Franklin Hollander

THE TIME FACTOR IN THE ADJUSTMENT OF FOOD INTAKE TO VARIED CALORIC REQUIREMENT IN THE DOG: A STUDY OF THE PRECISION OF APPETITE REGULATION

The factors that regulate the intake of food in men and animals are incompletely known, in spite of the great precision with which the body adjusts intake to its needs under ordinary physiological conditions. The information available a t present suggests that many variables are involved, among them environmental temperature, the integrity of several hypothalamic structures, oropharyngeal stimuli, gastrointestinal distention, “emotional” and other conditioned responses, energy requirements, and perhaps circulating metabolites, as well as genetically determined metabolic pathways. In the various experimental analyses of these factors already published, an underlying assumption has been that changes in these variables are promptly reflected in eating behavior through the regulatory devices concerned with food intake, In the study here reported, this presupposition was abandoned, with the thought that complete adjustment might require long periods of time for its attainment. Consequently, the present experiments were designed to study the rate as well as the precision of the regulation of caloric intake under conditions of varied caloric need. Since the placing of food directly into the stomach of an animal can satisfy a t least part of its caloric requirement, the effect of such intragastric feeding on oral food intake appeared to be a suitable approach for the investigation of this problem. The earlier experiments of Janowitz and Grossman2 indicated that the placing of food into the stomachs of gastrostomized dogs, shortly before they were offered the regular oral meal, depressed oral intake by a corresponding volume, if the intragastric portions of the daily caloric requirement were given immediately before the time of feeding. If the intragastric feeding was performed four hours prior to the time of regular feeding, no effect was demonstrated. Since calorically inert material yielded essentially the same responses, these results were interpreted as being dependent solely on gastric distention. These experiments were later extended by Share, Martyniuk, and Gro~srnan,~ who also studied the effect of intragastric feeding on oral intake in fistula dogs. They fed 33, 50, 66, or 133 per cent of the voluntary daily caloric intake intragastrically four hours a.fter each regular daily ad lib. feeding for three or four weeks. Intragastric feeding of 33 per cent of the caloric requirement had no appreciable effect. Larger percentages reduced the amount eaten, h i t the depression in oral food intake was not fully compensatory; even a level above 100 per cent (133 per cent for one week) did not abolish oral intake completely. Both these studies were based on relatively short-term experiments.

Studies in Pancreatic Function: II. A Statistical Study of Pancreatic Secretion Following Secretin in Patients Without Pancreatic Disease

Summary Norms have been established for the volume, bicarbonate, and amylase responses to a standardized commercially available preparation of secretin. A study of the data has yielded evidence for the use of an 80-minute collection period and for the inclusion of enzyme determinations in the clinical application of the procedure. Body weight adjustment of the values for total volume of secretion and total quantity of amylase results in a marked decrease in the scatter of the data, and therefore, narrowing of the range of normalcy. For this reason, volume and enzyme data should be reduced to a per kilogram basis.

The electrolyte pattern of gastric mucinous secretions: its implication for cystic fibrosis.

Papers on the chemistry of various mucinous secretions presented previously in this monograph dealt almost exclusively with their organic constituents. My report concerns the electrolytes in a typical mucus secretion from a mammal, namely, the native mucinous secretion from the stomach of the dog. This problem is important for the work in our laboratory for a number of reasons. First, it bears on questions concerning the source of the cations in ordinary gastric juice and the nature of its alkaline component. Secondly, viscosity and other physicochemical properties of mucus depend on the physicochemical environment of its macromolecular constituents, as well as their chemical composition, intramolecular arrangement, and concentration. Thirdly, knowledge about the menstruum in which the mucins are dispersed may throw some light on the process of their extrusion from the mucus cells and their spread over the mucosal surface of the stomach. And finally, Dr. Kwart has previously described the cross-linkage of calcium with a mucoprotein obtained from snail mucus; hence we must seek evidence for the possible presence of one or more cations which may be an integral part of a gastric mucin. In addition knowledge of the electrolyte anatomy of a typical mucus secretion of the gastrointestinal tract may prove to be important in relation to current concepts of the etiology of cystic fibrosis-concepts which rest on abnormalities (1) in viscosity of exocrine mucus and (2) in certain electrolyte secretions. Although there is no direct evidence that the stomach is one of the organs which undergo these secretory disturbances, the growing belief that the incidence of peptic ulceration may somehow be correlated with that of cystic fibrosis demands that this organ be included in investigation of this disease whenever possible. Thus there seems to be considerable reason for an investigation of the electrolyte pattern of native gastric mucus, apart from the satisfaction of one’s scientific curiosity.

Viscosity of Cell-Free Canine Gastric Mucus

Summary Cell-free gastric mucus secreted by canine fundic pouches, stimulated by the topical application of acetylcholine to the mucosa, loses its initial high viscosity upon incubation at 37°C. This process is speeded up by the addition of cysteine, and retarded by oxalate or citrate ions (removing calcium) or by adding organic mercury. It has a pH optimum of 6.0–6.5, and it is accompanied by a parallel release of tyrosine-like substances. Addition of trypsin, papain and pectinase liquified mucus, but salivary amylase, desoxyribonuclease, snail digestive juice, lysozyme, hyaluronidase and soybean trypsin inhibitor, have no effect on this process of spontaneous liquefaction. This evidence is interpreted as supporting the concept that, under physiological conditions, liquefaction of the surface layer of mucus of the stomach may be constantly taking place, perhaps under the influence of a local mucolytic enzyme, which has not as yet been identified with known mucolytic or gastric enzymes.

Toxicity of Eugenol Determination of LD50 on Rats.

Summary The LD50 for pure eugenol, administered to rats by stomach tube, and without subsequent reaspiration, was estimated to be 1.8 ml (1.93 g/kg). Any use of this datum as a guide to safe dosage in man, however, may take cognizance of the fact that the conditions of the rodent studies are considerably more severe than any which might be encountered in clinical studies. In the first place, the rat experiments employed eugenol per se, whereas work with dog and man is done with aqueous emulsions of the irritant. Furthermore, the rat retains all of the eugenol administered, because of its inability to vomit, whereas dog and man can reject part of the irritant in this manner if the dose is excessive, and this affords an additional factor of safety. The salient features of the toxic manifestations of eugenol in the rat were as follows: Paralysis occurred initially in the hind legs and the lower jaw. The forelimbs were unaffected unless general prostration or coma ensued. In those animals in which the acute symptoms subsided, the animals remained lethargic, showed signs of urinary incontinence and frequently hematuria, and gave evidence of impaired function of the hind legs for several days. Gross and microscopic observations of the tissues suggested that profound changes in fluid distribution had occurred in response to acute irritation of the gastrointestinal tract. The net impression of the effect of the eugenol, from the microscopic evidence, was essentially that of circulatory collapse with resultant congestion.

Evidence regarding the chemical complexity of acetylcholine-stimulated gastric mucus.

Summary Some of the physical and chemical properties of acetylcholine-stimulated canine gastric mucus (anacid) are described. The native secretion was separated into a fluid fraction and a gel fraction by centrifugation. The gel contributes a significant though variable amount of organic solids to the secretion; it appears not to be an experimental artifact. The gel was insoluble or only poorly soluble in a variety of aqueous and organic solvents, and it differed from the fluid fraction by exhibiting a lower nitrogen to hexosamine molecular ratio. Examination of these fractions by paper electrophoresis revealed at least five protein components common to both. Hexosamine was associated with all of these components, but only negligibly with that of greatest mobility, i.e. , the leading anodal peak. Proteolytic activity at pH 1.5 was associated in part with the leading anodal peak protein, but appeared as a double peak, the slower part of which exhibited a lower enzyme activity per unit of weight of protein than did the faster. The mobility of the leading anodal peak is essentially the same as that of canine serum albumin in a number of buffer systems, and it is suggested that serum albumin, as well as other serum proteins, probably contributes to the protein content of this gastric mucinous secretion.

Critical Evidence that Vagal Stimulation Does Not Release Gastrin

Conclusions The failure of vagally denervated canine gastric pouches to secrete acid in response to intense vagal stimulation of the main stomach constitutes critical evidence that vagal stimulation does not release gastrin.

Serum albumin and gamma-globulin in normal human gastric juice.

Summary 1. With the aid of an intragastric buffering technic, albumin and γ-globulin were detected in gastric aspirates of human subjects without gastric disease. 2. The range of albumin concentration in these gastric aspirates was 17-451 μg/ml whereas that for γ-globulin was 33-95 μg/ml. Estimates of the corresponding minimum 24-hour outputs for these 2 proteins were 21-690 mg and 33-384 mg respectively. 3. Saliva aspirated concomitantly with gastric contents also contained these plasma proteins, but not invariably. 4. It is unlikely that the gastric juice proteins derived in significant degree from saliva because of (a) the careful continuous removal of saliva by oral aspiration, and (b) presence of significant amounts of plasma proteins in gastric aspirates of individuals whose saliva did not contain detectable amounts of these proteins.

The Significance of Sodium and Potassium in Gastric Secretion: A Review of the Problem

Summary This paper traces the development of present knowledge about the sources of Na and K in pure gastric secretion. K concentration in secretion induced by single or tandem histamine injections (dog and man) varies considerably, independently of acidity, volume-rate, and Na concentration. Immediately after injection, the K time curve rises above the preinjection level to a peak at least 3 times the concentration in plasma, then decreases to levels sometimes as low as 1 mEq. per L. In many such experiments this curve manifests a characteristic undershooting of its downward arm. Five hypotheses concerning the origin of gastric K are considered. One of these is based on numerous observations concerning the reversible release of K by various tissues following histamine, vagal, and vagomimetic stimulation. Thus it has been reported that time curves for plasma K concentration, following histamine injection, show an undershooting similar to that in the curves for gastric juice K; also, stomach and intestinal tissues may contribute more to these variations in plasma K than the cells of other organs. The mode of entry of such released K, whether directly into the secretion-by diffusion or active transport-or indirectly via interstitial fluid, is not yet evident.

Stimulation of cell-free gastric mucus by the topical application of acetylcholine.

Summary The topical application of acetylcholine or related parasympathomimetic drugs to the mucosa of canine fundic pouches results in the secretion of alkaline opalescent viscid mucus which is free of columnar cells. These studies confirm our previous conclusion, that the exfoliation of gastric surface cells is not an essential part of the process of mucus secretion.