Nervous control of gastric and pancreatic secretory response to 2-deoxy-D-glucose in the dog

The relative contribution of the vagus and splanchnic nerves as mediators of the action of 2-deoxy-D-glucose (2-DG) on the stomach and the pancreas is largely unknown. In conscious dogs with gastric and pancreatic fistulas, the effect of 2-DG (100 mg kg-1, given as an intravenous bolus) on gastric acid and pancreatic exocrine secretion was tested before and after bilateral truncal vagotomy and after truncal vagotomy plus celiac and superior mesenteric ganglionectomy (i.e. extrinsic denervation of the stomach and the pancreas). In another set of dogs, only ganglionectomy was performed and the same experiments were done as in the first set of dogs. With the extrinsic nerves intact, 2-DG caused a rapid (within 15 min) and prolonged increase in gastric acid output as well as in pancreatic flow rate, bicarbonate and protein output. Truncal vagotomy abolished the gastric acid and pancreatic secretory response to 2-DG; additional ganglionectomy had no further effect. Ganglionectomy alone did not significantly alter 2-DG-stimulated gastric acid output, pancreatic flow rate and bicarbonate output; protein output, however, was significantly diminished by 57%. These results indicate that (a) intravenous 2-DG is a potent stimulant of gastric acid and pancreatic bicarbonate and protein output; (b) the vagus nerves are the major mediators of the gastric and pancreatic secretory response to 2-DG; (c) the sympathetic nerve fibers running through the celiac and superior mesenteric ganglia are probably not involved in the mediation of the 2-DG-induced gastric acid and pancreatic bicarbonate secretion. The diminished protein response to 2-DG after ganglionectomy is probably due to cut vagal fibers running through these ganglia.     

Cephalic phase of colonic pressure response to food.

A cephalic phase of colonic pressure response to food was sought in five normal subjects (mean age (22.6) years, 22-24), studied on six separate occasions by recording intraluminal pressures in the unprepared sigmoid colon. Gastric acid secretion was measured simultaneously by continuous aspiration through a nasogastric tube. After a 60 minute basal period, one of five 30 minute food related cephalic stimuli, or a control stimulus was given in random order; records were continued for a further 120 minutes. The cephalic stimuli were: food discussion, sight and smell of food without taste, smell of food without sight or taste, sight of food without smell or taste, and modified sham feeding; the control stimulus was a discussion of neutral topics. Colonic pressures were expressed as study segment activity index (area under curve, mm Hg.min) derived by fully automated computer analysis. Gastric acid output was expressed as mmol/30 min. Food discussion significantly (p < 0.02, Wilcoxon's rank sum test) increased colonic pressure activity compared with control or basal activity. Smell of food without sight or taste also significantly (p < 0.03) increased the colonic pressure activity compared with control and basal periods. Sham feeding and sight and smell of food without taste significantly (p < 0.02 and p < 0.03) increased colonic pressures compared with control but not basal activity. The increase in colonic activity after sight of food without smell or taste was not significantly different from control or basal activity (p = 0.44 and p = 0.34). Food discussion was the strongest colonic stimulus tested. Food discussion and sham feeding significantly (p<0.02) stimulated gastric acid output above control and basal values. Sight and smell of food without taste significantly (p<0.02) increased acid output above basal. Smell of food without sight or taste and sight of food without smell or taste did not significantly (p=0.06, p=0.34) increase acid output. In contrast with the effect on colonic pressures, sham feeding was the best stimulus of acid output. Increased colonic pressure activity after food discussion correlated significantly (r=0.45, p<0.02) with gastric acid output. There was no correlation (r=-0.1, p>0.5) between colonic pressure activity and gastric acid output in the control study. These data show that there is a cephalic phase of the colonic response to food.     

Central alpha 2 adrenoceptor-mediated pancreatic exocrine response to yohimbine in anesthetized dog

Effects of yohimbine on the secretion of pancreatic juice in anesthetized dogs were investigated. Intravenous yohimbine (0.1-1 mg/kg) caused dose-dependent increases in the secretion of pancreatic juice and vasodilation. However, intra-arterial yohimbine (0.3-1 mg) did not cause any secretory responses. The secretory activity of 0.3 mg/kg of yohimbine was approximately equal to that of 0.04 U/kg of secretin and 40 mg/kg of 2-deoxy-D-glucose (2-DG). Secretory responses to yohimbine were inhibited by pretreatment with clonidine or atropine and abolished by vagotomy. The concentration of protein in the pancreatic juice induced by yohimbine was increased, but the bicarbonate concentration was scarcely changed. These results indicate that yohimbine stimulates, at least in part, pancreatic exocrine secretion by acting on the central alpha 2 adrenoceptor in the dog.     

Diabetic autonomic neuropathy and impaired human pancreatic polypeptide secretion in response to food

In normal subjects, the early human pancreatic polypeptide (hPP) increase induced by food is mainly dependent on vagal activity. Parasympathetic function and plasma hPP response to a standard mixed meal were evaluated in 10 long term insulin-dependent (type I) diabetic patients (group A), 6 age-matched newly diagnosed type I diabetic patients (group B), and 8 normal subjects. The indices of vagal function (beat to beat heart rate variation during deep breathing and the Valsalva maneuver) were uniformly altered in group A, while they were in the normal range in group B, thus excluding in these latter patients the presence of vagal damage. Plasma hPP in response to standard mixed meal was measured at 5, 15, 30, 60, and 120 min. Fasting plasma hPP concentrations (determined by RIA) in groups A and B (mean +/- SEM, 113 +/- 21 and 83 +/- 21 pg/ml, respectively) did not significantly differ from normal (59 +/- 12 pg/ml). In group A, the initial meal-induced hPP increase was significantly lower than normal (5 min, 139 +/- 12; 15 min, 173 +/- 24; 30 min, 137 +/- 17 pg/ml; P less than 0.01 vs. 5 min, 412 +/- 76; 15 min, 446 +/- 57; 30 min, 325 +/- 56 pg/ml). All group B patients had a marked early increase in the peptide, similar to that in the normal subjects. These results suggest that diabetic autonomic neuropathy is associated with dysfunction of hPP secretion, and the evaluation of hPP in response to SMM may be considered a sensitive and nonstressful method for the assessment of parasympathetic impairment in diabetes.     

Influence of environmental conditions on exocrine pancreatic response to intravenous injection of ethanol or 2-deoxyglucose in the dog

When dogs have free access to the outside, an intravenous injection of ethanol depresses secretin-stimulated exocrine pancreatic secretion by a vagally mediated mechanism. This was shown in two separate series of six and seven dogs each. When dogs were kept in air-conditioned windowless kennels, the response to a meal was unchanged but the response to ethanol was reversed to stimulation. In four dogs, ethanol 1 g/kg was given during a secretin infusion. Three months after changing from open to closed kennels the inhibition (–86% for protein output) was still present, but after 6 months ethanol produced a stimulation (+62%) of pancreatic secretion. This increase was abolished, but not reversed, by keeping the animals outside during the day for four weeks, whereas after three months there was a partial restoration of the inhibitory effect (–39%). In contrast, changing from an open to a closed kennel changed the initial response to 2-deoxy-d-glucose (2-DG), 100 mg/kg, from stimulation to inhibition. These results suggest that environmental conditions affect the cranial regulation of pancreatic secretion.     

The gastric secretory response to a continuous insulin infusion in the dog

The gastric acid response to graded doses of insulin given by continuous infusion was studied in four dogs, each surgically provided with a gastric fistula. All doses of insulin resulted in a prolonged plateau of hypoglycaemia and the degree of hypoglycaemia correlated significantly (p <0.05) with the insulin dose, up to 0.15 u/kg hr. Similarly, graded doses of insulin (up to 0.15 u/kg hr) produced graded acid responses and both the peak acid output and the total acid output correlated significantly with blood glucose changes. No initial inhibitory phase of acid secretion followed the start of the infusion, but a dose-related delay in the onset of the acid response was observed. Our results indicate that insulin provides a quantitative glycopenic stimulus producing a quantitative vagal acid response.     

The integrated response of the cardiovascular system to food.

To obtain information about the integrated response of the cardiovascular system to food, cardiac output and regional blood flow (superior mesenteric artery, renal artery and calf blood flow) were measured in 14 normal young healthy subjects after an overnight fast and following a standard 800-kcal meal. Results were compared with 8 subjects who remained fasted throughout the study. Cardiac output increased from a mean (SEM) fasting value of 4.8 (0.3) l/min to a peak after 30 min of 6.1 (0.5) l/min (p < 0.001). Superior mesenteric blood flow increased from a fasting value of 463 (45) to a peak of 854 (110) ml/min also after 30 min (p < 0.001). These changes were accompanied by a significant fall in both systemic vascular resistance and superior mesenteric vascular resistance (p < 0.001). Only at the 15-min postprandial measurements was there a significant relationship between the increase in cardiac output and superior mesenteric artery blood flow (r = 0.62, p = 0.02). Calf blood flow increased and vascular resistance fell postprandially (p < 0.05), but there was little change in right renal artery blood flow. There was an insignificant fall in renal vascular resistance. Heart rate increased from a resting value of 65 (3) to a peak of 77 (4) beats/min after 15 and 30 min (p < 0.001), diastolic blood pressure fell postprandially with little change in systolic blood pressure. These results suggest that in healthy young subjects the increase in gut blood flow is met by an increase in cardiac output, with little evidence of redirection from other vascular beds. The early postprandial increase in superior mesenteric blood flow may account for the increase in cardiac output, although the magnitude of the change is much greater for cardiac output than superior mesenteric artery blood flow.     

Colonic response to food in constipation

Objectives Colonic response to food is possibly abnormal in constipation.Methods The colonic response to food was evaluated in 323 patients and 60 healthy subjects by following the movements of radiopaque markers after ingestion of a standard 1,000-cal test meal. Constipated patients were divided into four groups: one with a normal, and three with a delayed colorectal transit time. When the delay was found mainly in the ascending colon, the group was labeled as suffering from “colonic inertia”. In “hindgut dysfunction”, the delay was predominantly found in the descending colon, whereas the term “outlet obstruction” was reserved for constipated patients whose major site of delay was the rectosigmoid area. Colonic response to food was quantified by evaluating the variation of markers in a given abdominal region and the evolution of the geometric center on the entire plain film of the abdomen.Results Emptying of the caecum-ascending colon and filling of the rectosigmoid area characterize the colonic response to food in healthy subjects. Constipated patients also filled the rectosigmoid, but different patterns were found in the colon. In constipated patients with transit in the normal range, there was a frequent (41%) absence of colonic response to food as compared to controls (13%) and constipated patients with delayed transit (p<0.0001). The response to food of patients with colonic inertia was similar to that of healthy subjects in terms of distal progression, but less marked. The hindgut dysfunction group emptied the entire left colon but failed to empty the caecum and ascending colon. In the outlet obstruction group, there was no distal progress of the geometric center after meal.Conclusions Abnormal colonic response to food is frequently found in constipated patients, with different patterns according to the type of constipation.     

The effect of pancreatic polypeptide and peptide YY on pancreatic blood flow and pancreatic exocrine secretion in the anesthetized dog

Pancreatic polypeptide (PP) and peptide YY (PYY) are inhibitors of pancreatic exocrine secretion in vivo but not in vitro, which suggests intermediate mechanisms of action. To examine the role of pancreatic blood flow in these inhibitory effects, xenon-133 gas clearance was used to measure pancreatic blood flow while simultaneously measuring pancreatic exocrine secretion. PP or PYY (400 pmol/kg/h) was administered during the intermediate hour of a 3-h secretin (125 ng/kg/h)/cholecystokinin octapeptide (CCK-8) (50 ng/kg/h) infusion. Exocrine secretion and pancreatic blood flow during the PP or PYY hours were compared with that observed in the first and third hours of the secretin/CCK-8 infusion. PP and PYY significantly inhibited secretin/CCK-8-induced pancreatic exocrine secretion. In addition, PYY (but not PP) significantly reduced pancreatic blood flow during secretin/CCK-8 stimulation. Nevertheless, there was no correlation between pancreatic blood flow and bicarbonate or protein outputs. It is concluded that changes in pancreatic blood flow do not mediate the inhibitory effects of PP or PYY on the exocrine pancreas.     

Allopurinol stimulates pancreatic exocrine secretion in the dog

The effects of allopurinol on the secretion of pancreatic juice were investigated both in live animals and in preparations of isolated, blood-perfused dog pancreas and were compared with those of secretin. An i.v. administration of allopurinol (3-10 mg/kg) caused a dose-dependent increase in the pancreatic secretion. The secretory responses to 3 and 10 mg/kg of allopurinol were approximately equal to those to 0.03 and 0.1 U/kg of secretin, respectively. An intra-arterial (i.a.) infusion of allopurinol (0.5-1.2 mg/min) also elicited dose-dependent increases in flow rates, bicarbonate concentrations, and outputs of pancreatic exocrine secretion, but protein concentrations were little affected by allopurinol. Similar results were obtained in the juice induced by an i.a. infusion of secretin (0.012-0.05 U/min). Both bicarbonate and protein concentrations in the juice obtained with allopurinol were almost the same as those obtained with secretin at a similar flow rate of pancreatic secretion. The secretory activities at 0.5, 1.0, and 1.2 mg/min of i.a. allopurinol infusion corresponded roughly to those at 0.012, 0.025, and 0.05 U/min of i.a. secretin infusion, respectively. Therefore, the secretory action of allopurinol was similar to that of secretin. The allopurinol-induced secretion was not modified by pretreatment with atropine sulfate, cimetidine, or sulpiride hydrochloride. These results suggest that allopurinol stimulates pancreatic secretion by acting directly on ductular cells of the dog pancreas.     

Exocrine pancreas response to a test meal in the dog

Three dogs, equipped with a chronic gastric fistula (Thomas cannula) and a new type of chronic pancreatic fistula that allows collection of pure nonactivated pancreatic juice after ingestion of a test meal, were subjected to the following protocols: (1) Nonalcoholic period: a test meal (400 g canned dog meal) was given and simultaneously 200 ml isotonic saline was infused through the gastric cannula. Volume, bicarbonate concentration and output, and protein output showed a peak 40 min after ingestion of the test meal. Protein concentration showed an opposite pattern. (2) Alcoholic period: during 3 months, animals were daily given through the gastric cannula 50% ethanol (2.0 g/kg) associated with a protein-supplemented diet, and test-meal experiments were repeated at the end of this period. When compared with the nonalcoholic period, the secretory response to the meal was significantly modified: Volume (–42%), bicarbonate concentration (–19%) and output (–54%) were significantly lower, protein output remained unchanged, and protein concentration increased (+74%). All 3 dogs excreted protein plugs through the catheter collecting pancreatic juice from the main pancreatic duct. It is postulated that a depression of secretin release and an increased gastrin release and cholinergic tone could be the basis of the ethanolevoked change in response to a test meal.This work was supported in part by a fellowship from Deutsche Forschungsgemeinschaft (Germany) to M. S., and a fellowship from Conselho Nacional de Desinvolvimento Cientifico e Technologico of Brazil to J.P.M.d.O.     

Acute response of urinary N-acetyl-beta-D-glucosaminidase to mannitol infusion in the dog

Urinary activity of N-acetyl-beta-D-glucosaminidase (NAG) has been used as an indicator of subtle renal injury in a variety of conditions. Such enzyme activity has been shown to be increased in human and other animals with diabetes mellitus. The mechanism of this increase in urinary NAG activity is not known. To determine if the osmotic diuretic effect of the glycosuria could stimulate urinary NAG activity, mannitol was infused into the left renal artery of six dogs to cause a unilateral osmotic diuresis and compared to the right side. During three control periods of 20 minutes, each urinary NAG excretion (expressed in units as the ratio of NAG activity to urinary creatinine, NAG/Cr) was equal from both left and right kidneys, 5.0 +/- 1.5 vs 6.0 +/- 3.6 units, respectively. During the 11 mannitol infusion periods urine volume and sodium excretion rose significantly from the left kidney, .50 +/- 2 to 1.5 +/- .3 ml/min and 21 + 5 to 99 +/- 16 u Eq/min, respectively. However urinary NAG/Cr did not change, 5.0 +/- 1.5 to 5.1 +/- 1.0 units. In six control dogs not infused with mannitol, urinary NAG/Cr tended to rise with time from control to experimental collection periods, 4.7 +/- 2.0 to 8.1 +/- 3.0 respectively; however these are not significantly different. In all dogs urine volume and sodium excretion tended to rise throughout the course of the study due to hydration with normal saline; thus it is possible that the tendency for urinary NAG activity to rise may have been due to the increase in sodium excretion. However, these studies demonstrate that the osmotic diuresis induced by mannitol produced no significant change in urinary NAG activity. Thus it may be that the hyperglycemia itself, and not the glycosuria, produces the increase in urinary NAG activity seen in the diabetic.