Effect on gastric secretion, gastrin and histamine release during and after long-term treatment by pirenzepine in dogs.

We assessed the effects of pirenzepine (2 mg/kg per os) on gastric secretion and gastrin and histamine release in response to food and histamine dihydrochloride infusion in four dogs during 24 weeks of treatment and for 15 weeks after the end of treatment. The results were compared to those obtained in the same animals in control experiments, before treatment, and in four untreated dogs. Pirenzepine absorption was checked by measuring plasma concentrations. Pirenzepine led to a significant reduction in acid and pepsin secretion in response to histamine. In response to food, the reduction in secretion was concomitant with a reduction in gastrin and histamine release. Baseline concentrations of gastrin were reduced, while those of histamine were unchanged. No side effects were observed. After treatment, a long time lapse (about 15 weeks) was required for acid and pepsin secretion and gastrinemia to return to control levels, while histamine release in response to food normalized rapidly. Pirenzepine fixes selectively to M1 muscarinic receptors of the synaptic ganglion, thus inhibiting the effect of vagal stimulation, especially on pepsin secretion. Our data suggest that it might also fix to M1 receptors located on ECL cells, thereby reducing histamine release. In addition, pirenzepine probably fixes to other muscarinic receptors inhibiting gastrin release and resulting in a G and secretory cell mass reduction, probably by increasing somatostatin release.

[Psychosensory initiation of gastric secretion in dogs. Inter-relation of vagal component, gastrin, histamine and somatostatin]. / Initiation psycho-sensorielle de la sécrétion gastrique du chien. Inter-relations entre composante vagale, gastrine, histamine et somatostatine.

The effects of vagal stimulation on gastric secretion and on blood gastrin, histamine and somatostatin release have been assessed in three esophagostomized dogs equipped with gastric fistula and Heidenhain pouch. The animals were submitted to sham feeding of variable duration (from 2.5 to 12.5 min) and composition. In response to standard composition of the sham feeding, acid and pepsin responses were observed in the gastric fistula only; they were closely related to the sham feeding duration. Integrated histamine responses were also closely related to sham feeding duration and were correlated with acid or pepsin responses. Gastrin was released by sham feeding induced-vagal stimulation, but there were no relationship between gastrin and secretory responses. Somatostatin release decreased as duration of sham feeding stimulation increased and correlated negatively with acid or pepsin responses. Modified standard sham feeding, by adding either lipids or glucids resulted in the same gastric and hormonal responses as standard sham feeding. It appears that 1 degree) vagal stimulation resulting in the psychosensorial receptors stimulation can be quantified, 2 degrees) histamine reduces somatostatin release and could represent a non cholinergic vagal mediator, capable of controlling somatostatin release in the cephalic phase of gastric secretion.

[Experimental models in studying gastric secretion in dogs: innervated pouch, denervated pouch, cervical esophagostomy. Execution, monitoring, use]. / Modèles expérimentaux d'étude de la sécrétion gastrique chez le chien: poche innervée, poche dénervée, oesophagostomie cervicale. Réalisation, surveillance, utilisation.

Different surgical models are used in the dog for studying gastric secretion: gastric fistula, denervated Heidenhain pouch, innervated Amdrup pouch and cervical esophagostomy. The surgical procedures are described as well as the care and the monitoring allowing long-term survival of the animals. The association of gastric fistula - Heidenhain pouch has been assessed 30 times and 8 times with cervical esophagostomy. The death-rate was been 7% and the morbidity 24%. Three dogs were provided with an Amdrup pouch. Calibration of the animals allowed the acid and pepsin secreting dose-response to be platted and translation according to lineweaver-Burk or Dowd and Riggs is used to calculate the efficient dose (ED 50) and the maximal response (maxR). Pharmacological or physiological effects might be analyzed in regard to the modification of these parameters in response to a pharmacological agonist or antagonist substance. Some physiological studies could be made using sham-feeding on dogs fitted with a cervical esophagostomy.

The somatostatin/histaminic pathway balance on gastric secretion could be based on a competitive antagonism.

Measurements of acid and pepsin secretions and of histamine release in response to food alone or in combination with graded doses of antramine (AH), a molecular form of histamine isolated from antral mucosa, with or without somatostatin were performed simultaneously in dogs equipped with a denervated pouch. AH restored somatostatin-inhibited acid and pepsin secretions but with different intensities in regard to the different inhibitory levels induced by somatostatin. AH competitively antagonized somatostatin (1 microgram/kg/h) inhibition of acid secretion, but when stronger levels of inhibition were achieved, AH restored weakly acid secretion. Recovery of pepsin secretion occurred through a competitive mechanism between AH and somatostatin (1 and 2 micrograms/kg/h). There was a close relationship between the secretory outputs and the integrated histamine responses; the slopes of the regression lines might be considered as reflecting the stimulatory activity of blood histamine on secreting cells. For acid secretion, this activity is similar in control and somatostatin (1 microgram/kg/h) tests, while for pepsin secretion it is identical in control and 1 or 2 micrograms/kg/h somatostatin tests. One can speculate that the suppression of the somatostatin inhibitory effects by antramine, within the limits of physiological conditions, results from a competitive mechanism.

The antigastrinic effect of a phenothiazine (LM 24056) prevents gastric secretory activity of histamine.

Gastric antisecretory phenothiazine LM 24056 inhibited acid and pepsin responses to feeding in dogs. Administered perorally two hours before feeding, LM 24056 reduced significantly the secretory responses to combinations of feeding either with antramine, a natural histamine derivate, or with synthetic histamine. LM 24056 reduced circulating gastrin levels (p less than 0.01 and p less than 0.001) and gastrin responses to feeding (p less than 0.01) without modifying neither circulating histamine concentrations nor histamine responses to feeding. The residual acid and pepsin secretions were closely related to gastrin reduction and endogenous or exogenous histamine, by themselves, seemed to be unable to recover the levels of secretory responses observed in response to feeding alone or in combination with antramine or histamine. These data favour a new scheme of gastric secretion regulation where gastrin would be the last step for stimulating parietal and chief cells. LM 24056 by reducing circulating gastrin prevents stimulatory effect of exogenous or feeding-released endogenous histamine. Histamine would not be thus the final common mediator for gastric secretion.