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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.

When the evolution of surgery in the treatment of duodenal ulcer is traced it is evident that during the last half-century surgeons have directed their efforts along two main channels. Firstly, search has been made for an operation which would cure the existing ulcer and guarantee prevention of recurrent ulceration; new procedures have been numerous and varied, but, after a brief vogue, most have been shown deficient in some respect. Secondly, and more recently, there have been well-planned clinical trials with accurate follow-up results on some of these procedures, in the hope that a particular single operation would be found to be so superior to others as to be suitable for all patients with duodenal ulcer. Partial gastrectomy, vagotomy with drainage, and antrectomy with vagotomy are well-tried and useful operations, but each carries a risk of recurrent ulceration and of other unpleasant side-effects. The quest for an ideal operation is now being relinquished in favour of a new objective-the selection of an operation or combination of operations which will most accurately meet the requirements of the individual case. The current studies are directed towards the identification of these requirements.Surgical vagotomy, which regularly reduces the basal secretion of gastric juice, the nocturnal secretion, insulinstimulated secretion, and histamine-induced secretion (0.5 mg. of histamine acid phosphate), has also been shown to cause a significant reduction in the maximal histamine secretion as judged by the augmented histamine test (Gillespie, Clark, Kay and Tankel, 1960). This test, preferred to the others on account of its ability to give reproducible results, is routinely used by us to measure the effect of surgical vagotomy on acid gastric secretion.More recently it has been shown that hexamethonium and atropine in combination (" medical vagotomy") is also capable of reducing the augmented histamine response and that a significant correlation exists between this reduction and the reduction due to subsequent surgical vagotomy (McArthur, Tankel, and Kay, 1960). The possible application of these findings to the selection of duodenal ulcer cases suited to vagotomy as surgical treatment was envisaged. In this paper we report the results of such a study. MethodsAll patients included in this study were males with proved duodenal ulcer who had been accepted for surgical treatment. They were selected only in so far B that elderly and poor-risk patients were excluded; treatment by gastro-jejunostomy was preferred in these circumstances. A total of 40 patients have been studied. Regardless of the results of the pre-operative acid tests, each was treated by vagotomy with gastro-jejunostomy.The vagal trunks were divided subdiaphragmatically after mobilization of the lower oesophagus, and a posterior gastrojejunostomy was made at the most dependent part of the stomach.Before operation each patient had two tests: the first was an augmented histamine test; in the second, the effect of medical vagotomy on the augmented histamin...

SUMMARY Purified human urogastrone was given by intravenous infusion to 12 normal volunteer subjects and measurements made of gastric acid, pepsin and intrinsic factor secretion, and of plasma gastrin concentration. Clinical, haematological, and biochemical screening tests were made throughout the period of study. Urogastrone inhibited acid and intrinsic factor secretion whether stimulated by pentagastrin, histamine, or insulin, but had a much less marked effect on gastric pepsin output. Plasma gastrin levels did not alter significantly. Limited dose-response studies showed that 0.25 ,g urogastrone kg-' hr-1 resulted in inhibition of acid output of 80 % and was not associated with clinical side-effects. No significant alteration in any of the haematological or biochemical measurements was observed in any of the subjects.

MATERIALS AND METHODSFive dogs with Heidenhain type denervated fundic pouches created more than six months previously were studied.Secretin and cholecystokinin, prepared by the method of Jorpes and Mutt (1959), were obtained from Vitrum (Stockholm). Gastrin extract was prepared from hog antral mucosa by a modification of the method of Gregory and Tracy (1961) previously described (Gillespie and Grossman, 1963); doses are expressed as the equivalent weight in grams of wet antral mucosa.The dogs were deprived of food overnight before each test. The inhibitory action of the secretin and cholecystokinin was tested against a background of secretion stimulated by continuous intravenous infusion of gastrin extract or histamine given throughout each experiment by a Sigmamotor pump, the rate of flow being 20 ml. per hour. The concentration of gastrin extract or of histamine dihydrochloride in 0.9% sodium chloride solution was adjusted to give the desired dose rates. After the response had reached a plateau of at least four approximately equal successive 15-minute collections, a single intravenous injection of secretin or cholecystokinin (75 clinical units = 0.1 mg. for secretin, 3 mg. for cholecystokinin) was given and collections were continued at 15-minute intervals for at least one and a half hours.The acid concentration was determined by titration with 0.2N sodium hydroxide with phenol red indicator. The results are given as microequivalents per 15 minutes. The control output is the mean of the four 15-minute outputs immediately preceding the secretin or cholecystokinin injection, each subsequent 15-minute output being expressed as a percentage of the control response. In all instances duplicate observations were made on each dog. RESULTS

During studies on Heidenhain pouches in dogs we noted that the responses to certain combinations of gastrin extract plus histamine were greater than would be anticipated on the basis of summation of stimulatory effects ( 1 ) .The study reported here was performed to determine whether the combination of gastrin plus histamine resulted in true potentiation of stimulation of secretion of acid.Methods. Four dogs with Heidenhain pouches were fasted overnight before each study and studies were performed no oftener than twice a week. Gastrin and histamine were given by continuous intravenous injection using a calibrated peristaltic pump that delivered 20 ml/hr. An infusion of 01.15 M NaCl at this rate was maintained throughout the study and the concentration of gastrin and histamine in the infusion fluid was varied to give the desired dosage rates. Gastrin was prepared from mucosa of the pyloric gland area of the stomach of hogs by a method previously described ( 1 ) . Doses of gastrin are expressed as the wet weight of mucosa from which the extract was derived. Doses of histamine are expressed as weight of the dihydrochloride salt. Collections of gastric juice were made every 15 minutes. The volume was measured and the acidity determined by titration with 0.2 N NaOH with phenol red indicator. Output of acid is expressed as niEq/hr for the last 60 minutes of each 75-minute period.As pointed out previously, the simple criterion that response to a combination of agents given simultaneously is greater than the sum

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