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Effect of Atropine on Vagal Release of Gastrin and Pancreatic Polypeptide

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Effect of Atropine on Vagal Release of Gastrin and Pancreatic Polypeptide Effect of Atropine on Vagal Release of Gastrin and Pancreatic Polypeptide MARK FELDMAN, CHARLES T. RICHARDSON, IAN L. TAYLOR, and JOHN H. WALSH, Departments of Internal Medicine, Veterans Administration Hospital, Dallas, Texas 75216; University of California at Los Angeles Health Science Center, Los Angeles, California 90093; and The University of Texas Health Science Center at Dallas, Southwestern Medical School, Dallas, Texas 75235 A B S TRA C T We studied the effect of several doses of the rise in serum gastrin concentration induced by in- atropine on the serum gastrin and pancreatic poly- sulin hypoglycemia was further increased by atropine peptide responses to vagal stimulation in healthy premedication (1). In addition, several workers have human subjects. Vagal stimulation was induced by shown that atropine increases the serum gastrin con- sham feeding. To eliminate the effect of gastric acidity centration after an eaten meal (2-4). These observa- on gastrin release, gastric pH was held constant (pH 5) tions, together with the fact that basal and postprandial and acid secretion was measured by intragastric titra- gastrin levels rise after vagotomy (5-7), have led to tion. Although a small dose of atropine (2.3 ,ug/kg) speculation that the vagus nerve can inhibit, as well as significantly inhibited the acid secretory response and stimulate, gastrin release. completely abolished the pancreatic polypeptide re- For several reasons, however, none of these observa- sponse to sham feeding, this dose of atropine signifi- tions proves that the vagus nerve actually inhibits cantly enhanced the gastrin response. Higher atropine gastrin release under normal circumstances. First, doses (7.0 and 21.0,g/kg) had effects on gastrin and studies using insulin hypoglycemia as a vagal stimulant pancreatic polypeptide release which were similar to must be interpreted with caution because there is the 2.3-pAg/kg dose. Atropine (0.78 and 2.3 ,ug/kg) with- evidence that hypoglycemic gastrin release is nonvagal out sham feeding significantly inhibited basal acid (8-10). For example, the gastrin response to hypo- secretion and also led to significant increases in serum glycemia persists after a complete vagotomy (8, 9). gastrin above basal levels. The gastrin response to sham Second, meal studies that have been done with atropine feeding with 2.3 ug/kg atropine was significantly (2-4) are not definitive because atropine reduces acid greater than the sum of the gastrin responses to sham secretion, and the resulting higher antral pH would feeding alone and to 2.3 ,ug/kg atropine alone, indicat- facilitate gastrin release in response to any stimulant. ing potentiation ofvagal gastrin release by atropine. We This criticism is also pertinent to vagotomy studies in conclude: (a) Unlike vagally mediated gastric acid which gastric pH was not controlled. Third, many secretion and pancreatic polypeptide release which can studies that have been done with atropine are inconclu- be blocked by atropine, vagal gastrin release is poten- sive because the effect of atropine alone was not tiated by atropine. This observation suggests the studied. If atropine alone increased serum gastrin con- existence of a vagal-cholinergic pathway which centrations, higher meal- or insulin-stimulated gastrin normally (i.e., in the absence of atropine) inhibits levels would be expected after atropine simply on an gastrin release. (b) Because atropine (without sham additive basis. feeding) increased basal gastrin levels, it is likely that The purpose of our studies was to evaluate more the cholinergic pathway which inhibits gastrin release definitively the effect of atropine on vagal gastrin is active even when the vagus nerve is not stimulated release in man. To do this, we employed a method of by sham feeding. vagal stimulation that acts only through the vagus nerve: sham feeding (11, 12). Antral pH was lield INTRODUCTION constant by in vivo intragastric titration during the The effect of atropine on vagally mediated gastrin course of the experiments so that changes in acid release in man is poorly understood. In a recent study, secretion could not affect gastrin release. We evaluated the effect of several doses of atropine in combination Receivedfor publication 21 April 1978 and in revisedform with sham feeding as well as the effect ofatropine alone 11 August 1978. on serum gastrin concentration. For comparison, the 294 J. Clin. Invest. g The American Society for Clinical Investigation, Inc., 0021-9738179/02/0294/05 $1.00 Volume 63 February 1979 294-298 effect of atropine on vagal release of another hormone, measured at 15 min and immediately before atropine injec- human pancreatic polypeptide, was also studied. tion. Mean basal gastrin levels varied 5 pg/ml or less at these time periods and were therefore averaged. Serum gastrin was also measured at 15, 22.5, 30, 37.5, 45, 60, and 75 min after METHODS atropine. Serum HPP concentration was also measured by radio- Subjects. 10 normal human subjects participated in these immunoassay. Antiserum against HPP (a generous gift of Dr. studies. Six were men and four were women. Their mean age R. A. Chance, Eli Lilly & Co., Indianapolis, Ind.) was used was 29 yr (range, 20-46 yr). Subjects fasted for at least 10 h at a final dilution of 1:1,250,000. Bovine pancreatic polypep- before each study. Their mean (±SEM) peak acid output to tide was labeled by modification of the chloramine T method 6.0 pg/kg pentagastrin subcutaneously (Peptavlon, Ayerst (18), and the tracer was pruified on a 1 x 100-cm Sephadex G- Laboratories, New York) was 37.5±5.4 meq/h. Studies were 50 superfine column (Pharmacia Fine Chemicals, Div. of approved by a Human Research Review Committee and in- Pharmacia Inc., Piscataway, N. J.). Highly purified HPP was formed consent was obtained from each subject. used as a standard for all the assays. Serum was assayed at a Intubation and intragastric titration technique. In all final dilution of 1:10. Separation was performed with charcoal, experiments a radiopaque triple lumen nasogastric tube was and a control tube without antibody was used to correct for used. Tubes 1 and 2 terminated 14 cm proximal to the tip of nonspecific binding. No displacement of tracer from anti- tube 3. Under fluoroscopic guidance the triple lumen tube was serum was found with concentrations of 100 nmol/liter of little positioned so that the tip of tube 3 was in the gastric antrum. gastrin, big gastrin, secretin or vasoactive intestinal peptide, To initiate each experiment 50 ml saline (300 mosm/kg), ad- or with 10 nmol/liter of monocomponent insulin, pancreatic justed to pH 5.0, was infused into the stomach through tube 3. glucagon, or cholecystokinin. The experimental detection This was followed by a continuous intragastric saline infusion limit was 34 pg/ml of serum. The ratio of bound:free (pH 5.0) through tube 1 at a rate of 4.2 ml/min (Brinkman labeled bovine pancreatic polypeptide was inhibited by Peristalic Pump, Desaga Inc., Heidelberg, Germany). Gastric 50% at a concentration of 17 pg/ml HPP in the incubation pH was held constant and acid secretion measured by in vivo tube. The intra-assay precision was 4% and the interassay intragastric titration. Every 2 min, 0.5 ml gastric fluid was precision 8%. Recovery of HPP added to serum deviated no removed through tube 3 and the pH was determined. Sodium more than 17% from the expected values over the range of bicarbonate (0.3 N) was infused into the stomach through tube 40-340 pg/ml serum. Mean (±SE) basal HPP levels with this 2 at a rate sufficient to maintain gastric pH at 5.0. The number assay were 90±8 pg/ml. of milliequivalents of bicarbonate added is equal to the Statistical analysis. All results are expressed as mean±1 number of milliequivalents of acid secreted (13). Previous SE. Differences were determined by paired t test, and values studies have shown (14), and it was confirmed again in this <0.05 were considered significant (19). Integrated gastrin and study, that this continuous intragastric saline infusion has no were calculated effect on basal serum gastrin concentrations. integrated pancreatic polypeptide responses Atropine. After a 60-min control period, atropine sulfate as described (20). (Wyeth Laboratories, Philadelphia, Pa.) was injected intra- muscularly in doses of 0 (saline control), 0.78,2.3,7.0, and 21.0 RESULTS ug/kg total body weight. One atropine dose was given per study day, and the order in which the atropine doses were Gastrin given was randomized. Sham feeding (SF).' 15 min after atropine (or saline) was SF without atropine. As shown in Fig. 1 (left panel), injected, subjects chewed for 30 min, but did not swallow, an SF without atropine led to rises in serum appetizing meal consisting of sirloin steak, french-fried significant potatoes, and water (15). Meals were cooked in a separate gastrin concentrations. By the end of SF (i.e., at 45 min), building so that subjects could not see or smell food until time serum gastrin had risen 15+4 pg/ml (P < 0.005). for SF. Subjects were trained in preliminary experiments not Atropine without SF. Four subjects were given to swallow food. During all experiments, gastric aspirates were 0.78 or 2.3 ,g/kg atropine, without SF, on two sepa- examined for swallowed food and none was found. As shown in Ta- Gastrin and human pancreatic polypeptide (HPP) measure- rate test days in random order. ment. Venous blood was collected through an indwelling ble I, gastrin levels increased in all four subjects in catheter kept open by a slow intravenous 0.15 M NaCl infu- response to the 0.78-,ug/kg dose. The peak gastrin rise sion.
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