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Chronic stimulation of the antral gastrin cells by elevated antral pH was achieved by fundectomy, antrum exclusion, fundectomy plus antrum exclusion, antrocolic transposition, and vagal denervation plus pyloroplasty. For comparison we studied also the effects of pyloroplasty alone and of portacaval shunting. All operations that elevated the antral pH resulted in high gastrin concentrations in serum. Particularly high concentrations were observed in fundectomized rats. Vagal denervation of fundectomized or antrum excluded rats reduced the serum gastrin concentration slightly compared with the corresponding innervated animals. Portacaval shunting reduced the gastrin concentration in serum. The antral gastrin concentration was raised or unchanged following fundectomy and vagal denervation, and reduced following antrum exclusion, antrum exclusion plus vagotomy, fundectomy plus antrum exclusion, fundectomy plus vagotomy, antrocolic transposition and portacaval shunt. The gastrin cell density in the antral mucosa was raised following fundectomy, vagotomy, and fundectomy plus vagotomy, unchanged following fundectomy plus antrum exclusion and antrocolic transposition, and reduced following antrum exclusion and portacaval shunting. Ultrastructurally the gastrin (G) cells in the excluded antrum and in the antrum of fundectomized rats showed signs of secretory activity in that the granule volume density or the number of granules per unit cytoplasm was lowered. In the fundectomized rats moreover, the endoplasmic reticulum of the G cells was increased, the Golgi area enlarged and the proportion and volume density of electron dense granules greatly increased. The granule profile diameter was not affected by either antrum exclusion or fundectomy. The results on the excluded antrum indicate that elevated antral pH per se is not sufficient to produce gastrin cell proliferation. In the fundectomized rats, where the hyperlasia of antral gastrin cells was considerable, there is the added stimulus of ingested food. In fundectomized plus antrum excluded rats this stimulus is eliminated and no proliferation ensues. The passage of intestinal material, as in the rats subjected to antrocolic transposition, did not elicit gastrin cell proliferation which seems to suggest that the character of the luminal material is important. We propose therefore that gastrin cell proliferation is due to the combined stimulation of high antral pH and passage of food. Vagal innervation is not required.

1. Pylorus ligation stimulated the acid output in vagally intact rats. The serum gastrin concentration and the gastric mucosal histamine content were not affected. The gastric histidine decarboxylase activity was initially slightly elevated and then greatly reduced (12-20 hr after ligation).2. Pylorus ligation stimulated the acid output in chronically, but not in acutely, vagotomized rats. Chronic vagotomy raises the serum gastrin concentration, the gastric histamine content and histidine decarboxylase activity. The serum gastrin concentration was further raised by pylorus ligation. The histamine content was initially lowered but returned to preligation values after 20 hr. The histidine decarboxylase activity first decreased, but increased to very high levels 5-6 hr after ligation. Twelve hours after ligation it was lower than before ligation.3. Following pylorus ligation pentagastrin and histamine stimulated the acid output in vagally intact and in acutely vagotomized but not in chronically vagotomized rats. By contrast, pentagastrin raised the histidine decarboxylase activity in vagally intact and in chronically vagotomized, but not in acutely vagotomized rats.4. The two major populations of endocrine cells of the oxyntic gland area (ECL cells and A-like cells) are argyrophil, store histamine and are capable of taking up exogenous DOPA and of decarboxylating it to dopamine which is retained in the cytoplasm for several hours. As evidenced by light and fluorescence microscopy pylorus ligation did not affect their argyrophilia or their ability to produce and store dopamine.5. Pylorus ligation caused ultrastructural changes in the gastrin cells of the pyloric gland area and in the histamine-storing ECL and A-like cells of the oxyntic gland area. The two endocrine cell types in the oxyntic gland area were enlarged by pylorus ligation, more so after 16 hr than after 4 hr. The size of the gastrin cells seemed unaffected. In all three cell types pylorus ligation reduced the number of cytoplasmic granules. There was no increase in the Golgi area or in the endoplasmic reticulum in any of the endocrine cell types of the oxyntic gland area. It appears unlikely that the ultrastructural changes of the ECL and A-like cells reflect an increased rate of histamine mobilization.6. The acid response to pylorus ligation probably reflects neuronal reflex mechanisms exclusively. There is no evidence that gastrin or histamine released from gastric endocrine cells mediate the response.

1. The effect of vagotomy on gastric acid secretion was studied in chronic gastric fistula rats at various times after denervation. In these rats basal and pentagastrin-induced acid output was permanently reduced. Thus, the magnitude of the acid response to pentagastrin in the conscious fistula rat is dependent upon an intact vagus. 2. The acid response to pylorus ligation in vagally intact rats was unaffected by drainage of the stomach and therefore not caused by distension. Bilateral vagotomy, performed simultaneously with the ligation, completely abolished acid secretion, while unilateral vagotomy reduced the acid output by half. Hence, in innervated rats, an intact vagal impulse flow appears to be essential for the acid response to pylorus ligation. When the pylorus ligation was performed 2-8 weeks after truncal vagotomy, the acid output showed a progressive return towards pre-denervation values. In the denervated rats the acid response to pylorus ligation was blocked by drainage of the stomach and therefore probably caused by distension, a mechanism which is independent of the vagal impulse flow. 3. The response to pylorus ligation in innervated rats was blocked by atropine and chlorisondamine but not by metiamide. In the denervated rats, the response to pylorus ligation was blocked by all three drugs. 4. Following ligation of both the pylorus and the oesophagus the acid response was poor. With drainage of the oesophagus the acid response was much enhanced, suggesting that oesophageal distension inhibits acid secretion. In the vagotomized rat the poor acid response to oesophageal + pyloric ligation could not be overcome by drainage of the oesophagus. In the innervated rat gastric distension could overcome the inhibition induced by oesophageal ligation. Also in chronically, but not in acutely vagotomized rats, gastric distension brought about a good acid response. Conceivably, gastric reflex mechanisms can activate acid secretion through vagal and/or intramural pathways. Both in innervated and denervated rats the response to gastric distension was inhibited by atropine, chlorisondamine and metiamide. 5. The results suggest that in the innervated rat vago-vagal reflexes are important for the gastric hypersecretion following ligation of the pylorus, and for the acid response to gastric distension following ligation of the pylorus and oesophagus. In the chronically vagotomized rat local intramural reflexes elicited by gastric distension are responsible for the acid response.