished in V + BII patients. Acid output was reliably reduced after all five operations; reduction was greatest in patients after antrectomy and least in patients after SPV. No beneficial results were found with drainage in SPV patients. Acid secretion increased with time in SPV patients, especially those with drainage.