Effects of Ethanol on the Determinants of Intestinal Transport Linda L. Shanbour, Ph.D. The interplay between the stomach, liver. pancreas, and the small intestine and their influence on the effects of ethanol on the determinants of intestinal transport are examined.
NY discussion of intestinal transport, at A least from a physiologic viewpoint, should take into consideration influences from other gastrointestinal tissues. Figure 1 illustrates the interplay between the stomach, liver, pancreas, and the small intestine. Alterations in gastric acid secretion may influence intestinal transport by altering the pH of the environment for the intestinal enzymes involved in the breakdown of foodstuff and, thus, presentation of material for transport, as well as possibly affecting the transport process itself. Indirectly, alterations in gastric acid secretion may influence hormonal release mechanisms, such as gastrin, from the antral m u m a and secretin and glucagon from the small intestine. These hormones may then influence the pancreas and liver with secretin inducing pancreatic water and bicarbonate secretion, and glucagon stimulating gluconeogenesis in the liver. There are obviously many other actions, but these are the major areas that will be discussed. STOMACH
The stomach, which receives high concentrations of alcohol as compared to most other regions of the body, has received relatively little attention in terms of basic mechanisms that may be altered by ethanol. For many years it has been assumed that ethanol stimulates gastric acid From the Lkpartment of Physiology, University of Texas Medical School at Houston. Texas Medical Center, Houston, Texas. Supported by NIAAA Grants 2 ROI AA 00194-07. L.L.S. is the recipient of Research Scientist Development Award 5 KO2 AA 70463-05. Reprint requests should be addressed to Linda L. Shanbow, Ph.D.. Department of Physiology, University of Texas Medical School at Houston, Texas Medical Center. Houston, Texas 77025. 01979 by Gmne & Stratton. Inc. 014 5 - 6 ~ / 7 9 / 0 3 0 2 ~ $ .00/0 01 142
secretion. However, in most literature reports of stimulated acid secretion, it is impossible to discriminate between a direct action of ethanol on the parietal cells or an indirect effect through the possible release of gastrin from the antral m u m or other effects. In a preparation designed to separate the fundic or acid-secreting portion of the stomach from the antral or gastrin-releasing segment, the effects of alcohol on acid secretion in the dog were determined (Fig. 2). A laparotomy was performed, the stomach antrectomized, and the fundic portion mounted in the double lucite chamber. Acid secretion collected at intervals cannot distinguish between possible increase in back-diffusion of H+ or decrease in the active secretion of H+. Therefore, the luminal solution was maintained neutral, and acid secreted was titrated continually with a pH stat technique (Fig. 3). A second method, maintaining the luminal solution neutral with TES buffer [ 100 mM Ntris (hydroxymethyl) methyl-z-aminoethanesulfonic acid], was used to verify results.' Some investigators have used potential difference (PD) measurements to indicate damage or increased permeability of the mucosa. However, potential difference alone cannot distinguish between increased tissue permeability and inhibition of active transport of ions (Fig. 4). An automatic voltage-clamp system2 was developed to permit continuous monitoring of PD and periodic determination of electrical current, in order to calculate electrical resistance. A decrease in electrical resistance implies an increase in tissue permeability, and increased resistance suggests inhibition of active transport. Figure 5 illustrates the effects of ethanol as compared to pre-ethanol values in the histaminestimulated preparation. Ethanol, at a 20% concentration, which is equivalent to one martini on an empty stomach, decreased acid secretion to one-third of control values. The potential difference was also markedly decreased. Ethanol increased electrical resistance, thus suggesting a prime effect on the inhibition of active ion transport in the gastric mucosa. Other studies on the isolated gastric mucosa, in which unidirectional
A M i s m : Umical and ECperimental Reseerch. Vd. 3,No. 2 (April), 1979
EFFECTS OF ETHANOL ON INTESTINAL TRANSPORT
STOMACH
-
143
ACID OUTPUT 1 back diffusion 2.4 acid secretion
.+
PANCREAS
METHODS 1. stirring with gas mixture 2. continuous pH-stat technique Fig. 3. Methods for meeauringgestric acid secretion.
Fig. 1. The interactions of the various tiaauea of the gastrointestinal system.
and net isotopic flux determinations were made, have confirmed the inhibition of active ion transport by ethanoL3 Concomitant studies have demonstrated that ethanol does not alter the CAMP content of the gastric mucosa, but does decrease ATP content: The decrease in ATP content may be the mechanism by which ethanol inhibits active transport of ions in the gastric mucosa. These effects are observed only when ethanol is present on the luminal side of the gastric mucosa. Intraarterial infusion of ethanol into the stomach at concentrations as high as 30% fail to produce any changes in the measured parameters.' In order to test the possibility that ethanol may stimulate acid secretion by producing the release of gastrin from the antral mucosa, the
previous preparation was used, with the excep tion that the antrum was made into a pouch for the instillation of ethanol or other test substances.5 Ethanol in the antral pouch produced essentially no change in acid output or potential difference in the fundic chamber or in the serum gastrin level (Fig. 6). However, when glycine was instilled in the antral pouch, acid output from the fundic chamber increased by approximately 70% with a slight decrease in the potential difference, and serum gastrin increased by 50%. These studies suggest that any release of gastrin from the antrum is insufficient to stimulate fundic acid secretion. PANCREAS
Consideration of any net effects of ethanol on intestinal absorption should include factors that may influence absorptive processes, such as pancreatic exocrine secretion. The pancreas secretes digestive enzymes, water, and electrolytes into the duodenum. Until recently, it has been assumed that ethanol stimulates pancreatic secretion. However, Mott et a1.,6 using human subjects, and Bayer et al.: using conscious dogs, have shown that ethanol inhibits secretin and POTENTIAL DIFFERENCE 1. f tissue permeability 2. active transport
+
METHODS 1. tissue electrical resistance with+ PD
=.) tissue permeability .) R =
(
= ir0801
Fig. 2.
Currant Elactn(mi
The intact fundic chamber preparation.
+g) +
tissue electrical resistance with PD
2.
+
active transport
+ R = ,Z, ) ++I
Fig. 4. Interpretations of potenthl dflereme and electrical resistance measurements.
LINDA L. SHANBOUR
1 44
STOMACH
PERCENT
-.
OF
PRE-ETHANOL VALUES
ACID SECRLTION
WTENTUL DIFFERENCE
ELECTRICAL RESISTANCE
cholecystokinin-stimulated pancreatic secretion of water, bicarbonate, and protein. Since the preparations prevented acid from entering the duodenum, the inhibition was probably due to a direct effect of ethanol on pancreatic secretory cells. We have tested this hypothesis by using the isolated perfused rabbit pancreas preparation of Rothman and Brooks* and an in vivo perfusion method? Figure 7 illustrates that ethanol inhibits volume and bicarbonate output by approximately 50% and markedly decreases protein
AW
CAMP
Fig. 6. Effects of 20% ethanol on acid secretion. potential difference, electrical resistonce, tissue ATP and cAMP contents in tho fundic mucosa as compared with pre-ethanol values.
output. Studies have shown that ATP is necessary for pancreatic enzyme secretion" and that secretion of water and bicarbonate depend on oxidative phosphorylation. Cyclic AMP has been implicated as a mediator of secretin-stimulated pancreatic water and bicarbonate secretion." Ethanol decreases pancreatic ATP content, but has essentially no effect on tissue cAMP content. The decrease in ATP may be the mechanism by which ethanol inhibits pancreatic exocrine secretion.
STOMACH
PERCENT
OF CONTROL VALUES
Fig. 8. Effects of othanol and glycim in the intact amrel pouch on fundic acid output and potential difference and serum gastrin levels as corn pared with control values.
EFFECTS OF ETHANOL ON INTESTINAL TRANSPORT
145
PANCREAS
PERCENT OF PRE-ETHANOL VALUES
Fig. 7. Effects of intravenous ethanol on pancreatic secretion and tissue ATP and cAMP contents as compared with preethanol values.
VOLUME
LIVER
Oral ingestion of ethanol may produce the release of hormones from the small intestine. These hormones may then influence other tissues in the body. There is only one report in the literature, by Straus et al.,” demonstrating an ethanol-induced increase in secretin release. This is one area of alcohol studies where knowledge is severely limited and is due primarily to the technical difficulties in establishing the radioimmunoassays for the gastrointestinal hormones. Some excellent studies have been conducted on the metabolic effects of ethanol on the liver. Unfortunately, many of these studies have been conducted using isolated perfused liver preparations or tissue slices. In order to determine whether the effects of ethanol on the liver are different when ethanol is administered
HCO 3’ OUTPUT
PROTEIN OUTPUT
ATP
CAMP
via a more physiologic route, i.e., orally, studies were designed to evaluate the effects of ethanol given orally versus intravenously on the glucagon-mediated increase in hepatic C A M P . ‘ ~ Figure 8 summarizes the results of this study. Each group is compared with saline control values. Ethanol, infused intravenously to achieve blood alcohol levels ranging from 60 to 200 mg/ 100 ml did not alter hepatic cAMP or ATP values. However, glucagon (50 pg/kg) increased hepatic cAMP by approximately 21/2-fold, but did not alter hepatic ATP levels. When ethanol was administered orally as a 20% solution, cAMP levels more than doubled as compared with saline controls, but ATP levels were unaltered. The glucagon response in the presence of oral pretreatment with ethanol was approximately 5$-fold the saline controls and more than double the glucagon-alone response. The syner-
LIVER
PERCENT OF CONTROL VALUES
Fig. 8. The effects of oral versus intravenous ethan d administration on tissue cAMP and ATP contents in the liver.
LINDA L. SHANBOUR
146
DIARRHEA 1 absorption 2. secretion 3.+ motitity
+
Fig. 9.
Mechanismsof d i e r r h production.
gistic effect of oral ethanol on the glucagonmediated increase in hepatic CAMP was also demonstrated to be inversely correlated with the blood alcohol level. This suggests that the more alcohol retained in the intestinal tract, the greater the degree of intestinal hormones released. When released, these hormones may then activate hepatic adenyl cyclase, the hormone involved in the formation of CAMP, or change the sensitivity of the hepatic receptor to glucagon. The most likely candidates for hormones released from the intestinal tract are gut glucagon and secretin. These hormones evoke hyperglycemia under normal physiologic conditions. Both hormones stimulate adenyl cyclase, but apparently via different receptors." These results emphasize the importance of integrated studies under as physiologic conditions as possible.
JEJUNUM
Diarrhea is a common Occurrence in chronic alcohol abuse. There are basically three mechanisms by which diarrhea may be produced (Fig. 9). The jejunum is the major gastrointestinal region for absorption, and all enzymatic activity of pancreatic enzymes is performed in duodenal and jejunal lumen. The absorption of amino acids and small peptides is 80% completed in the upper 100 cm of the jejunum. The jejunum actively transports sodium, glucose, and amino acids and thus requires the expenditure of metabolic energy. Ethanol has been demonstrated to inhibit the absorption of glucose and amino acid^.'^'' The absorption of these substances is dependent to a considerable extent on the active transport of sodium in the intestine. Dinda et al.'* have reported that ethanol inhibits glucose transport and mucosal to serosal Na' flux but does not affect net Na' flux. However, in their studies, the presence of electrochemical gradients prevents definitive interpretation concerning the effect of ethanol on active transport of Na'. With the Ussing chamber preparation, by which electrochemical gradients across the mumsa can be maintained at zero, and passive (unidirectional) and active transport (difference between unidirectional fluxes) can be determined, studies were designed to evaluate the
PERCENT OF
PRE-ETHANOL VALUES
PoTLNTlAL DlWERI!NCE
-
NET
J Z OJ L -NET -
Fig. 10. E i f e c t s of 3 % ethanol on elmt r i a l potential difference and active tramport of sodium. 3-O-mothylgluco~eend L&nine in the jejunum.
EFFECTS OF ETHANOL ON INTESTINAL TRANSPORT
147
effects of ethanol on the active transport of sodium, 3-O-methylglucose, and ~-alanine.’~ Figure 10 illustrates the effects of 3% ethanol on the jejunum. This concentration of ethanol may be found in the human upper jejunum during moderate drinking.” The potential difference, which was determined periodically during the experiments, was decreased to approximately 60% of pre-ethanol values. The active transport of Na’, 3-O-methylglucose, and Lalanine was decreased to less than 50% of pre-
ethanol values. These effects were observed when ethanol was present on only the luminal side of the jejunal mucosa or on both sides. However, when ethanol was present on only the serosal or blood side, the values were essentially unchanged from controls. Thus, the primary mechanism involved in alcohol-induced diarrhea is apparently inhibition of the energy-requiring active absorption of nutrient substances by the intestinal tract.
REFERENCES I . Sernka TJ, Gilleland CW. Shanbour LL: Effects of ethanol on active transport in the dog stomach. Am J Physiol 226:397-400, 1974 2. Shanbour LL: An automatic voltage-clamp system for in vivo or in vitro studies. Am J Dig Dis 19:367-371, 1974 3. Kuo Y-J, Shanbour LL. Sernka TJ: Effect of ethanol on permeability and ion transport in the isolated dog stomach. Am J Dig Dis I9:8 18-824, 1974 4. Tague LL. Shanbour LL: Effects of ethanol on bicarbonate-stimulated ATPase, ATP. and cyclic AMP in canine gastric mucosa. Proc Soc Exp Biol Med 154:3740, 1977 5. Bo-Linn GW. Shanbour LL: Effects of antral ethanol on gastric acid secretion, potential difference and serum gastrin. Proc Soc Exp Biol Med 155:594-598.1977 6. Mott C, Sarles H, Tiscornia 0,Gullo L Inhibitory action of alcohol on human exocrine pancreatic secretion. Am J Dig Dis 17:902-910, 1972 7. Bayer M,Rudick J. Lieber CS, Janowitz H D Inhibitory effect of ethanol on canine exocrine pancreatic secretion. Gastroenterology 63:619-626, 1972 8. Rothman SS, Brooks F P Electrolyte secretion from rabbit pancreas in vitro. Am J Physiol208:1171-1176, 1965 9. Solomon N. Solomon TE, Jacobson ED, Shanbour LL: Direct effects of alcohol on in vivo and in vitro exocrine pancreatic secretion and metabolism. Am J Dig Dis 19:253260. 1974 10. Jamieson JD, Palade GE: Condensing vacuole conversion and zymogen granule discharge in pancreatic exocrine cells: Metabolic studies. J Cell Biol48:503-522. 1971 11. Case RM, Johnson M. Scratcherd T, Sherratt HSA: Cyclic adenosine 3’5’-monophosphate concentration in the
pancreas following stimulation by secretin, cholecystokininpancreozymin and acetylcholine. J Physiol 223:669-684. 1972 12. Straus E, Urbach HJ, Yalow RS: Alcohol-stimulated secretion of immunoreactive secretin. N Engl J Med 293: I03 1-1032,1975 13. Shanbour LL, Huang CPC: Importance of route of administration in evaluating the hepatic effects of alcohol. Alcoholism 1 :154, 1977 14. Desbuquois B, Laudat MH, Laudat P Vasoactive intestinal polypeptide and glucagon:stimulation of adenylate cyclase activity via distinct receptors in liver and fat cell membranes. Biochem Biophys Res Commun 53:1187-1194, 1973 IS. Chang T,Lewis J, Glazko AJ: Effect of ethanol and other alcohols on the transport of amino acids and glucose by everted sacs of rat small intestine. Biochim Biophys Acta 135:1000-1007,1967 16. Israel Y, Salazar 1, Rosenmann E: Inhibitory effect of alcohol on intestinal amino acid transport in vivo and in vitro. J Nutr 96:499-504,1968 17. Israel Y, Valenzuela JE, Salazar I, Ugarte G:Alcohol and amino acid transport in the human small intestine. J Nutr 98:222-224,1969 18. Dinda PK, Beck IT, Beck M. McElligott T F Effect of ethanol on sodium-dependent glucose transport in the small intestine of the hamster. Gastroenterology 68:1517-1526, 1975 19. Kuo Y-J, Shanbour L L Effects of ethanol on sodium, 3-0-methyl glucose and ~-alaninetransport in the jejunum. Am J Dig Dis 2351-56,1978
NY discussion of intestinal transport, at A least from a physiologic viewpoint, should take into consideration influences from other gastrointestinal tissues. Figure 1 illustrates the interplay between the stomach, liver, pancreas, and the small intestine. Alterations in gastric acid secretion may influence intestinal transport by altering the pH of the environment for the intestinal enzymes involved in the breakdown of foodstuff and, thus, presentation of material for transport, as well as possibly affecting the transport process itself. Indirectly, alterations in gastric acid secretion may influence hormonal release mechanisms, such as gastrin, from the antral m u m a and secretin and glucagon from the small intestine. These hormones may then influence the pancreas and liver with secretin inducing pancreatic water and bicarbonate secretion, and glucagon stimulating gluconeogenesis in the liver. There are obviously many other actions, but these are the major areas that will be discussed. STOMACH
The stomach, which receives high concentrations of alcohol as compared to most other regions of the body, has received relatively little attention in terms of basic mechanisms that may be altered by ethanol. For many years it has been assumed that ethanol stimulates gastric acid From the Lkpartment of Physiology, University of Texas Medical School at Houston. Texas Medical Center, Houston, Texas. Supported by NIAAA Grants 2 ROI AA 00194-07. L.L.S. is the recipient of Research Scientist Development Award 5 KO2 AA 70463-05. Reprint requests should be addressed to Linda L. Shanbow, Ph.D.. Department of Physiology, University of Texas Medical School at Houston, Texas Medical Center. Houston, Texas 77025. 01979 by Gmne & Stratton. Inc. 014 5 - 6 ~ / 7 9 / 0 3 0 2 ~ $ .00/0 01 142
secretion. However, in most literature reports of stimulated acid secretion, it is impossible to discriminate between a direct action of ethanol on the parietal cells or an indirect effect through the possible release of gastrin from the antral m u m or other effects. In a preparation designed to separate the fundic or acid-secreting portion of the stomach from the antral or gastrin-releasing segment, the effects of alcohol on acid secretion in the dog were determined (Fig. 2). A laparotomy was performed, the stomach antrectomized, and the fundic portion mounted in the double lucite chamber. Acid secretion collected at intervals cannot distinguish between possible increase in back-diffusion of H+ or decrease in the active secretion of H+. Therefore, the luminal solution was maintained neutral, and acid secreted was titrated continually with a pH stat technique (Fig. 3). A second method, maintaining the luminal solution neutral with TES buffer [ 100 mM Ntris (hydroxymethyl) methyl-z-aminoethanesulfonic acid], was used to verify results.' Some investigators have used potential difference (PD) measurements to indicate damage or increased permeability of the mucosa. However, potential difference alone cannot distinguish between increased tissue permeability and inhibition of active transport of ions (Fig. 4). An automatic voltage-clamp system2 was developed to permit continuous monitoring of PD and periodic determination of electrical current, in order to calculate electrical resistance. A decrease in electrical resistance implies an increase in tissue permeability, and increased resistance suggests inhibition of active transport. Figure 5 illustrates the effects of ethanol as compared to pre-ethanol values in the histaminestimulated preparation. Ethanol, at a 20% concentration, which is equivalent to one martini on an empty stomach, decreased acid secretion to one-third of control values. The potential difference was also markedly decreased. Ethanol increased electrical resistance, thus suggesting a prime effect on the inhibition of active ion transport in the gastric mucosa. Other studies on the isolated gastric mucosa, in which unidirectional
A M i s m : Umical and ECperimental Reseerch. Vd. 3,No. 2 (April), 1979
EFFECTS OF ETHANOL ON INTESTINAL TRANSPORT
STOMACH
-
143
ACID OUTPUT 1 back diffusion 2.4 acid secretion
.+
PANCREAS
METHODS 1. stirring with gas mixture 2. continuous pH-stat technique Fig. 3. Methods for meeauringgestric acid secretion.
Fig. 1. The interactions of the various tiaauea of the gastrointestinal system.
and net isotopic flux determinations were made, have confirmed the inhibition of active ion transport by ethanoL3 Concomitant studies have demonstrated that ethanol does not alter the CAMP content of the gastric mucosa, but does decrease ATP content: The decrease in ATP content may be the mechanism by which ethanol inhibits active transport of ions in the gastric mucosa. These effects are observed only when ethanol is present on the luminal side of the gastric mucosa. Intraarterial infusion of ethanol into the stomach at concentrations as high as 30% fail to produce any changes in the measured parameters.' In order to test the possibility that ethanol may stimulate acid secretion by producing the release of gastrin from the antral mucosa, the
previous preparation was used, with the excep tion that the antrum was made into a pouch for the instillation of ethanol or other test substances.5 Ethanol in the antral pouch produced essentially no change in acid output or potential difference in the fundic chamber or in the serum gastrin level (Fig. 6). However, when glycine was instilled in the antral pouch, acid output from the fundic chamber increased by approximately 70% with a slight decrease in the potential difference, and serum gastrin increased by 50%. These studies suggest that any release of gastrin from the antrum is insufficient to stimulate fundic acid secretion. PANCREAS
Consideration of any net effects of ethanol on intestinal absorption should include factors that may influence absorptive processes, such as pancreatic exocrine secretion. The pancreas secretes digestive enzymes, water, and electrolytes into the duodenum. Until recently, it has been assumed that ethanol stimulates pancreatic secretion. However, Mott et a1.,6 using human subjects, and Bayer et al.: using conscious dogs, have shown that ethanol inhibits secretin and POTENTIAL DIFFERENCE 1. f tissue permeability 2. active transport
+
METHODS 1. tissue electrical resistance with+ PD
=.) tissue permeability .) R =
(
= ir0801
Fig. 2.
Currant Elactn(mi
The intact fundic chamber preparation.
+g) +
tissue electrical resistance with PD
2.
+
active transport
+ R = ,Z, ) ++I
Fig. 4. Interpretations of potenthl dflereme and electrical resistance measurements.
LINDA L. SHANBOUR
1 44
STOMACH
PERCENT
-.
OF
PRE-ETHANOL VALUES
ACID SECRLTION
WTENTUL DIFFERENCE
ELECTRICAL RESISTANCE
cholecystokinin-stimulated pancreatic secretion of water, bicarbonate, and protein. Since the preparations prevented acid from entering the duodenum, the inhibition was probably due to a direct effect of ethanol on pancreatic secretory cells. We have tested this hypothesis by using the isolated perfused rabbit pancreas preparation of Rothman and Brooks* and an in vivo perfusion method? Figure 7 illustrates that ethanol inhibits volume and bicarbonate output by approximately 50% and markedly decreases protein
AW
CAMP
Fig. 6. Effects of 20% ethanol on acid secretion. potential difference, electrical resistonce, tissue ATP and cAMP contents in tho fundic mucosa as compared with pre-ethanol values.
output. Studies have shown that ATP is necessary for pancreatic enzyme secretion" and that secretion of water and bicarbonate depend on oxidative phosphorylation. Cyclic AMP has been implicated as a mediator of secretin-stimulated pancreatic water and bicarbonate secretion." Ethanol decreases pancreatic ATP content, but has essentially no effect on tissue cAMP content. The decrease in ATP may be the mechanism by which ethanol inhibits pancreatic exocrine secretion.
STOMACH
PERCENT
OF CONTROL VALUES
Fig. 8. Effects of othanol and glycim in the intact amrel pouch on fundic acid output and potential difference and serum gastrin levels as corn pared with control values.
EFFECTS OF ETHANOL ON INTESTINAL TRANSPORT
145
PANCREAS
PERCENT OF PRE-ETHANOL VALUES
Fig. 7. Effects of intravenous ethanol on pancreatic secretion and tissue ATP and cAMP contents as compared with preethanol values.
VOLUME
LIVER
Oral ingestion of ethanol may produce the release of hormones from the small intestine. These hormones may then influence other tissues in the body. There is only one report in the literature, by Straus et al.,” demonstrating an ethanol-induced increase in secretin release. This is one area of alcohol studies where knowledge is severely limited and is due primarily to the technical difficulties in establishing the radioimmunoassays for the gastrointestinal hormones. Some excellent studies have been conducted on the metabolic effects of ethanol on the liver. Unfortunately, many of these studies have been conducted using isolated perfused liver preparations or tissue slices. In order to determine whether the effects of ethanol on the liver are different when ethanol is administered
HCO 3’ OUTPUT
PROTEIN OUTPUT
ATP
CAMP
via a more physiologic route, i.e., orally, studies were designed to evaluate the effects of ethanol given orally versus intravenously on the glucagon-mediated increase in hepatic C A M P . ‘ ~ Figure 8 summarizes the results of this study. Each group is compared with saline control values. Ethanol, infused intravenously to achieve blood alcohol levels ranging from 60 to 200 mg/ 100 ml did not alter hepatic cAMP or ATP values. However, glucagon (50 pg/kg) increased hepatic cAMP by approximately 21/2-fold, but did not alter hepatic ATP levels. When ethanol was administered orally as a 20% solution, cAMP levels more than doubled as compared with saline controls, but ATP levels were unaltered. The glucagon response in the presence of oral pretreatment with ethanol was approximately 5$-fold the saline controls and more than double the glucagon-alone response. The syner-
LIVER
PERCENT OF CONTROL VALUES
Fig. 8. The effects of oral versus intravenous ethan d administration on tissue cAMP and ATP contents in the liver.
LINDA L. SHANBOUR
146
DIARRHEA 1 absorption 2. secretion 3.+ motitity
+
Fig. 9.
Mechanismsof d i e r r h production.
gistic effect of oral ethanol on the glucagonmediated increase in hepatic CAMP was also demonstrated to be inversely correlated with the blood alcohol level. This suggests that the more alcohol retained in the intestinal tract, the greater the degree of intestinal hormones released. When released, these hormones may then activate hepatic adenyl cyclase, the hormone involved in the formation of CAMP, or change the sensitivity of the hepatic receptor to glucagon. The most likely candidates for hormones released from the intestinal tract are gut glucagon and secretin. These hormones evoke hyperglycemia under normal physiologic conditions. Both hormones stimulate adenyl cyclase, but apparently via different receptors." These results emphasize the importance of integrated studies under as physiologic conditions as possible.
JEJUNUM
Diarrhea is a common Occurrence in chronic alcohol abuse. There are basically three mechanisms by which diarrhea may be produced (Fig. 9). The jejunum is the major gastrointestinal region for absorption, and all enzymatic activity of pancreatic enzymes is performed in duodenal and jejunal lumen. The absorption of amino acids and small peptides is 80% completed in the upper 100 cm of the jejunum. The jejunum actively transports sodium, glucose, and amino acids and thus requires the expenditure of metabolic energy. Ethanol has been demonstrated to inhibit the absorption of glucose and amino acid^.'^'' The absorption of these substances is dependent to a considerable extent on the active transport of sodium in the intestine. Dinda et al.'* have reported that ethanol inhibits glucose transport and mucosal to serosal Na' flux but does not affect net Na' flux. However, in their studies, the presence of electrochemical gradients prevents definitive interpretation concerning the effect of ethanol on active transport of Na'. With the Ussing chamber preparation, by which electrochemical gradients across the mumsa can be maintained at zero, and passive (unidirectional) and active transport (difference between unidirectional fluxes) can be determined, studies were designed to evaluate the
PERCENT OF
PRE-ETHANOL VALUES
PoTLNTlAL DlWERI!NCE
-
NET
J Z OJ L -NET -
Fig. 10. E i f e c t s of 3 % ethanol on elmt r i a l potential difference and active tramport of sodium. 3-O-mothylgluco~eend L&nine in the jejunum.
EFFECTS OF ETHANOL ON INTESTINAL TRANSPORT
147
effects of ethanol on the active transport of sodium, 3-O-methylglucose, and ~-alanine.’~ Figure 10 illustrates the effects of 3% ethanol on the jejunum. This concentration of ethanol may be found in the human upper jejunum during moderate drinking.” The potential difference, which was determined periodically during the experiments, was decreased to approximately 60% of pre-ethanol values. The active transport of Na’, 3-O-methylglucose, and Lalanine was decreased to less than 50% of pre-
ethanol values. These effects were observed when ethanol was present on only the luminal side of the jejunal mucosa or on both sides. However, when ethanol was present on only the serosal or blood side, the values were essentially unchanged from controls. Thus, the primary mechanism involved in alcohol-induced diarrhea is apparently inhibition of the energy-requiring active absorption of nutrient substances by the intestinal tract.
REFERENCES I . Sernka TJ, Gilleland CW. Shanbour LL: Effects of ethanol on active transport in the dog stomach. Am J Physiol 226:397-400, 1974 2. Shanbour LL: An automatic voltage-clamp system for in vivo or in vitro studies. Am J Dig Dis 19:367-371, 1974 3. Kuo Y-J, Shanbour LL. Sernka TJ: Effect of ethanol on permeability and ion transport in the isolated dog stomach. Am J Dig Dis I9:8 18-824, 1974 4. Tague LL. Shanbour LL: Effects of ethanol on bicarbonate-stimulated ATPase, ATP. and cyclic AMP in canine gastric mucosa. Proc Soc Exp Biol Med 154:3740, 1977 5. Bo-Linn GW. Shanbour LL: Effects of antral ethanol on gastric acid secretion, potential difference and serum gastrin. Proc Soc Exp Biol Med 155:594-598.1977 6. Mott C, Sarles H, Tiscornia 0,Gullo L Inhibitory action of alcohol on human exocrine pancreatic secretion. Am J Dig Dis 17:902-910, 1972 7. Bayer M,Rudick J. Lieber CS, Janowitz H D Inhibitory effect of ethanol on canine exocrine pancreatic secretion. Gastroenterology 63:619-626, 1972 8. Rothman SS, Brooks F P Electrolyte secretion from rabbit pancreas in vitro. Am J Physiol208:1171-1176, 1965 9. Solomon N. Solomon TE, Jacobson ED, Shanbour LL: Direct effects of alcohol on in vivo and in vitro exocrine pancreatic secretion and metabolism. Am J Dig Dis 19:253260. 1974 10. Jamieson JD, Palade GE: Condensing vacuole conversion and zymogen granule discharge in pancreatic exocrine cells: Metabolic studies. J Cell Biol48:503-522. 1971 11. Case RM, Johnson M. Scratcherd T, Sherratt HSA: Cyclic adenosine 3’5’-monophosphate concentration in the
pancreas following stimulation by secretin, cholecystokininpancreozymin and acetylcholine. J Physiol 223:669-684. 1972 12. Straus E, Urbach HJ, Yalow RS: Alcohol-stimulated secretion of immunoreactive secretin. N Engl J Med 293: I03 1-1032,1975 13. Shanbour LL, Huang CPC: Importance of route of administration in evaluating the hepatic effects of alcohol. Alcoholism 1 :154, 1977 14. Desbuquois B, Laudat MH, Laudat P Vasoactive intestinal polypeptide and glucagon:stimulation of adenylate cyclase activity via distinct receptors in liver and fat cell membranes. Biochem Biophys Res Commun 53:1187-1194, 1973 IS. Chang T,Lewis J, Glazko AJ: Effect of ethanol and other alcohols on the transport of amino acids and glucose by everted sacs of rat small intestine. Biochim Biophys Acta 135:1000-1007,1967 16. Israel Y, Salazar 1, Rosenmann E: Inhibitory effect of alcohol on intestinal amino acid transport in vivo and in vitro. J Nutr 96:499-504,1968 17. Israel Y, Valenzuela JE, Salazar I, Ugarte G:Alcohol and amino acid transport in the human small intestine. J Nutr 98:222-224,1969 18. Dinda PK, Beck IT, Beck M. McElligott T F Effect of ethanol on sodium-dependent glucose transport in the small intestine of the hamster. Gastroenterology 68:1517-1526, 1975 19. Kuo Y-J, Shanbour L L Effects of ethanol on sodium, 3-0-methyl glucose and ~-alaninetransport in the jejunum. Am J Dig Dis 2351-56,1978
