- Email: [email protected]
Reply to Dr. Demand
676
COMMENTS
REFERENCES 1. Makhlouf, G. M., J. P. A. McManus, and W. 1. Card. 1966. A quantitative statement of the
two-component hypothesis of gastric secretion. Gastroenterology 51: 149-171. 2. Hollander, F. 1961. The significance of sodium and potassium in gastric secretion. A review of the problem. Gastroenterology 40: 477490.
3. Powell, D. W., R. C. Robbins, J. D. Boyett, and B. 1. Hirschowitz. 1962. Evaluation of the gastric Na:H exchange mechanism using histamine and Diamox. Amer. J. Physiol. 202: 293-301.
Vol. 54, No.4, Part 1
4. Hirschowitz, B. 1. 1961. Electrolytes in human gastric secretion. Amer. J. Dig. Dis. 6: 199228.
5. Riddell, M. J., J. A. Strong, and D. Cameron. 1960. The electrolyte concentration of human gastric secretion. Quart. J. Exp. Physio!. 45: 1-11.
6. Vagne, M., F. Martin, A. Berard, and R. Lambert. 1966. Lea electrolytes du sue gastrique. Rev. Franc. Etud. Clin. Biol.l1: 493-509. 7. Werther, J . L., J. G. Parker, and F. Hollander. 1960. Potassium in histamine-stimulated gastric secretion in man. Gastroenterology 38: 368-373.
REPLY TO DR. DEMAND Briefly, Dr. Demand's objections to the of [N a] as high as 117 to 120 mEq per liter two-component model can be resolved into (i.e., to within 2 mEq of the sodium interthose relating to the entry of sodium and cept at 0 acid) were obtained. (c) The value attributed to titratable those relating to the secretion of potassium. The Relationship between sodium and acidity differs from one study to another hydrogen concentrations. Our view was that and has its own influence on the magnitude the relationship between [Na] and [H] was of the slope and, in particular, on the sonot only strongly negative but also linear. dium intercept. A number of factors can lead to alteration All the factors outlined above will tend of the [Na]: [H] slope or to apparent curvi- to affect, although to an unequal extent, linearity. the intercept for primary acidity. In both (a) The composition of the interstitial Dr. Nordgren's series and our several sefluid component depends on and reflects the ries,3-5 the calculated value for primary changes in the composition of the plasma in acidity was close to 150 mEq per liter. a particular individual. If the secretory The single subject whose data were redata obtained from a series of individuals ported by Hirschowitz6 (personal comare not equally distributed along the munication) appears to have been an [Na] : [H] slope, considerable scatter is in- unique secretor who responded erratically troduced and linearity is disturbed. This is to the same dose of stimulant and who on evident from the table of data given by occasion produced large volumes of anacid Riddell et aU juice. (b) Salivary contamination has an imThe data of one subject from Dr. Nordportant bearing on the scatter of data at gren's series were singled out for analysis low secretory rates. Vigorous admonition of by us because they spanned the slope adethe subject to spit is clearly inadequate. quately. Analysis of the data from all 5 The application of a suction apparatus to subjects-to allay Dr. Demand's suspicions the mouth leads-as pointed out by Nord- on this score-showed that the linear relagrenZ-to considerable increase in salivary tionship between [Na] and [H] was well flow. Our technique of introducing and fre- maintained (r = 0.99). The average soquently changing dental pJedgets under the dium intercept for Nordgren's subjects was tongue and in the sulci of the cheeks ap- around 130 mEq per liter, a figure almost pears to have insured virtual elimination identical to that obtained by us in two of salivary contamination: the linear rela- series of subjects tested with histamine and tionship between [Na] and [H] was main- gastrin. 4 • 5 The subject whose data were tained at all levels of secretion and values mainly reported in our paper3 had a pJasma
April 1968
COMMENTS
sodium which was consistently above the average by 8 mEq and expectedly, therefore, an intercept for sodium correspondingly higher. The secretion of potassium. The problem of potassium secretion requires that an immediate distinction be drawn (a) between steady and nonsteady state secretion and (b) between man and dog for all states of secretion. In the dog, the lowest and highest levels of potassium are about half those found in man. Thus, potassium concentrations of 2.5 to 3 mEq per liter are not infrequently encountered in canine juice at the end of prolonged experiments and accompany the fall of plasma potassium concentration, while, in man, a gastric potassium concentration of less than 5 mEq per liter is a rarity. A discriminating reference to published data should take this species' difference into account. The studies with acetozolamide offer little comfort for the proponents or critics of secretory models. In the presence of acid, acetozol amide disrupts the surface epithelium of the stomach: secreted as well as instilled acid leaks back across the damaged mucosa.7 These findings by Werther and co-workers have never been challenged and should be taken into account in reinterpreting earlier studies with acetozolamide. Thus table 3 (reference 3), quoted by Dr. Demand in support of "inhibition" by acetozolamide, shows just as clearly the disappearance of most of the secreted acid and water and the entry into the lumen of twice as much sodium as during the control period. Fitting secretory data to any model in the presence of a damaged mucosa is, in my view, a fruitless exercise. Perhaps the main defect of Dr. Demand's critique is his failure to appreciate the distinction, clearly laid in our paper,3 for the behavior of potassium during steady and non-steady state secretion. During steady state secretion , the linear relationship between [K] and [H] and the hyperbolic relationship between [K] and volume flow rate fit well the predictions of the two-component model. These strict correlations are masked but not entirely abolished during
677
non-steady state secretion. In a subsequent and more detailed analysis of potassium under these conditions,S it was possible to show that the rates of change of [K], [H], and volume flow rate were similar during the rise of secretion to a peak but were disparate during its decline. Furthermore, the rates of change of these three variables were dose-dependent. It became evident that combining the data for different doses and at all intervals of secretion would mask the relationships. This unusual behaviour of potassium did not suggest to us that the two-component model was incorrect, since the linear relationship of [Na] and [H] was maintained under all conditions of secretion, but that the assumption of a constant primary parietal concentration of potassium during non-steady state secretion could not be maintained. The obscurity surrounding this aspect of secretion is only dimly lightened by in vit ro studies on amphibian and marine gastric mucosae. Gastric mucosal potassium appears to be located in several compartments across which it exchanges at different rates. During constant secretion in vivo, primary potassium concentration could be viewed as the over-all steady efflux of potassium into the secretory bulk solution. During rapidly changing secretion, the expected lags in the movements of potassium across the different compartments is likely to be reflected in an unsteady efflux, represented by an inconstant concentration of potassium in the secretory solution. The proposit ion is purely speculative and the full story of potassium, like many fairy tales, is yet to be told. Compariso.n of the two-component and backdiffusion models. Identical equations to account for the secretion of hydrogen ions can be derived on the basis of the twocomponent and backdiffusion models. The corresponding equations describing the movement of sodium are somewhat different. In the backdiffusion model, sodium is considered to enter the lumen passively along its concentration gradient, while, in the two-component model, sodium is considered to accompany the bulk flow of interstitial fluid. The former model predicts
678
COMMENTS
a curvilinear relationship between sodium and hydrogen concentration, while the latter, in line with the experimental findings in man, predicts a linear relationship between the two variables. The calculated value for the diffusion coefficient of sodium is so small, however, that when its effect is discounted the diffusion equation assumes the form of a bulk flow equation. s Thus the two models are only conceptually different, representing different avenues of approach to the same problem but leading to similar formal descriptions. The two-component model leads to the view that the observed alterations in the composition of gastric juice are "not so much the product of a specific regulatory mechanism as a concomitant of the normal outward passage of interstitial fluid into the gastric lumen." Gabriel M. M akhlouf Division of Gastroenterology University of Alabama Medical Center Birmingham, Alabama REFERENCES 1. Riddell, M. J., J. A. Strong, and D. Cameron. 1960. The electrolyte concentration of hu-
2.
3.
4.
5.
6.
7.
8.
Vol. 54, No.4, Part 1
man gastric secretion. Quart. J. Exp. Physioi. 45: 1-11. Nordgren, B. 1963. The rate of secretion and electrolyte content of normal gastric juice. Acta Physiol. Scand. 58: (suppi. 202). Makhlouf, G. M., J. P. A. McManus, and W. 1. Card. 1966. A quantitative statement of the two-component hypothesis of gastric secretion. Gastroenterology 51: 149-171. Makhlouf, G. M., J. P. A. McManus, and W. 1. Card. 1966. Action of the pentapeptide (ICI 50123) on gastric secretion in man. Gastroenterology 51: 455-465. Makhlouf, G. M., J. P. A. McManus, and W. 1. Card. 1967. Comparative effects of gastrin II and histamine on pepsin secretion in man. Gastroenterology 52: 787-791. Hirschowitz, B. 1. 1961. Electrolytes in human gastric secretion. Amer. J. Dig. Dis. 6: 199228. Werther, J. L., F. Hollander, and M. Altamirano. 1965. Effect of acetozolamide on gastric mucosa in canine vivo-vitro preparations. Amer. J. Physiol. 209: 127-133. Makhlouf, G. M. 1967. Characteristics of potassium secretion. In Proceedings Symposium on gastric electrolytes. NATO Advanced Studies Institute, Oslo, Norway, 1967.
COMMENTS
REFERENCES 1. Makhlouf, G. M., J. P. A. McManus, and W. 1. Card. 1966. A quantitative statement of the
two-component hypothesis of gastric secretion. Gastroenterology 51: 149-171. 2. Hollander, F. 1961. The significance of sodium and potassium in gastric secretion. A review of the problem. Gastroenterology 40: 477490.
3. Powell, D. W., R. C. Robbins, J. D. Boyett, and B. 1. Hirschowitz. 1962. Evaluation of the gastric Na:H exchange mechanism using histamine and Diamox. Amer. J. Physiol. 202: 293-301.
Vol. 54, No.4, Part 1
4. Hirschowitz, B. 1. 1961. Electrolytes in human gastric secretion. Amer. J. Dig. Dis. 6: 199228.
5. Riddell, M. J., J. A. Strong, and D. Cameron. 1960. The electrolyte concentration of human gastric secretion. Quart. J. Exp. Physio!. 45: 1-11.
6. Vagne, M., F. Martin, A. Berard, and R. Lambert. 1966. Lea electrolytes du sue gastrique. Rev. Franc. Etud. Clin. Biol.l1: 493-509. 7. Werther, J . L., J. G. Parker, and F. Hollander. 1960. Potassium in histamine-stimulated gastric secretion in man. Gastroenterology 38: 368-373.
REPLY TO DR. DEMAND Briefly, Dr. Demand's objections to the of [N a] as high as 117 to 120 mEq per liter two-component model can be resolved into (i.e., to within 2 mEq of the sodium interthose relating to the entry of sodium and cept at 0 acid) were obtained. (c) The value attributed to titratable those relating to the secretion of potassium. The Relationship between sodium and acidity differs from one study to another hydrogen concentrations. Our view was that and has its own influence on the magnitude the relationship between [Na] and [H] was of the slope and, in particular, on the sonot only strongly negative but also linear. dium intercept. A number of factors can lead to alteration All the factors outlined above will tend of the [Na]: [H] slope or to apparent curvi- to affect, although to an unequal extent, linearity. the intercept for primary acidity. In both (a) The composition of the interstitial Dr. Nordgren's series and our several sefluid component depends on and reflects the ries,3-5 the calculated value for primary changes in the composition of the plasma in acidity was close to 150 mEq per liter. a particular individual. If the secretory The single subject whose data were redata obtained from a series of individuals ported by Hirschowitz6 (personal comare not equally distributed along the munication) appears to have been an [Na] : [H] slope, considerable scatter is in- unique secretor who responded erratically troduced and linearity is disturbed. This is to the same dose of stimulant and who on evident from the table of data given by occasion produced large volumes of anacid Riddell et aU juice. (b) Salivary contamination has an imThe data of one subject from Dr. Nordportant bearing on the scatter of data at gren's series were singled out for analysis low secretory rates. Vigorous admonition of by us because they spanned the slope adethe subject to spit is clearly inadequate. quately. Analysis of the data from all 5 The application of a suction apparatus to subjects-to allay Dr. Demand's suspicions the mouth leads-as pointed out by Nord- on this score-showed that the linear relagrenZ-to considerable increase in salivary tionship between [Na] and [H] was well flow. Our technique of introducing and fre- maintained (r = 0.99). The average soquently changing dental pJedgets under the dium intercept for Nordgren's subjects was tongue and in the sulci of the cheeks ap- around 130 mEq per liter, a figure almost pears to have insured virtual elimination identical to that obtained by us in two of salivary contamination: the linear rela- series of subjects tested with histamine and tionship between [Na] and [H] was main- gastrin. 4 • 5 The subject whose data were tained at all levels of secretion and values mainly reported in our paper3 had a pJasma
April 1968
COMMENTS
sodium which was consistently above the average by 8 mEq and expectedly, therefore, an intercept for sodium correspondingly higher. The secretion of potassium. The problem of potassium secretion requires that an immediate distinction be drawn (a) between steady and nonsteady state secretion and (b) between man and dog for all states of secretion. In the dog, the lowest and highest levels of potassium are about half those found in man. Thus, potassium concentrations of 2.5 to 3 mEq per liter are not infrequently encountered in canine juice at the end of prolonged experiments and accompany the fall of plasma potassium concentration, while, in man, a gastric potassium concentration of less than 5 mEq per liter is a rarity. A discriminating reference to published data should take this species' difference into account. The studies with acetozolamide offer little comfort for the proponents or critics of secretory models. In the presence of acid, acetozol amide disrupts the surface epithelium of the stomach: secreted as well as instilled acid leaks back across the damaged mucosa.7 These findings by Werther and co-workers have never been challenged and should be taken into account in reinterpreting earlier studies with acetozolamide. Thus table 3 (reference 3), quoted by Dr. Demand in support of "inhibition" by acetozolamide, shows just as clearly the disappearance of most of the secreted acid and water and the entry into the lumen of twice as much sodium as during the control period. Fitting secretory data to any model in the presence of a damaged mucosa is, in my view, a fruitless exercise. Perhaps the main defect of Dr. Demand's critique is his failure to appreciate the distinction, clearly laid in our paper,3 for the behavior of potassium during steady and non-steady state secretion. During steady state secretion , the linear relationship between [K] and [H] and the hyperbolic relationship between [K] and volume flow rate fit well the predictions of the two-component model. These strict correlations are masked but not entirely abolished during
677
non-steady state secretion. In a subsequent and more detailed analysis of potassium under these conditions,S it was possible to show that the rates of change of [K], [H], and volume flow rate were similar during the rise of secretion to a peak but were disparate during its decline. Furthermore, the rates of change of these three variables were dose-dependent. It became evident that combining the data for different doses and at all intervals of secretion would mask the relationships. This unusual behaviour of potassium did not suggest to us that the two-component model was incorrect, since the linear relationship of [Na] and [H] was maintained under all conditions of secretion, but that the assumption of a constant primary parietal concentration of potassium during non-steady state secretion could not be maintained. The obscurity surrounding this aspect of secretion is only dimly lightened by in vit ro studies on amphibian and marine gastric mucosae. Gastric mucosal potassium appears to be located in several compartments across which it exchanges at different rates. During constant secretion in vivo, primary potassium concentration could be viewed as the over-all steady efflux of potassium into the secretory bulk solution. During rapidly changing secretion, the expected lags in the movements of potassium across the different compartments is likely to be reflected in an unsteady efflux, represented by an inconstant concentration of potassium in the secretory solution. The proposit ion is purely speculative and the full story of potassium, like many fairy tales, is yet to be told. Compariso.n of the two-component and backdiffusion models. Identical equations to account for the secretion of hydrogen ions can be derived on the basis of the twocomponent and backdiffusion models. The corresponding equations describing the movement of sodium are somewhat different. In the backdiffusion model, sodium is considered to enter the lumen passively along its concentration gradient, while, in the two-component model, sodium is considered to accompany the bulk flow of interstitial fluid. The former model predicts
678
COMMENTS
a curvilinear relationship between sodium and hydrogen concentration, while the latter, in line with the experimental findings in man, predicts a linear relationship between the two variables. The calculated value for the diffusion coefficient of sodium is so small, however, that when its effect is discounted the diffusion equation assumes the form of a bulk flow equation. s Thus the two models are only conceptually different, representing different avenues of approach to the same problem but leading to similar formal descriptions. The two-component model leads to the view that the observed alterations in the composition of gastric juice are "not so much the product of a specific regulatory mechanism as a concomitant of the normal outward passage of interstitial fluid into the gastric lumen." Gabriel M. M akhlouf Division of Gastroenterology University of Alabama Medical Center Birmingham, Alabama REFERENCES 1. Riddell, M. J., J. A. Strong, and D. Cameron. 1960. The electrolyte concentration of hu-
2.
3.
4.
5.
6.
7.
8.
Vol. 54, No.4, Part 1
man gastric secretion. Quart. J. Exp. Physioi. 45: 1-11. Nordgren, B. 1963. The rate of secretion and electrolyte content of normal gastric juice. Acta Physiol. Scand. 58: (suppi. 202). Makhlouf, G. M., J. P. A. McManus, and W. 1. Card. 1966. A quantitative statement of the two-component hypothesis of gastric secretion. Gastroenterology 51: 149-171. Makhlouf, G. M., J. P. A. McManus, and W. 1. Card. 1966. Action of the pentapeptide (ICI 50123) on gastric secretion in man. Gastroenterology 51: 455-465. Makhlouf, G. M., J. P. A. McManus, and W. 1. Card. 1967. Comparative effects of gastrin II and histamine on pepsin secretion in man. Gastroenterology 52: 787-791. Hirschowitz, B. 1. 1961. Electrolytes in human gastric secretion. Amer. J. Dig. Dis. 6: 199228. Werther, J. L., F. Hollander, and M. Altamirano. 1965. Effect of acetozolamide on gastric mucosa in canine vivo-vitro preparations. Amer. J. Physiol. 209: 127-133. Makhlouf, G. M. 1967. Characteristics of potassium secretion. In Proceedings Symposium on gastric electrolytes. NATO Advanced Studies Institute, Oslo, Norway, 1967.