Potentiation between Urecholine and gastrin extract and between Urecholine and histamine in the stimulations of Heidenhain pouches

Abstract

EDITORIAL SYNOPSIS These studies clearly establish the existence of true potentiation between Urecholine and gastrin and between Urecholine and histamine in stimulating secretion both of acid and of pepsin.It is frequently said that cholinergic activity, induced either by drugs or by vagal activity, 'potentiates' the acid secretory responses to gastrin or to histamine. The assumption that these combinations of stimuli act in a 'potentiated' rather than an 'additive' fashion is based upon the large augmentations that occur. So far as we have been able to determine, no previous study has provided data that can be analyzed in the manner required to determine whether the combined actions represent addition or potentiation (Gaddum, 1959). Now that methods are available for the preparation of reliably potent gastrin extracts (Gregory and Tracy, 1960) the problem can be studied both with histamine and with gastrin. To provide quantitative data suitable for answering the question about potentiation, we have studied the secretion of acid and pepsin by Heidenhain pouch dogs in response to a range of dose rates of Urecholine (urethane of ,B-methylcholine chloride, a stable choline ester that mimics the muscarinic actions of acetylcholine), gastrin extract, and histamine, given separately and in combination. METHODSObservations were made on five Heidenhain pouch dogs.On each day Urecholine (bethanechol chloride, Merck, Sharp, and Dohme) was given by continuous intravenous injection at a constant rate, the rates on different days varying from 0 25 to 4 mg. per hour. After two hours of Urecholine alone, gastrin extract or histamine dihydrochloride was given by a second continuous intravenous infusion while continuing the injection of Urecholine. The dose rate of gastrin extract or of histamine was doubled every 75 minutes. Secretory rates became relatively steady within 15 minutes ofstarting or increasing the dose of gastrin or of histamine. For this reason the one-hour output from 15 to 75 minutes after each alteration in dose rate was taken as a measure of the response to the combination of drugs. With all but the lowest doses of Urecholine, side-effects occurred, namely, increased salivation, micturition, and defaecation. Because of the severity of these side-effects no test was done with a dose of Urecholiiie greater than 4 mg. per hour. Control runs of Urecholine alone, gastrin extract alone, and histamine alone, over the same dose ranges used in the combined studies, were also done on separate days.Gastrin extracts were prepared from the mucosa of the pyloric gland area of hog stomach by a modification of the method of Gregory and Tracy (1960), as previously described (Gillespie and Grossman, 1963). A single pooled batch of gastrin extract was used for all of the studies reported here. Doses of gastrin are expressed in terms of the wet weight of mucosa represented by the extract.

The Interaction of Histamine with Gastrin and Carbamylcholine on Oxygen Uptake by Isolated Mammalian Parietal Cells

“…Furthermore the presence of phosphodiesterase inhibition by IMX did not alter these findings with carbamylcholine and gastrin. It (16,(21)(22)(23)(24)(25); however, interactions demonstrated in this manner are species dependent and variable in magnitude (15,(26)(27)(28). A dramatic demonstration of secretagogue interactions has been made in studies with the ex vivo canine stomach preparation where marked potentiation was found between histamine and pentagastrin, between histamine and bethanechol, and between pentagastrin and bethanechol (29,30).…”

Gastric secretion in relation to mucosal blood flow studied by a clearance technic.

“…After 1 hour the dose of the stimulant was doubled, followed by successive doublings of the dose each hour until the secretory rate no longer increased with increments in drug dosage (maximal response). At this point bethanechol (0.5 mg) was infused for 1 hour, along with the maximal dose of histamine or gastrin, to induce a supramaximal secretory response (15). In some experiments a steady submaximal secretory response was maintained with histamine or gastrin, and a secretory inhibitory agent (vasopressin, epinephrine, isoproterenol, or secretin) was added to observe the effect of these agents on both secretion and clearance.…”

Rat gastric acid secretion studies with histamine and synthetic gastrin‐like pentapeptide

“…Studies concerning the potentiation between gastric acid secretary stimulants have been made principally in the dog (Brooks, Johnson & Grossman, 1970;Gillespie & Grossman, 1964; Olbe, 1964; Passaro, Gillespie & Grossman, 1963) and in man (Brooks et al 1970;Konturek & Oleksy, 1967;Makhlouf, McManus & Knill, 1968). As the rat is convenient to use in the study of gastric secretion it is desirable to obtain fundamental information concerning the acid secretary process in this species.…”