Clin. Biochem. 9, (3) 117-120 (1976)
Intestinal Absorption of Water and Electrolytes J. J. SIDOROV Department
of Medicine, Dalhousie
University,
Sidorov, J. J.
Dalhoasie
Scotia B3H 4H7
p a n c r e a s and intestine. T h i s l a r g e a m o u n t of f l u i d (ff v a r i e d t o n i c i t y is r e n d e r e d isotonic b e f o r e it e n t e r s the jejunum.
CLBIA, 9, (3) 117-120 (1976) Clin. Biochem.
Department of Medicine, Halifax, Nova Scotia
Halifax, Nova
University,
I N T E S T I N A L ABSORPTION OF W A T E R AND ELECTROLYTES 1. Recent advances in knowledge of intestinal physiology have provided some insight into disturbed mechanisms and their clinical effects; for example, diarrhoea can now be defined biochemically as excessive fluid and electrolyte loss due to their realabsorption or excessive secretion. 2. Because of differences in structure and in absorptive and secretory mechan{sms, the various parts of the gut perform different functions. In the jejunum, t r a n s p o r t activity is extensive and the rapid equilibration of its content provides the optimal absorptive mixture. Functionally, the ileum and colon are similar; compared with the jejunum, they have greater absorptive capacity for electrolytes and generate significantly higher transmural electrical potentials. In the colon, some transport mechanisms are potentiated by adrenocortical steroids. 3. W a t e r and electrolyte absorption and secretion are the end-products of bidirectional fluxes across the intestinal wall that are several times greater than net movement in either direction. Secretion is the surplus of negative flux (into the lumen) and absorption the surplus of positive flux (out of it). 4. Many electrolyte t r a n s p o r t mechanisms require the absorption of other electrolytes or non-electrolytes, and some are concerned with electrolyte exchange. W a t e r t r a n s p o r t is always passive, in the direction of solute flow, but its solvent drag can move solutes across the intestinal membrane.
SIGNIFICANT PROGRESS HAS BEEN MADE IN RECENT ~'F.~RS in o u r u n d e r s t a n d i n g of i n t e s t i n a l a b s o r p t i o n of w a t e r a n d electrolytes. F o r instance, it is now known t h a t both t h e small i n t e s t i n e and the colon have a dual role, in a b s o r p t i o n as well as secretion, and t h a t t h e a b s o r p t i v e m e c h a n i s m s of t h e colon and ileum a r e s i m i l a r . The overall p i c t u r e is one of i n t e g r a t i o n and division of labour, c r e a t i n g an int r i c a t e m e c h a n i s m f o r e l e c t r o l y t e and w a t e r s e c r e t i o n and a b s o r p t i o n f r o m t h e v a r i o u s s e g m e n t s of t h e gut.
Jejunum I n t h e a v e r a g e adult, a b o u t 10 l i t r e s of fluid e n t e r s t h e lumen of t h e j e j u n u m e v e r y 24 h o u r s : 1-3 l i t r e s is i n g e s t e d , and t h e r e m a i n d e r is supplied by secret i o n s f r o m t h e s a l i v a r y glands, stomach, b i l i a r y t r e e .
O r d i n a r i l y , m o s t of the w a t e r and e l e c t r o l y t e abs o r p t i o n t h a t occurs in the j e j u n u m is f r o m an isotonic solution. W h e n the j e j u n u m is p e r f u s e d f a s t enough (10-20 m l / m i n ) w i t h isotonic saline alone, however, only small a m o u n t s of w a t e r , sodium, and chloride a r e absorbed, and d i a r r h o e a usually results. The a b s o r p t i o n of f l u i d and electrolytes, p a r t i c u l a r l y sodium, is m a r k e d l y i n c r e a s e d by the a d d i t i o n of glucose ( F i g . 1) "), the r a t e of w a t e r a b s o r p t i o n b e i n g m a x i m a l when the p e r f u s a t e ' s glucose c o n c e n t r a t i o n reaches i g p e r 100 ml p e r f u s a t e (56 raM). O t h e r s u g a r s also, such as g a l a c t o s e and maltose, s i m i l a r l y i n c r e a s e the r a t e of f l u i d a b s o r p t i o n . S t i m u l a t i o n of w a t e r a b s o r p t i o n by glucose cannot be a t t r i b u t e d to osmosis alone - - a t all c o n c e n t r a t i o n s , glucose s t i m u l a t e s w a t e r a b s o r p t i o n in excess of its p u r e l y osmotic e f f e c t ( F i g . 2). Glucose-induced i n c r e a s e s in w a t e r a b s o r p t i o n a r e accompanied by i n c r e a s e d d i f f e r e n c e s in electrical p o t e n t i a l across t h e i n t e s t i n e , an e f f e c t due to s o d i u m a b s o r p t i o n . Since m o s t e l e c t r i c a l - p o t e n t i a l d i f f e r e n c e s in t h e j e j u n u m a r e t h e r e s u l t of s o d i u m t r a n s p o r t , glucose's e f f e c t on t h e s e d i f f e r e n c e s is s e c o n d a r y to its s t i m u l a t i o n of s o d i u m t r a n s p o r t . W a t e r moves p a s s i v e l y t h r o u g h t h e w a t e r - f i l l e d pores in t h e int e s t i n a l m e m b r a n e . These pores decrease in d i a m e t e r down the gut, f r o m R = 7.5 ,h in the j e j u n u m , 3.4 in t h e ileum, to p r o b a b l y 2.3 A in the colon. W a t e r accompanies n e t m o v e m e n t of solute in isotonic prop o r t i o n s a n d is n o t a b s o r b e d in t h e absence of solute absorption. T h e exact m e c h a n i s m b y which s o d i u m moves o u t of the i n t e s t i n a l lumen and helps to r e g u l a t e i n t e s t i n a l a b s o r p t i o n is n o t known. The t h e o r y (9" ~) t h a t seems to accord m o s t closely w i t h t h e t r a n s p o r t events so f a r known ( F i g 3). p o s t u l a t e s t h e existence of 2 m e m b r a n e s w i t h d i f f e r e n t - s i z e pores s e p a r a t i n g 3 compartments: compartment II (lateral intercellular space) is s e p a r a t e d f r o m I ( i n t e s t i n a l lumen) b y a m e m b r a n e w i t h small pores, and f r o m c o m p a r t m e n t I I I (small blood vessels and l y m p h a t i c s ) b y a m e m b r a n e w i t h l a r g e r pores. The b r u s h b o r d e r of t h e s m a l l - i n t e s t i n a l cell c o n t a i n s a common c a r r i e r f o r sodium ions and glucose, which f a c i l i t a t e each o t h e r ' s e n t r y into t h e apical p a r t of t h e cell; s o d i u m t h e n d i f f u s e s down the i n t r a c e l l u l a r c o n c e n t r a t i o n g r a d i e n t t o w a r d s t h e base of t h e cell. The i n t e s t i n a l a b s o r p t i v e cell is p o s t u l a t e d to cont a i n an e n e r g y - r e q u i r i n g ' s o d i u m pump', close to c o m p a r t m e n t I I . S o d i u m t r a n s f e r f r o m t h e cell i n t o
118 400
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Fig. 1. Mean water absorption ~'ates from isotonic saline and D'om ~otonic sugar~saline mixtzo'es (sugar concentration, ~.5 g / l O0 ml ) per fused through a 30-cm segment of normal human iejunum at ZO mll~nin. (Adapted from the report by Sladen ~, with kind permission of the autho~ and pt~blisher.)
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with (b) the calculated rate of water absoption du~ng the observed ~'ates o/ glucose abzorption, necessary to maintain an isotonic solution (glucose, 300 raM). Pcr, usion ,'ate, 20 , d i m i n . (Adapted from the report by Sladcn ~, with kind permission of the anthor and publisher.)
this comp~rtment maintains a low sodium gradient in basal parts of the cell, facilitating further movement of sodium from the brush-border site down ~he intracellular gradient; meanwhile, the 'pump' moves ,Na continuously through the small pores into compartment II, and water follows the movement of sodium in response to the latter's higher concentration in this compartment. Recent electron-microscopy studies have shown ~) that the absorption of sodium and water distends compartment II and that bulkflow of water then occurs through the larger pores into compartment I I I ; back-flow is limited by the smaller pores in the membrane separating compartment II from I. According to this mechanism, the sodium pump generates the differences in electrical Imtenti~l-that~ occur during. Na, absorption. Glucose stimulates N a absorption to provide the necessary concentration of N a for the pump, but in itself, has no effect on the differences. Another theory ~) attributes the primary role in water and solute absorption to glucose, which creates a gradient for the flow of water through the 'tight junction'; water then carries sodium and chloride by 'solvent drag'. Diffusion potentials are created during solvent drag through a different rate of diffusion of electrolytes, cations (Na) diffusing more rapidly than anions (Cl). Fixed negative charges lining the pores are believed to facilitate the movement of cations and retard the movement of anions. Whichever theory (~'~,~ is correct, the mechanism requires sodium, whose replacement by another ion (particularly lithium) immediately inhibits glucose transports ~). But this dependence is not confined to glucose: the transport of both sodium and water is promoted by galactose and maltose, also, and by some amino acids and bicarbonate. The mechanism of bicarbonate absorption, which is rapid, is virtually unknown..The considerable amount t h a t reaches the jejunum in biliary and pancreatic secretions can be absorbed against the electrochemical gradient, and its transport mechanism can be saturated. Bicarbonate can also be absorbed independently
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from Na absorption, in which circumstances its absorption seems to be linked to the secretion of chloride ions; this is of particular interest, since chloride is ordinarily absorbed by the jejunum (~). When the absorbate contains both bicarbonate and chloride, the preference for bicarbonate remains - - even when the concentration.of chloride is high enough to favour its absorption. This preference is of considerable physiological significance, as bicarbonate absorption is a major stimulus of sodium and water absorption - even when sugars and amino acids are absent from the absorbate ~9). A significant proportion of chloride is probably absorbed by following sodium passively; however, some is absorbed independently in the lower bowel, particularly the ileum and colon, and this may occur to some degree higher up the intestine. Furthermore, under certain conditions, chloride is actively secreted into the intestinal lumen (g). Potassium, also, moves across the jejunal wall passively. Thus, when the jejunum of a normal young human is perfused with isotonic solution, and the K concentration is adjusted, net transport rates are linearly related to luminal concentration °°) (Fig. 4). At low luminal concentrations, K is secreted into the lumen, but at higher concentrations it is absorbed. Under these experimental conditions, differences in electrical potential during potassium transport remain unchanged. Perfusion of the jejunum with a solution whose osmolarity induces gross movement of water in or out across the membrane, while the mean luminal concentration K is kept constant, results in K transport in the direction of water flow (11). Although the K concentration gradient across the membrane does not change, water absorption is associated with K
WATER AND ELECTROLYTE ABSORPTION -LO• ~, -
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hange
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absorption and water secretion with K secretion. These observations suggest that K transport is passive, which would accord with the theory of solvent drag. Small-intestinal secretory mechanisms, independent of the absorption mechanisms so far described, have been demonstrated recently in stu~lies of patients with cholera '1~'. Exotoxin released by V. cholerae, and that produced by other bacteria (including some strains of E. coli) and some polypeptides, can activate a cyclicAMP-dependent mechanism of the small-intestinal cell, resulting in profuse secretion of electrolytes and water. Although no physiological mechanisms of this nature have been delineated, such mechanisms could exist and could play a role in creating an optimal absorptive mixture in the upper small bowel. Ileum
The absorption of water and electrolytes in the ileum differs from that in the jejunum. The pores in its luminal membrane are considerably smaller, probably about the size of those in the colon; therefore, both of these segments offer significantly greater resistance than the jejunum to solvent drag. Probably for the same reason, the smaller pores preventing back-flow of water and electrolytes, the active transport of electrolytes is much more efficient in the ileum than in the jejunum; consequently, the electrochemical gradients in the ileum and colon have significantly higher electric-potential differences. The absorptive mechanisms in the ileum and colon are similar but not identical; for example, the colon offers even greater resistance than the ileum to the bulk flow of water. Sodium can be absorbed against a large concentration gradient, and the absorption of sodium and water in the human ileum is,independent of absorption of sugar, amino acids, or bicarbonate. Although much higher, electric-potential differences across ileal and colonic mucosa are, as in the jejunum, generated predominatly by the active transport of sodium ~a~. Another ion-transport mechanism, termed the double-exchange carrier, is postulated to exist in the ileum"4L According to this hypothesis (Fig. 5), the
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absorption of sodium ion is linked to the secretion of hydrogen ion, and chloride absorption to bicarbonate ion secretion. Hydrogen ion and bicarbonate secreted into the lumen of the ileum form water and carbon dioxide, which can diffuse back across the intestinal membrane. The jejunum probably contains an additional, similar mechanism, but only for sodium-ion and chloride-ion exchange; no electrical potential is generated by this system, because the ratio of ionic exchange is 1:1, anion being exchanged for anion and cation for cation.
Colon The role played by the colon in water and electrolyte absorption was first suggested from studies of ileostomy patients. It was estimated "~', from measurements of the effluent, that the normal colon daily absorbs about 500 ml water, 45-50 mEq sodium, and 50 mEq chloride, and secretes 3-5 mEq potassium. Recent studies in normal human subjects "6~ suggested that the volume of ileal content entering the colon may be as much as 3 times that in ileostomy patients, and it was calculated that the maximal daily absorptive capacity of the perfused colon is not more than 8 litres of water, 400 mEq sodium, and 550 mEq chloride. Although these latter daily rates of absorpttion and secretion were achieved during perfusion with 10-20 ml of isotonic solution per min - rates that probably never occur in health - - these findings nevertheless demonstrate that the colon's large absorptive capacity uniquely equips it to help cope with the increased load of water and electrolytes when ileal absorption is impaired. Although Na absorption from the colon is by active transport, it depends to some degree upon the lumina! concentration. Sodium can move against the concentration gradient until the luminal concentration falls below 15 mEq/litre (the critical luminal concentration); below this, Na secretion replaces absorption. Sodium can move up the electrical gradient (30-50 mV). Active Na transport accounts for most of the colonic transmucosal electrical potentialsC"L
120
SIDOROV
A c t i v a t i o n and s t i m u l a t i o n of t h e N a t r a n s p o r t m e c h a n i s m by glucose, a m i n o acids, and b i c a r b o n a t e have not been d e m o n s t r a t e d in t h e ileum a n d colon ''~', a l t h o u g h s u b s t a n c e s such as a d r e n o c o r t i c a l s t e r o i d s and a n g i o t e n s i n p r o m o t e N a a b s o r p t i o n '''~' and t h e colon conserves N a when i n c r e a s e d a l d o s t e r o n e secretion is induced by d i e t a r y s o d i u m r e s t r i c t i o n ''-'°~. The a d m i n i s t r a t i o n of a l d o s t e r o n e o r m i n e r a l o c o r t i c o i d s has been r e p o r t e d to i n c r e a s e e l e c t r i c a l - p o t e n t i a l d i f ferences across the r e c t a l mucosa and the r a t e of Na a b s o r p t i o n ' ~ , and to reduce t h e c r i t i c a l luminal conc e n t r a t i o n for N a a b s o r p t i o n below 15 m E q / l i t r e ''~'. Chloride a p p e a r s to be a b s o r b e d passively. I t cont i n u e s to be a b s o r b e d until r e a c h i n g its c r i t i c a l l u m i n a l c o n c e n t r a t i o n (24 m E q / l i t r e ) ~'~', below which Cl a b s o r p t i o n is replaced by its secretion. T h o u g h t h e C1 c o n c e n t r a t i o n in p l a s m a is c o n s i d e r a b l y h i g h e r ( ~ 96 m E q / l i t r e ) , and t h i s ion is a b s o r b e d a g a i n s t the c o n c e n t r a t i o n g r a d i e n t , its t r a n s p o r t is considered p a s s i v e because of l a r g e t r a n s m u c o s a l electricalp o t e n t i a l d i f f e r e n c e s (30-40 m V ) , w i t h serosal side positive to mucosal side. W h e r e a s chloride and b i c a r b o n a t e can be a b s o r b e d t o g e t h e r in the j e j u n u m , chloride a b s o r p t i o n seems to be linked to b i c a r b o n a t e s e c r e t i o n in the colon; and a l t h o u g h t o t a l ionic c o n c e n t r a t i o n in t h e lumen of the colon r e m a i n s c o n s t a n t d u r i n g chloride a b s o r p t i o n , b i c a r b o n a t e s e c r e t i o n occurs s i m u l t a n e o u s l y w i t h chloride a b s o r p t i o n . This has been c o n f i r m e d b y r e c e n t f i n d i n g s s u g g e s t i v e of a coupled t r a n s p o r t m e c h a n i s m w i t h r e c i p r o c a l anion exchange of bic a r b o n a t e and chloride s i m i l a r to t h a t in t h e h u m a n ileum cm. As in t h e j e j u n u m and ileum, w a t e r p a s s i v e l y follows a b s o r b e d solutes t h r o u g h the colon. The g r e a t e r a m o u n t of p o t a s s i u m excreted in the stools t h a n was f o u n d in i l e o s t o m y e f f l u e n t s u g g e s t s its s e c r e t i o n by t h e colon. T h i s has been c o n f i r m e d b y r e s u l t s of p e r f u s i o n s t u d i e s ('6~, w h i c h showed the c r i t i c a l c o n c e n t r a t i o n of K to be 15 m E q / l i t r e ; a t lower c o n c e n t r a t i o n s p o t a s s i u m is secreted into t h e lumen, and a t h i g h e r c o n c e n t r a t i o n s i t is absorbed. N e v e r t h e l e s s , active K s e c r e t i o n in t h e colon r e m a i n s a p o s s i b i l i t y , since a h i g h c o n c e n t r a t i o n in colonic l u m i n a l f l u i d ( > 100 m E q / l i t r e ) can be achieved in c e r t a i n c i r c u m s t a n c e s c*~).
REFF~ENCES 1. Sladen, G. E. and Dawson, A. M. (1969). Clin Sci. 36, 119-132. 2. Curran, P. F. and Macintosh, J. R. (1962). Natltre 193, 347-348. 3. Crane, R. K. (1965). Fed. Proc. 24, 1000-1006. 4. Tomasini, J. T. and Dobbins, W. O., III. (1970). Am. J. Dig. Dis. 15, 226-238. 5. Fordtran, J. S. (1967). Fed. Proc. 26, 1405-1414. 6. Cz~iky, T. Z. and Zollicoffer, L. (1960). Am . J. Physiol. 198, 1056-1058. 7. Sladen, G. E. G. (1972). In: Transport across the Intestine, ed. by W. L. Burland and P. D. Samuel. Edinburgh & London, Churchill Livingstone, pp 14-34. 8. Fordtran, J. S., Rector, F. C., Jr. and Carter, N. W. (1968). J. Clin. Invest. 47, 884-900. 9. Taylor, A. E., Wright, E. M., Schultz, S. G. and Curran, P. F. 1968. Am. J. Physiol. 214, 836-842. 10. Turnberg, L. A. (1972). In: T r a n s p o r t across the Intestine, ed. by W. L. Burland and P. D. Samuel. Edinburgh & London, Churchill Livingstone, pp 35-41. 11. Phillips, S. F. and Summerskill, W. H. J. (1967). J. Lab. Cli~e. Med. 70. 686-698. 12. Pierce, N. F., Sack, R. B., Mitra, R. C., Banwell, J. G., Brigham, K. L., Fedson, D. S. and Mondal, A. (1969). A n m lute rn. Med. 70, 1173-1181. 13. Edmonds, C. J. and Marriott, J. (1968). J. Physiol. (Lond.) 194, 479-494. 14. Turnberg, L. A., Bieberdorf, F. A., Morawski, S. G. and Fordtran, J. S. (1970). J. Clin. Invest. 49, 557567. 15. Shields, R. and Miles, J. B. (1965). Postgrad. Med. J. 41, 435-439. 16. Devroede, G. J. and Phillips, S. F. (1969). Gastroenterology 56, 101-109. 17. Grady, G. F., Duhamel, R. C. and Moore, E. W. (1970). Gastroenterology 59, 583-588. 18. Edmonds, C. J. and Pilcher, D. (1972). In: Transport across the Intestine, ed. by W. L. Burland and P. D. Samuel. Edinburgh & London, Churchill Livingstone, pp 43-57. 19. Edmonds, C. J. and Godfrey, R. C. (1970). Gut 11, 330-337. 20. Field, H., Jr., Swell, L., Dailey, R. E., Trout, E. C., Jr. and Boyd, R. S. (1955). Circulation 12, 625-629. 21. Wrong, O., Metcalfe-Gibson, A., Morrison, R. B. I., NG, S. T. and Howard, A. V. (1965). Clin. Sci. 28, 357-375.
Intestinal Absorption of Water and Electrolytes J. J. SIDOROV Department
of Medicine, Dalhousie
University,
Sidorov, J. J.
Dalhoasie
Scotia B3H 4H7
p a n c r e a s and intestine. T h i s l a r g e a m o u n t of f l u i d (ff v a r i e d t o n i c i t y is r e n d e r e d isotonic b e f o r e it e n t e r s the jejunum.
CLBIA, 9, (3) 117-120 (1976) Clin. Biochem.
Department of Medicine, Halifax, Nova Scotia
Halifax, Nova
University,
I N T E S T I N A L ABSORPTION OF W A T E R AND ELECTROLYTES 1. Recent advances in knowledge of intestinal physiology have provided some insight into disturbed mechanisms and their clinical effects; for example, diarrhoea can now be defined biochemically as excessive fluid and electrolyte loss due to their realabsorption or excessive secretion. 2. Because of differences in structure and in absorptive and secretory mechan{sms, the various parts of the gut perform different functions. In the jejunum, t r a n s p o r t activity is extensive and the rapid equilibration of its content provides the optimal absorptive mixture. Functionally, the ileum and colon are similar; compared with the jejunum, they have greater absorptive capacity for electrolytes and generate significantly higher transmural electrical potentials. In the colon, some transport mechanisms are potentiated by adrenocortical steroids. 3. W a t e r and electrolyte absorption and secretion are the end-products of bidirectional fluxes across the intestinal wall that are several times greater than net movement in either direction. Secretion is the surplus of negative flux (into the lumen) and absorption the surplus of positive flux (out of it). 4. Many electrolyte t r a n s p o r t mechanisms require the absorption of other electrolytes or non-electrolytes, and some are concerned with electrolyte exchange. W a t e r t r a n s p o r t is always passive, in the direction of solute flow, but its solvent drag can move solutes across the intestinal membrane.
SIGNIFICANT PROGRESS HAS BEEN MADE IN RECENT ~'F.~RS in o u r u n d e r s t a n d i n g of i n t e s t i n a l a b s o r p t i o n of w a t e r a n d electrolytes. F o r instance, it is now known t h a t both t h e small i n t e s t i n e and the colon have a dual role, in a b s o r p t i o n as well as secretion, and t h a t t h e a b s o r p t i v e m e c h a n i s m s of t h e colon and ileum a r e s i m i l a r . The overall p i c t u r e is one of i n t e g r a t i o n and division of labour, c r e a t i n g an int r i c a t e m e c h a n i s m f o r e l e c t r o l y t e and w a t e r s e c r e t i o n and a b s o r p t i o n f r o m t h e v a r i o u s s e g m e n t s of t h e gut.
Jejunum I n t h e a v e r a g e adult, a b o u t 10 l i t r e s of fluid e n t e r s t h e lumen of t h e j e j u n u m e v e r y 24 h o u r s : 1-3 l i t r e s is i n g e s t e d , and t h e r e m a i n d e r is supplied by secret i o n s f r o m t h e s a l i v a r y glands, stomach, b i l i a r y t r e e .
O r d i n a r i l y , m o s t of the w a t e r and e l e c t r o l y t e abs o r p t i o n t h a t occurs in the j e j u n u m is f r o m an isotonic solution. W h e n the j e j u n u m is p e r f u s e d f a s t enough (10-20 m l / m i n ) w i t h isotonic saline alone, however, only small a m o u n t s of w a t e r , sodium, and chloride a r e absorbed, and d i a r r h o e a usually results. The a b s o r p t i o n of f l u i d and electrolytes, p a r t i c u l a r l y sodium, is m a r k e d l y i n c r e a s e d by the a d d i t i o n of glucose ( F i g . 1) "), the r a t e of w a t e r a b s o r p t i o n b e i n g m a x i m a l when the p e r f u s a t e ' s glucose c o n c e n t r a t i o n reaches i g p e r 100 ml p e r f u s a t e (56 raM). O t h e r s u g a r s also, such as g a l a c t o s e and maltose, s i m i l a r l y i n c r e a s e the r a t e of f l u i d a b s o r p t i o n . S t i m u l a t i o n of w a t e r a b s o r p t i o n by glucose cannot be a t t r i b u t e d to osmosis alone - - a t all c o n c e n t r a t i o n s , glucose s t i m u l a t e s w a t e r a b s o r p t i o n in excess of its p u r e l y osmotic e f f e c t ( F i g . 2). Glucose-induced i n c r e a s e s in w a t e r a b s o r p t i o n a r e accompanied by i n c r e a s e d d i f f e r e n c e s in electrical p o t e n t i a l across t h e i n t e s t i n e , an e f f e c t due to s o d i u m a b s o r p t i o n . Since m o s t e l e c t r i c a l - p o t e n t i a l d i f f e r e n c e s in t h e j e j u n u m a r e t h e r e s u l t of s o d i u m t r a n s p o r t , glucose's e f f e c t on t h e s e d i f f e r e n c e s is s e c o n d a r y to its s t i m u l a t i o n of s o d i u m t r a n s p o r t . W a t e r moves p a s s i v e l y t h r o u g h t h e w a t e r - f i l l e d pores in t h e int e s t i n a l m e m b r a n e . These pores decrease in d i a m e t e r down the gut, f r o m R = 7.5 ,h in the j e j u n u m , 3.4 in t h e ileum, to p r o b a b l y 2.3 A in the colon. W a t e r accompanies n e t m o v e m e n t of solute in isotonic prop o r t i o n s a n d is n o t a b s o r b e d in t h e absence of solute absorption. T h e exact m e c h a n i s m b y which s o d i u m moves o u t of the i n t e s t i n a l lumen and helps to r e g u l a t e i n t e s t i n a l a b s o r p t i o n is n o t known. The t h e o r y (9" ~) t h a t seems to accord m o s t closely w i t h t h e t r a n s p o r t events so f a r known ( F i g 3). p o s t u l a t e s t h e existence of 2 m e m b r a n e s w i t h d i f f e r e n t - s i z e pores s e p a r a t i n g 3 compartments: compartment II (lateral intercellular space) is s e p a r a t e d f r o m I ( i n t e s t i n a l lumen) b y a m e m b r a n e w i t h small pores, and f r o m c o m p a r t m e n t I I I (small blood vessels and l y m p h a t i c s ) b y a m e m b r a n e w i t h l a r g e r pores. The b r u s h b o r d e r of t h e s m a l l - i n t e s t i n a l cell c o n t a i n s a common c a r r i e r f o r sodium ions and glucose, which f a c i l i t a t e each o t h e r ' s e n t r y into t h e apical p a r t of t h e cell; s o d i u m t h e n d i f f u s e s down the i n t r a c e l l u l a r c o n c e n t r a t i o n g r a d i e n t t o w a r d s t h e base of t h e cell. The i n t e s t i n a l a b s o r p t i v e cell is p o s t u l a t e d to cont a i n an e n e r g y - r e q u i r i n g ' s o d i u m pump', close to c o m p a r t m e n t I I . S o d i u m t r a n s f e r f r o m t h e cell i n t o
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this comp~rtment maintains a low sodium gradient in basal parts of the cell, facilitating further movement of sodium from the brush-border site down ~he intracellular gradient; meanwhile, the 'pump' moves ,Na continuously through the small pores into compartment II, and water follows the movement of sodium in response to the latter's higher concentration in this compartment. Recent electron-microscopy studies have shown ~) that the absorption of sodium and water distends compartment II and that bulkflow of water then occurs through the larger pores into compartment I I I ; back-flow is limited by the smaller pores in the membrane separating compartment II from I. According to this mechanism, the sodium pump generates the differences in electrical Imtenti~l-that~ occur during. Na, absorption. Glucose stimulates N a absorption to provide the necessary concentration of N a for the pump, but in itself, has no effect on the differences. Another theory ~) attributes the primary role in water and solute absorption to glucose, which creates a gradient for the flow of water through the 'tight junction'; water then carries sodium and chloride by 'solvent drag'. Diffusion potentials are created during solvent drag through a different rate of diffusion of electrolytes, cations (Na) diffusing more rapidly than anions (Cl). Fixed negative charges lining the pores are believed to facilitate the movement of cations and retard the movement of anions. Whichever theory (~'~,~ is correct, the mechanism requires sodium, whose replacement by another ion (particularly lithium) immediately inhibits glucose transports ~). But this dependence is not confined to glucose: the transport of both sodium and water is promoted by galactose and maltose, also, and by some amino acids and bicarbonate. The mechanism of bicarbonate absorption, which is rapid, is virtually unknown..The considerable amount t h a t reaches the jejunum in biliary and pancreatic secretions can be absorbed against the electrochemical gradient, and its transport mechanism can be saturated. Bicarbonate can also be absorbed independently
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from Na absorption, in which circumstances its absorption seems to be linked to the secretion of chloride ions; this is of particular interest, since chloride is ordinarily absorbed by the jejunum (~). When the absorbate contains both bicarbonate and chloride, the preference for bicarbonate remains - - even when the concentration.of chloride is high enough to favour its absorption. This preference is of considerable physiological significance, as bicarbonate absorption is a major stimulus of sodium and water absorption - even when sugars and amino acids are absent from the absorbate ~9). A significant proportion of chloride is probably absorbed by following sodium passively; however, some is absorbed independently in the lower bowel, particularly the ileum and colon, and this may occur to some degree higher up the intestine. Furthermore, under certain conditions, chloride is actively secreted into the intestinal lumen (g). Potassium, also, moves across the jejunal wall passively. Thus, when the jejunum of a normal young human is perfused with isotonic solution, and the K concentration is adjusted, net transport rates are linearly related to luminal concentration °°) (Fig. 4). At low luminal concentrations, K is secreted into the lumen, but at higher concentrations it is absorbed. Under these experimental conditions, differences in electrical potential during potassium transport remain unchanged. Perfusion of the jejunum with a solution whose osmolarity induces gross movement of water in or out across the membrane, while the mean luminal concentration K is kept constant, results in K transport in the direction of water flow (11). Although the K concentration gradient across the membrane does not change, water absorption is associated with K
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absorption and water secretion with K secretion. These observations suggest that K transport is passive, which would accord with the theory of solvent drag. Small-intestinal secretory mechanisms, independent of the absorption mechanisms so far described, have been demonstrated recently in stu~lies of patients with cholera '1~'. Exotoxin released by V. cholerae, and that produced by other bacteria (including some strains of E. coli) and some polypeptides, can activate a cyclicAMP-dependent mechanism of the small-intestinal cell, resulting in profuse secretion of electrolytes and water. Although no physiological mechanisms of this nature have been delineated, such mechanisms could exist and could play a role in creating an optimal absorptive mixture in the upper small bowel. Ileum
The absorption of water and electrolytes in the ileum differs from that in the jejunum. The pores in its luminal membrane are considerably smaller, probably about the size of those in the colon; therefore, both of these segments offer significantly greater resistance than the jejunum to solvent drag. Probably for the same reason, the smaller pores preventing back-flow of water and electrolytes, the active transport of electrolytes is much more efficient in the ileum than in the jejunum; consequently, the electrochemical gradients in the ileum and colon have significantly higher electric-potential differences. The absorptive mechanisms in the ileum and colon are similar but not identical; for example, the colon offers even greater resistance than the ileum to the bulk flow of water. Sodium can be absorbed against a large concentration gradient, and the absorption of sodium and water in the human ileum is,independent of absorption of sugar, amino acids, or bicarbonate. Although much higher, electric-potential differences across ileal and colonic mucosa are, as in the jejunum, generated predominatly by the active transport of sodium ~a~. Another ion-transport mechanism, termed the double-exchange carrier, is postulated to exist in the ileum"4L According to this hypothesis (Fig. 5), the
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Colon The role played by the colon in water and electrolyte absorption was first suggested from studies of ileostomy patients. It was estimated "~', from measurements of the effluent, that the normal colon daily absorbs about 500 ml water, 45-50 mEq sodium, and 50 mEq chloride, and secretes 3-5 mEq potassium. Recent studies in normal human subjects "6~ suggested that the volume of ileal content entering the colon may be as much as 3 times that in ileostomy patients, and it was calculated that the maximal daily absorptive capacity of the perfused colon is not more than 8 litres of water, 400 mEq sodium, and 550 mEq chloride. Although these latter daily rates of absorpttion and secretion were achieved during perfusion with 10-20 ml of isotonic solution per min - rates that probably never occur in health - - these findings nevertheless demonstrate that the colon's large absorptive capacity uniquely equips it to help cope with the increased load of water and electrolytes when ileal absorption is impaired. Although Na absorption from the colon is by active transport, it depends to some degree upon the lumina! concentration. Sodium can move against the concentration gradient until the luminal concentration falls below 15 mEq/litre (the critical luminal concentration); below this, Na secretion replaces absorption. Sodium can move up the electrical gradient (30-50 mV). Active Na transport accounts for most of the colonic transmucosal electrical potentialsC"L
120
SIDOROV
A c t i v a t i o n and s t i m u l a t i o n of t h e N a t r a n s p o r t m e c h a n i s m by glucose, a m i n o acids, and b i c a r b o n a t e have not been d e m o n s t r a t e d in t h e ileum a n d colon ''~', a l t h o u g h s u b s t a n c e s such as a d r e n o c o r t i c a l s t e r o i d s and a n g i o t e n s i n p r o m o t e N a a b s o r p t i o n '''~' and t h e colon conserves N a when i n c r e a s e d a l d o s t e r o n e secretion is induced by d i e t a r y s o d i u m r e s t r i c t i o n ''-'°~. The a d m i n i s t r a t i o n of a l d o s t e r o n e o r m i n e r a l o c o r t i c o i d s has been r e p o r t e d to i n c r e a s e e l e c t r i c a l - p o t e n t i a l d i f ferences across the r e c t a l mucosa and the r a t e of Na a b s o r p t i o n ' ~ , and to reduce t h e c r i t i c a l luminal conc e n t r a t i o n for N a a b s o r p t i o n below 15 m E q / l i t r e ''~'. Chloride a p p e a r s to be a b s o r b e d passively. I t cont i n u e s to be a b s o r b e d until r e a c h i n g its c r i t i c a l l u m i n a l c o n c e n t r a t i o n (24 m E q / l i t r e ) ~'~', below which Cl a b s o r p t i o n is replaced by its secretion. T h o u g h t h e C1 c o n c e n t r a t i o n in p l a s m a is c o n s i d e r a b l y h i g h e r ( ~ 96 m E q / l i t r e ) , and t h i s ion is a b s o r b e d a g a i n s t the c o n c e n t r a t i o n g r a d i e n t , its t r a n s p o r t is considered p a s s i v e because of l a r g e t r a n s m u c o s a l electricalp o t e n t i a l d i f f e r e n c e s (30-40 m V ) , w i t h serosal side positive to mucosal side. W h e r e a s chloride and b i c a r b o n a t e can be a b s o r b e d t o g e t h e r in the j e j u n u m , chloride a b s o r p t i o n seems to be linked to b i c a r b o n a t e s e c r e t i o n in the colon; and a l t h o u g h t o t a l ionic c o n c e n t r a t i o n in t h e lumen of the colon r e m a i n s c o n s t a n t d u r i n g chloride a b s o r p t i o n , b i c a r b o n a t e s e c r e t i o n occurs s i m u l t a n e o u s l y w i t h chloride a b s o r p t i o n . This has been c o n f i r m e d b y r e c e n t f i n d i n g s s u g g e s t i v e of a coupled t r a n s p o r t m e c h a n i s m w i t h r e c i p r o c a l anion exchange of bic a r b o n a t e and chloride s i m i l a r to t h a t in t h e h u m a n ileum cm. As in t h e j e j u n u m and ileum, w a t e r p a s s i v e l y follows a b s o r b e d solutes t h r o u g h the colon. The g r e a t e r a m o u n t of p o t a s s i u m excreted in the stools t h a n was f o u n d in i l e o s t o m y e f f l u e n t s u g g e s t s its s e c r e t i o n by t h e colon. T h i s has been c o n f i r m e d b y r e s u l t s of p e r f u s i o n s t u d i e s ('6~, w h i c h showed the c r i t i c a l c o n c e n t r a t i o n of K to be 15 m E q / l i t r e ; a t lower c o n c e n t r a t i o n s p o t a s s i u m is secreted into t h e lumen, and a t h i g h e r c o n c e n t r a t i o n s i t is absorbed. N e v e r t h e l e s s , active K s e c r e t i o n in t h e colon r e m a i n s a p o s s i b i l i t y , since a h i g h c o n c e n t r a t i o n in colonic l u m i n a l f l u i d ( > 100 m E q / l i t r e ) can be achieved in c e r t a i n c i r c u m s t a n c e s c*~).
REFF~ENCES 1. Sladen, G. E. and Dawson, A. M. (1969). Clin Sci. 36, 119-132. 2. Curran, P. F. and Macintosh, J. R. (1962). Natltre 193, 347-348. 3. Crane, R. K. (1965). Fed. Proc. 24, 1000-1006. 4. Tomasini, J. T. and Dobbins, W. O., III. (1970). Am. J. Dig. Dis. 15, 226-238. 5. Fordtran, J. S. (1967). Fed. Proc. 26, 1405-1414. 6. Cz~iky, T. Z. and Zollicoffer, L. (1960). Am . J. Physiol. 198, 1056-1058. 7. Sladen, G. E. G. (1972). In: Transport across the Intestine, ed. by W. L. Burland and P. D. Samuel. Edinburgh & London, Churchill Livingstone, pp 14-34. 8. Fordtran, J. S., Rector, F. C., Jr. and Carter, N. W. (1968). J. Clin. Invest. 47, 884-900. 9. Taylor, A. E., Wright, E. M., Schultz, S. G. and Curran, P. F. 1968. Am. J. Physiol. 214, 836-842. 10. Turnberg, L. A. (1972). In: T r a n s p o r t across the Intestine, ed. by W. L. Burland and P. D. Samuel. Edinburgh & London, Churchill Livingstone, pp 35-41. 11. Phillips, S. F. and Summerskill, W. H. J. (1967). J. Lab. Cli~e. Med. 70. 686-698. 12. Pierce, N. F., Sack, R. B., Mitra, R. C., Banwell, J. G., Brigham, K. L., Fedson, D. S. and Mondal, A. (1969). A n m lute rn. Med. 70, 1173-1181. 13. Edmonds, C. J. and Marriott, J. (1968). J. Physiol. (Lond.) 194, 479-494. 14. Turnberg, L. A., Bieberdorf, F. A., Morawski, S. G. and Fordtran, J. S. (1970). J. Clin. Invest. 49, 557567. 15. Shields, R. and Miles, J. B. (1965). Postgrad. Med. J. 41, 435-439. 16. Devroede, G. J. and Phillips, S. F. (1969). Gastroenterology 56, 101-109. 17. Grady, G. F., Duhamel, R. C. and Moore, E. W. (1970). Gastroenterology 59, 583-588. 18. Edmonds, C. J. and Pilcher, D. (1972). In: Transport across the Intestine, ed. by W. L. Burland and P. D. Samuel. Edinburgh & London, Churchill Livingstone, pp 43-57. 19. Edmonds, C. J. and Godfrey, R. C. (1970). Gut 11, 330-337. 20. Field, H., Jr., Swell, L., Dailey, R. E., Trout, E. C., Jr. and Boyd, R. S. (1955). Circulation 12, 625-629. 21. Wrong, O., Metcalfe-Gibson, A., Morrison, R. B. I., NG, S. T. and Howard, A. V. (1965). Clin. Sci. 28, 357-375.
