QUARTERLY JOURNAL OF EXPERIMENTAL PHYSIOLOGY. %Alt7(C. /,f AND COGNATE MEDICAL SCIENCES

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1 %Alt7(C /,f QUARTERLY JOURNAL OF EXPERIMENTAL PHYSIOLOGY AND COGNATE MEDICAL SCIENCES THE ELECTROLYTE CONCENTRATION OF HUMAN GASTRIC SECRETION. By M. J. RIDDELL,* J. A. STRONG and D. CAMERON. From the Western General Hospital and the Departments of Medicine and Public Health and Social Medicine, University of Edinburgh. (Received for publication 6th April 1959) The secretion by the stomach of hydrochloric acid, sodium, potassium and chloride has bepn studied in normal human subjects and in patients suffering from peptic ulcer. A close inverse relationship was demonstrated between the concentration of acid and sodium, and a direct relationship between potassium concentration and the rate of secretion of gastric juice. It is suggested that H and Na ions may share a secretory pathway, and that K concentration represents a part of the process of water secretion. These findings were consistent in over 300 samples of gastric juice, obtained without stimulation, and after stimulation with histamine or insulin. SINCE 1824 when Prout first reported the presence of hydrochloric acid in gastric juice, much attention has been given to the changes in the production of acid by the stomach in health and disease. This preoccupation with acid secretion has tended to diminish interest in the other components of gastric secretion. In recent years it has become apparent that adrenocortical hormones are capable of influencing gastric secretory activity. The use of these steroids in therapeutics is frequently associated with the reactivation of peptic ulcer, and sometimes with the more dangerous consequences of hkemorrhage and perforation [Sandweiss, 1954]. It is well known that changes in adrenocortical activity, or the administration of adrenocortical hormones or their analogues are associated with changes in the concentration of sodium, chloride and potassium in body fluids such as serum, urine, saliva and sweat, and changes might therefore be anticipated in the concentration or output of these ions in gastric juice under similar * Present address: Victoria Infirmary, Glasgow, S.2. VOL. XLV, NO

2 2 Riddell, Strong and Cameron circumstances. As part of a study of gastric secretion and peptic ulcer, the relation between hydrochloric acid and other electrolytes in gastric juice has been examined in patients with peptic ulcer and in normal subjects, to see whether we could detect any abnormality which might be attributable to unusual adrenocortical activity. Quantitative data on the relation between the amounts of hydrochloric acid, chloride, sodium and potassium in human gastric juice is limited [Hollander, 1952], so that before attempting to study disturbances of these relations it was essential to study normal subjects and untreated patients. Ihre [1939] in his classical report on Human Gastric Secretion described the relation between acid and total chloride concentration, and there are numerous references elsewhere to isolated observations and ranges of concentrations of this and the other ions under discussion. No systematic attempt appears to have been made in man to establish the relative concentrations of sodium, potassium, hydrogen and chloride ions as they are secreted. If these could be shown to be consistently related, then it might have a bearing on the present views on the mechanism of secretion of hydrochloric acid by the stomach. These theories have been comprehensively reviewed by Babkin [1950], Conway [1953], Davies [1951], Heinz and Obrink [1954] and many others, and will not be discussed further here. METHODS Normal male subjects and patients were examined after a fast of at least 5 hr. A radio-opaque Levin tube was passed into the stomach, usually through the nose. To ensure as complete a collection of gastric contents as possible the position of the tube in the stomach was then checked by radioscopy, confirming that the tube remained uncoiled, and that the tip lay near the pylorus. If necessary, the tube was partially withdrawn and reinserted. The subject then lay on the left side while continuous aspiration by a motor-driven pump was maintained at a subatmospheric pressure of 30 mm. Hg approximately. Samples of gastric juice were collected for periods of min., depending on the rate of secretion. Contamination of gastric contents by saliva was reduced by frequent expectoration. Although regurgitation of duodenal contents was sometimes recognizable by obvious bile staining, such samples have been included in our results. Juice collected for the first 10 min. after emptying the stomach was discarded. Any subsequent samples with a total chloride concentration of less than 120 meq/l. have not been included in the results, since such low values were likely to be due to heavy contamination with saliva. After the tube had been passed, mepyramine maleate ("Anthisan", May & Baker Ltd.) 50 mg. was injected subcutaneously in the arm, and shortly afterwards, histamine acid phosphate (0-04 mg./kg. of body wt.) was given by the same route. Mepyramine prevents most of the unpleasant effects following injection of large doses of histamine, and also induces drowsiness, so that the subjects frequently slept through most of the subsequent period of observation [Kay, 1953]. The volume of each sample of juice was measured, 2 ml. aliquots were titrated against N/10 NaOH, using Topfer's reagent and phenolphthalein as indicators. The results to be described refer to the values obtained with phenolphthalein, i.e. "total" acid. Sodium and potassium concentrations were estimated with a flame photometer, using lithium as an internal standard, and total chloride concentration by the method of Schales and Schales [1941] as modified by Asper, Schales and Schales [1947].

3 Electrolytes and Gastric Secretion 3 RESULTS The findings in a typical experiment in a normal subject are illustrated in fig. 1. Following the injection of histamine, the volume of gastric juice secreted increases, the concentration of acid rises, while that of sodium shows a reciprocal fall. The concentration of chloride and potassium both tend to rise and fall with the fluctuations in the rate of secretion of juice. It is apparent that in keeping with the law of electrical neutrality, the sum of the concentration of the cations measured is closely related to that of the total ISO ION CONC meq/1 No" s0 H+ SECRET ION RATE 3- ml / min HISTAMINE SO so TIME -MIN FIG. 1.-The relation between the rate of secretion and the electrolyte content of gastric juice in a normal subject. chloride concentration, and that the concentration of total anion and cation as measured rises with increasing rates of secretion. The concentration of other ions in gastric juice was not investigated systematically during this work, and in any case they are not relevant to the conclusions to be drawn. Approximately 300 samples have been examined in the manner described, and the ionic relations illustrated in fig. 1 were similar in all of these. In fig. 2, data from a patient are plotted to show the relation between Na+ and H+ concentration and between K+ and H+ concentration. It will be seen that there was a close negative correlation between the concentration of Na+ and H+, with the exception of one sample with a total Cl- concentration of 92 meq/l. As already pointed out, all such samples with a total Clconcentration of less than 120 meq/l. have been excluded from further consideration; the few samples discarded for this reason were all collected

4 4 Riddell, Strong and Cameron before histamine was given, when secretion rates were low. In contrast to Na+ and H+, the concentrations of K+ and H+ show a rough positive correlation. 130O * Na+ +K+ Boo Nao meq/l so0 10 meq/i * + +.t : I I a H+ meq/l FIG. 2.-The relation between the concentration of sodium, potassium and "total" acid in the gastric juice of a patient with a duodenal ulcer. 150 I?..j 100 r= - o0935 x = I113 y y= x Na' meq/i so so Ht meq/1 FIG. 3.-The relation between total acid concentration and sodium concentration in 100 samples of gastric juice obtained from seven individuals, both normal and patients with peptic ulcer. The Relationship between the Concentration of Sodium and Acid.-The relationship between the concentrations of sodium ions and of hydrogen ions in gastric juice was assessed by taking 100 consecutive observations on seven individuals. The full results are given in the appendix. When the values were -AX

5 Electrolytes and Gastric Secretion 5 plotted, it was at once apparent that the association between the two concentrations was very close indeed (fig. 3). When the concentration of sodium ions was high, that of hydrogen ions was low, and vice versa. The points on the graph fall on or close to a slightly curved line. A numerical estimate of this association was made by calculating a correlation coefficient and regression lines. As one would expect from inspection of the graph, a straight regression line fitted the data well, particularly the middle observations, a quadratic parabola fitted better (fig. 4), and 160 HUMAN GASTRIC SECRETION 140 = x X 120 : 100 No+ meq/ I H+ meq/l FIG. 4.-The same data as in fig. 3 are shown plotted against a quadrantic parabola (see text). a cubic parabola better still, but it was felt that these last two calculations were unnecessary refinements and indeed might lead to fallacious conclusions. Fig. 3 shows that the observations are erratic at the extremities of the line. At these extremities, one or other variables is small, and since the results obviously cannot have negative values, any error tending to diminish the small variable from its true value is limited. On the other hand, errors tending to exaggerate the small variable have no limit. This inequality of errors in observation of the small variable could make the regression line curved at its ends. For this reason we prefer the correlation coefficient and straight regression lines to other estimates of the association between the concentrations of these two ions. The calculated correlation coefficient is negative and numerically very high, namely , and the regression lines are: Y = X and X = Y, where X and Y represent the concentrations of hydrogen ions and sodium ions respectively. Samples of gastric juice collected from two normal males following the intravenous administration of insulin showed the same ionic relationships.

6 6 Riddell, Strong and Cameron The Relationship between the Concentration of Potassium and Acid.-In fig. 2 it was shown that K+ and H+ concentrations were roughly correlated, but it was also noted, though it is not apparent in the diagram, that as the rate of secretion declined, so the concentration of K+ fell, while the concentration of H+ fell to a considerably lesser extent. These relations are more clearly shown in fig. 5, where 30 min. after the administration of histamine, the volume of secretion and K+ concentration have begun to decline. 20 Is. K+ meq/l *0 lo: H* meq/1 20 req/ I ANTHISAN HISTAMINE SECRETION 8 RATE m.mn b P I80 TIME - MIN. FIG. 5.-The relation between the rate of secretion of gastric juice and the concentration of potassium in the same samples. The numbers over each point in the upper figure refer to the samples shown in the histogram below. In fig. 6, the data used in the construction of fig. 2 have been replotted to show the relation between K+ concentration and secretion rate, the coefficient of correlation being (P < 0 001). The limiting value of K+ concentration given by the regression equation for these values is 8-4 meq/l. K+ concentration is therefore seen to be more clearly related to secretion rate than to H+ concentration, but is much less close than that of Na+ and H+. In order to test the correlation of K+ concentration and the secretion rate of gastric juice further, 100 samples obtained from ten individuals during twelve experimental observations have been plotted in fig. 7. Although the coefficient of correlation (r) is (P < 0 001), it is obvious again that the relation between these two parameters of gastric juice secretion is much less close than between Na+ and H+.

7 Electrolytes and Gastric Secretion 7 DIscussIoN These results show that both Na+- and K+-ion secretion in gastric juice are closely related to the acid-secreting activity of the stomach. The relation 20 r-io9q2 KmE K" meq/1 0 'A 4 SECRETION RATE ml/min FIG. 6.-The relation between the rate of secretion and potassium concentration of gastric secretion in one subject. 22 r K+mEq/l I S 7 1' SECRETION RATE - ml / min. FIG. 7.-The relation between the potassium concentration and secretion rate of gastric juice (see text). between Na+ and H+ appears to be so close as to suggest that they might share a common secretory mechanism. Such close reciprocity could be accounted for in at least two ways. In the first place, it might be postulated

8 8 Riddell, Strong and Cameron that they share a common secretory pathway in such a manner that the sum of their concentrations represented the capacity of the secreting mechanism at a given secretory rate. Secondly, the analogy provided by the renal tubular mechanism for the excretion of H+ ions by the tubule in exchange for reabsorbed Na+ ions [Pitts, 1953], and the secretion of H+ ions by the parietal cell of the stomach, suggests a possible alternative explanation for this relationship. An "ion exchange" mechanism of this type would account for the close relation of Na+ and H+, since the sum of these two forms most of the cation being secreted by the stomach at any time. If the analogy is true, the exchange would be equimolar, and the failure to find a negative coefficient of correlation less complete than would be due only to errors in the methods used, particularly in the technique of collecting the samples. Contamination by swallowed saliva or regurgitated duodenal contents would also be expected to make the results less consistent. The concentration of K+ ions is most closely related to the volume of secretion being formed, and therefore to the amount of water in which the solutes of gastric juice are dissolved. This in turn suggests that K+ may be secreted as a result of, or as part of, the mechanism concerned in the diffusion or secretion of water between the blood and the lumen of the stomach. If this relation between water and K+ is more than incidental, it suggests further that the water of gastric juice collects as a result of active secretion rather than passive diffusion [Robinson, 1954]. Teorell [1947] studied the equilibrium between a model "stomach" containing HCI separated from a surrounding bath of NaCl by a dialysis membrane. From these experiments he drew certain conclusions which are in keeping with the findings now reported for the secretion of electrolytes by the human stomach. In the first place, he considered that the variation in the concentration of acid between zero and a maximal value depends on the secretion rate of the acid. At low rates of secretion this variation is very marked, and at higher rates there is a comparatively small change of the acidity with variations of the secretion rate. Secondly, he showed that the concentration of sodium varied inversely with the acidity, and finally that the total chlorides vary as a function of the secretion rate of the acid, though the variations tend to be relatively small. In an earlier paper, Teorell [1940] discussed the changes of concentration of acid in the stomach, and stated that ion exchange, acting by diffusion, seemed the only mechanism which could explain the fall in acidity. Since then, such a mechanism for regulating the secretion of acid and conserving sodium has been demonstrated in the kidney [Pitts, 1953]. The administration of carbonic anhydrase inhibitors such as acetazolamide ("Diamox") has been shown to inhibit the secretion of acid by the kidney and to reduce the secretion of acid by the stomach in animal [Janowitz, Colcher and Hollander, 1952] and in man [Texter and Barborka, 1955]. The analogies between the secretion of acid by the kidney and the stomach, together with the work now reported, add some support to the concept of acid secretion proposed by Teorell [1947].

9 Electrolytes and Gastric Secretion 9 APPENDIX SECRETION RATE AND ION CONCENTRATIONS OF 100 SAMPLES OF GASTRIC JUICE COLLECTED DURING THIRTEEN EXPERIMENTS ON SEVEN INDIVIDUALS Subject G.S. (71) d' Duodenal ulcer Diabetes mellitus Date Secretion rate ml./min. 1*5 2* *1 Ion concentration meq/l. H+ Na+ K+ C * * * * * W.M. (25) 6' Normal J.S. (40) d' Normal W.C. (45) 6' Normal * *6 1* @ *0 2*3 1* * X7 2X *8 1*3 1* * * * * * * F * *0 139

10 10 Riddell, Strong and Cameron ArPENDIx-(continued). Subject W.C. (45)-(contd.) Date Secretion rate ml./min. 1*9 1* * Ion concentration meq/1. H+ Na+ K+ C1F * * * * G.A. (41) 9 Duodenal ulcer *7 3* X * * * *1 07 1X * * M.R. (35) &3 Normal * * * * *

11 Electrolytes and Gastric Secretion APPENDIx-(continued). 11 Ion concentration Secretion Subject Date rate meq/l. ml./min. H+ Na+ K+ C1- S.A. (37) Duodenal ulcer * * * * * * * REFERENCES ASPER, S. P., SCHALES, 0. and SCHALES, S. S. (1947). J. biol. Chem. 168, 779. BABKIN, B. P. (1950). Secretory Mechanism of the Digestive Glands. 2nd Ed. New York: P. B. Hoeber Inc. CONwAY, E. J. (1953). Biochemistry of Gastric Acid Secretion. Springfield, Ill: Thomas. DAvIES, R. E. (1951). Biol. Rev. 26, 87. HEINZ, E. and OBRINK, K. J. (1954). Physiol. Rev. 34, 643. HOLLANDER, F. (1952). Fed. Proc. 11, 706. IimE, B. J. E. (1939). Human Gastric Secretion. London: O.U.P. JANOWITZ, H. D., COLCHER, H. and HOLLANDER, F. (1952). Amer. J. Physiol. 171, 325. KAY, A. W. (1953). Brit. med. J. 2, 77. PITTS, R. F. (1953). Harvey Lectures, Series 48, p PROUT, W. (1824). Phil. Trans. Roy. Soc. 114, i, 45. ROBINSON, J. R. (1954). S.E.B. Symposia, No. VIII. "Active Transport and Secretion'", p. 42. Secretion and Transport of Water. SANDWEISS, D. J. (1954). Gastroenterology, 27, 604. SCHALES, 0. and SCHALES, S. S. (1941). J. biol. Chem. 140, 879. TEORELL, T. (1940). J. gen. Physiol. 23, 263. TEORELL, T. (1947). Gastroenterology, 9, 425. TEXTER, E. C. and BARBORKA, C. J. (1955). Gastroenterology, 28, 519.