BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE
VOL. 54, No. 3
MARCH 1978
MODELING THE GASTROINTESTINAL SYSTEM* STANLEY M. FINKELSTEIN, Ph.D., DAVID A. DREILING, M.D., AND WILLIAM B. BLESSER, Sc. D. Department of Surgery The Mount Sinai School of Medicine of the City University of New York New York, New York Division of Bioengineering, Polytechnic Institute of New York Brooklyn, New York
W E have developed a basic block diagram model to describe the gastrointestinal system and to study the interaction between the various organs of the system during digestion. The primary blocks of the system represent the stomach, duodenum, pancreas, and gallbladder. Excitation signals for the system are the neural (vagus) responses to the intake of food and the volume effects of the constituents of food, particularly fat, carbohydrate, and protein. The initial study proposes that both the concentration of hydrogen ions (or pH) and the volume of the ingested foodstuff stimulate the primary system blocks. The model describes the acid and gastrin responses of the stomach wall, the duodenal hormonal response to the concentration of secretin, and the gallbladder response to cholecystokinin in a total closed-loop configuration. *Presented before the Section on Biomedical Engineering of the New York Academy of Medicine September 14, 1976.
S. M. FINKELSTEIN AND OTHERS 2522S2.FNESENADOHR 25
Once the model has been validated and quantitative values have been assigned to the various blocks, the model can be simulated on a digital computer and then can be used to study the interactive effect of each subsystem on total system function and the sensitivity of the system's response to variations in parameters. OBJECTIVES
The composite block diagram attempts to consolidate various isolated characteristics of the gastrointestinal system into a unified operating system. The project's purpose is twofold: to describe the overall operation of the gastrointestinal system and to serve as an educational tool for surgical residents in their training program. This program includes animal studies in gastrointestinal physiology and function and the application of modeling techniques to physiological systems. The modeling effort requires an application of analytic procedures to experimental and clinical observations, and thereby expands and reinforces their knowledge of both areas. Moreover, the development of models forces an integration of each student's experimental efforts with the overall function and interaction of the system. As a further advantage of this approach, when quantitative descriptions of each block are developed it will be possible to simulate the model on a computer so that specific quantitative and parametric studies which are not easily performed in vivo or by direct analytic methods can be pursued. The configuration described below is a preliminary attempt to represent the functioning parts of the gastrointestinal system and their interdependence. Some of the specifics of the model will be questioned, and suggestions for adding or deleting blocks are anticipated and welcome. The successful development of a physiologically valid and clinically useful model can be achieved only with feedback from experts in all areas related to the investigation. THE SYSTEM: PHYSIOLOGY
AND MODELING
The gastrointestinal system transfers ingested foodstuffs from the external to the internal environment, where they can be distributed throughout the body by the circulatory and lymphatic systems. Food, consisting primarily of proteins, carbohydrates, and fats, taken into the mouth must be broken down into small molecules which can cross the cell membranes Bull. N.Y. Acad. Med.
253
GASTROINTESTINAL SYSTEM
r
f,(SoIuv,
;;,Rr)
HL
H(free)IHC
VOL H (bound)
CH
-
AC}
-
VOL
VOI, VAGUS FAT
X
HT-DUDEU
-
FOD PARIETAL-
-L-
FET
ANTRUM
H+TO DUODENUM BL A" i|
STOMACH
_ DUODENUM
~~~~I L
DUODENUM
B
I JEJUM-|
Fig. 1. The gastrointestinal system. Reproduced by permission from A. G. Guyton: Textbook of Medical Physiology. Philadelphia, Saunders, 1966, p. 875.
Vol. 54, No. 3, March 1978
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MOUTHH
GLAND
SALIVARY GLANDS
ESOPH AGUS *STOMACH LIVER GALLBLADDER PANCREA m y DUODENUM ASC EN 91 FIG ~--o ..........41tlJEJUNJUM ILEUM COLON -SOACH
-ANUS Fig. 2. Block diagram model for the gastrointestinal system. See text for explanation of abbreviations. Points "B", " C", " D", and " E" indicate the connection points between the upper and lower portions of the overall block diagram in this figure.
of the intestinal tract (digestion) to enter the circulatory and lymphatic systems (absorption). Digestion and absorption are made possible by specific secretions and muscular contractions within the gastrointestinal system, and are regulated by both neural and hormonal activity. '2'3 The gastrointestinal system is detailed in Figure 1. Of particular interest is the portion of the system involved in basic digestion and absorption, consisting of the stomach, small intestine (duodenum, jejunum, and ileum), and those portions of the pancreas and liver which contribute to these functions. The model we have developed is shown in Figure 2. It describes interactions between these organs and does not include details of the predigestive (mouth through esophagus) or postdigestive (large intestine) portions of the gastrointestinal system. Gastrointestinal motility also is not discussed specifically; it is assumed that the contents of the stomach and intestine move forward at a rate sufficient for proper digestion and absorption to occur. The block diagram of this system, shown in Figure 2, details the effect of ingested foodstuffs on the acidity of the contents of the
Bull. N.Y. Acad. Med.
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GASTROINTESTINAL
SYSTEM
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255
gastrointestinal tract. The volume and hydrogen ion content of the ingested and digested material, it is assumed, are primary stimuli to the system. The specific blocks of this diagram represent potential operational functions between system variables. At present exact quantitative descriptions of each block are not available, so that an analytical study of the system cannot be undertaken. Blocks have been included where it is thought that significant interactions occur; many of these blocks may be omitted from a final quantitative model if the functions ascribed to these blocks turn out to be of negligible importance to the overall function of the system. Beginning at the left of the model, protein (PROT), carbohydrates (CHO), and fat inputs to the system are considered. In each case the constituent will have a particular volume (VOL) and contain an amount of available hydrogen ions (H+).* Only the protein pathway has been detailed, but the path of carbohydrate or fat would follow a similar pattern with different specific quantitative descriptions for each block. The saliva's function in freeing hydrogen ions from proteins is indicated by the fl (saliva) function. A similar function exists for carbohydrate and fat. The difference between the available and saliva-freed hydrogen ions is indicated as "H+ bound" on the diagram. Free H+, bound H+, and volume from each food constituent enter the stomach. Saliva volume adds to food volume entering the stomach. The stomach has been divided into parietal and antral portions to indicate the functional difference between the different glands of the stomach wall. Gastric glands located on the walls of the body and fundus of the stomach contain mucus, chief, and parietal cells. These cells secrete mucus, the digestive enzyme pepsin, and hydrochloric acid, respectively. Digestion requires the combined action of pepsin and hydrochloric acid. The antral portion of the stomach contains pyloric glands which contain the mucous cells (but almost no cells producing pepsin or acid). These cells provide the mucus lining which protects the stomach wall from self-digestion by gastric enzymes. In addition, the hormone gastrin (GAST) originates from the antral portion of the stomach mucosa. Gastrin, as will be described, has a feedback effect on gastric secretions. The hydrochloric acid (and its volume) secreted into the stomach by the parietal cells add to the stomach contents from the ingested foodstuff. The digestive action of the gastric juices on separating additional H+ from the *That hydrogen content of the inputs which may be contributory to the acidity of the stomach and intestinal contents.
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bound hydrogen within the foodstuff is indicated by the functions f2 (HCl). Again, a similar effect would be expected from the carbohydrate and fat pathways. At this point a concentration of hydrogen ion exists because of the sum of ingested and secreted effects, as does a volume consisting of ingested food volume, saliva, and gastric secretions. As indicated by the blocks labeled "stomach wall" in the upper left portion of Figure 2, parietal cells secrete acid in response to hormonal and neural stimuli. The sight and smell of food causes the vagus nerve to excite the acid-secreting gastric cells. Circulating levels of secretin (SEC), glucagon (GLU C), and enterogastrone-like hormones-gastric inhibitory polypeptide (GIP) and vasoactive inhibitory polypeptide (VIP)-inhibit the release of gastric acid, while gastrin provides a stimulus for the secretion of acid. Inhibitory hormones active in this feedback path are secreted downstream from the stomach, primarily from the upper intestinal mucosa and pancreas. Gastrin, in contrast, is secreted by the mucosa of the antral portion of the stomach and the intestinal mucosa.4 There appears to be a desired operating level or set point for stomach acidity which is internally generated, and the difference between desired and actual acid levels within the antral portion of the stomach provides one of the activating signals for the release of gastrin from the stomach mucosa into the circulation. A positive actuating signal indicates a lower acidity than desired and stimulates the release of gastrin, while a negative actuating signal indicates a high acid level and inhibits this release. Thus, high levels of stomach acidity reduce gastrin secretion, which, in turn, reduce gastric acid secretion and eventually lower stomach acidity to a desired level. In addition to this direct effect of acid level on the secretion of gastrin, there are hormonal, neural, and purely mechanical stimuli to such function. Food mass and volume, which causes distention of the stomach walls, stimulate the secretion of gastrin, as does direct vagal stimulation of the parietal cells. Circulating levels of secretin, glucagon, and possibly gastric and vasoactive inhibitory polypeptides each inhibit gastrin output. The rate of gastrin secretion caused by hormonal excitation (generally inhibition) is added to the rate of gastrin secretion from direct acid effects and the combined neural and mechanical effects to produce a total rate of gastrin release into the circulation by the stomach. This then is added to the rate of intestinal secretion of gastrin. This total is divided by a volume flow rate (the cardiac output) to give a circulating concentration of gastrin. In the gastrin loop additional interactions occur; these are indicated in Bull. N.Y. Acad. Med.
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Figure 2 by the blocks just below the summing junctions (encircled x) along the gastrin-concentration pathway to the stomach wall. Secretin, glucagon, and the enterogastrones, in addition to their direct inhibitory effect on gastrin secretion, attenuate the stimulatory effect of gastrin concentration on the secretion of gastric acid. Thus, in Figure 2 the point called "gastrin" entering the stomach-wall block is really the effective gastrin concentration. Note that the gastrin pathway does not proceed into the duodenum, but enters the circulatory feedback pathway with the other hormones released by the stomach and intestinal mucosa into the circulation. Pathway "A" is the flow direction for chyme as it passes the pylorus into the upper intestine and carries with it the instantaneous acid level of the stomach contents. The duodenum has been divided into two sections at the papilla of Vater, where the common bile duct and the pancreatic duct deliver bile and pancreatic juices to the duodenum. Upstream from this point the acidity of the chyme, which is the same as in the stomach, and its mass and volume (together indicated as food effect, FD on the diagram) regulate hormal secretions of the upper duodenum. These include intestinal gastrin, secretin, glucagon, and the gastric and vasoactive inhibitory polypeptides. The secretory rates of secretin and glucagon are regulated mostly by the acidity of duodenal chyme and much less by the mechanical properties of the chyme. Gastric and vasoactive inhibitory polypeptides are stimulated by the alkalinity, volume, and composition (especially fat) of intestinal chyme. These hormones inhibit the secretion of gastric acid by the stomach wall. They also inhibit gastric and intestinal motility so that a particularly fatty load remains in the stomach longer, allowing digestion to occur;5 this effect is not exhibited in our model. The acidity of chyme plays an almost negligible role in the secretion of intestinal gastrin, but the mass, volume, and composition of chyme are important. At the papilla of Vater the duodenal contents are augmented by bile and pancreatic juices, so that the chyme beyond this point has an alkaline level of hydrogen ion. Further secretions of intestinal hormone into the circulation, primarily from the lower duodenum and jejunum, are regulated by the mass and volume of chyme. However, the possibility of further hydrogen ion regulation of these hormones is accounted for by the blocks of the flow diagram, which represent possible relations between the input and output of each block. (The magnitude of each functional relation can be controlled by the quantitative description of each block, but the quantification Vol. 54, No. 3, March 1978
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of each component of the system will not be developed in this discussion.) Cholecystokinin (CCK) originates in the duodenal mucosa. Its appearance in the circulation is somewhat stimulated by the acidity and volume of the chyme, but the primary stimulant is the fat content of the chyme. The cholecystokinin controls release of bile from the gallbladder (GALL BLAD), where the continuous hepatic output of bile is collected and concentrated. Cholecystokinin stimulates the muscle of the gallbladder wall to contract, forcing the contents through the bile duct and into the duodenum where bile salts aid in the digestion and absorption of fat. Thus, in Figure 2 the input of cholecystokinin ("M") to the gallbladder results in an output of some volume of bile with some level of free hydrogen ion, and these variables enter the system at the appropriate summing junction. Pancreatic juices enter the system at the same junction. Again, the variables of interest for this model are volume and level of hydrogen ion. The pancreatic juices are the output variables of the pancreatic (PANC) block, which is excited by three inputs: secretin (from the upper and lower duodenum and the jejunum), intestinal gastrin (" N"), and cholecystokinin. These originate in the intestinal mucosa and enter the circulation under the regulation of the intestinal contents. Secretin stimulates pancreatic secretions which contain large quantities of sodium bicarbonate but almost no digestive enzymes. The bicarbonate reacts with and neutralizes the acid emptied into the duodenum along with the content from the stomach. In addition, the duodenal concentration of hydrogen ion is brought to a level at which the pancreatic digestive enzymes can function. The release of these enzymes is stimulated by cholecystokinin in the pancreatic circulation. This discussion, although omitting many of the quantitative details and chemical reactions, traces the ingestion of food by means of the block diagram describing gastrointestinal function. Additional hormonal secretions from the mucosa of the ileum can be included by using a scheme similar to that shown for the jejunum. However, we have assumed that these add little to the major secretions of the upper intestinal mucosa. Because digestion and absorption are completed within the small intestine, additional considerations of large intestinal function have been omitted from the diagram. DISCUSSION AND CONCLUSION
This model was developed to bring together the many functions of the Bull. N.Y. Acad. Med.
GASTROINTESTINAL SYSTEM
259
gastrointestinal system. In particular, it demonstrates the effect of direct neural and mechanical stimuli on the function of the system and the feedback function of hormonal stimuli. The concept of our model agrees with the accepted functions of the gastrointestinal system, and the individual operations and functional blocks of the model are comparable to descriptions in the literature. For example, Kline describes stimuli to gastric acid secretion and divides these stimuli into three phases: cephalic, gastric, and intestinal;6 this is equivalent to the blocks within the stomach section of Figure 2. Kline also presents a block diagram of each phase. The cephalic stimuli in Figure 2 are represented by direct vagal input to the stomach-wall block within the parietal-cell region and by the vagus component of inputs to the gastrin-secreting antral region of the stomach. Kline's diagram and Figure 2 both indicate that a combination of gastrin and direct neural stimuli to the parietal cells excites the release of hydrochloric acid into the stomach. A similar correspondence exists between Kline's representation and Figure 2 for the other two phases of gastric secretion. Quantitative descriptions of each block of the model are needed if detailed quantitative and parameter studies are to be performed. Such descriptions must relate stimulus and response for each block of the system. For example, the gallbladder block of Figure 2 would be described by experimental results showing the effect of various rates of cholecystokinin secretion (input) on volume and concentration of hydrogen ion (outputs) of bile entering the duodenum. Such data, when available, generally describe steady-state relations and often are presented as characteristic curves plotting constant cholecystokinin rates against the total collected output of bile from the gallbladder. However, if data could be obtained which show the dynamic changes in bile flow that occur from an initial flow of zero with zero collected volume to the final flow of zero with a total collected volume, the differential equations describing gallbladder response to the stimulus of cholecystokinin could be determined. These equations would represent gallbladder function (between cholecystokinin and bile flow) at every instant of time. The coefficients of the terms within these equations could be related to specific characteristics of the gallbladder, such as filling volume, wall compliance, and sphincter and duct resistance. After such relations are obtained for every block of the model, a computer simulation could be generated and used for educational, clinical, Vol. 54, No. 3, March 1978
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and research activities. Again, using the gallbladder as an example, a student could be presented with a computer representation of a patient with gallstones; this might be represented by an increased duct resistance on the model. Activating the model, the student could observe the effect of this abnormality on both the overall behavior of the system and the functions of each component of the model. It would be a simple exercise to modify the quantity of gallstones-increasing resistance as the situation deteriorates or decreasing resistance as it improves-and observe the differing effects in each case. This would provide a clearer illustration of system behavior than a qualitative textual description, and would be easier to implement and less costly than actual laboratory experiments. Thus, the block diagram representation is a first step in the overall development of such a useful simulation of gastrointestinal dynamics.
1. 2.
3. 4.
REFERENCES Guyton, A. C.: Textbook of Medical Saunders, 1974, chap. 20. Physiology, 3d ed. Philadelphia, Saun- 5. Rudick, J., Chapman, N. D., and Nyhus, L. M.: Gastroduodenal Physiology. In: ders, 1966, chap. 60, 61. Surgery of the Stomach and Duodenum, Maklouf, G. M.: The neuroendocrine Harkins, H. N. and Nyhus, L. M., design of the gut. Gastroenterology 67: editors. Boston, Little, Brown, 1969, 159-84, 1974. chap. 3. Rudick, J. and Pertsmilides, D.: Personal 6. Wiener, D.: The Gastrointestinal System. communication. In: Biological Foundations of Biomedical Rudick, J. and Janowitz, H. D.: Gastric Engineering, Kline, J., editor. Boston, Gastroenterology, In: Physiology. Little, Brown, 1976, chap. 47. Bockus, H., editor. Philadelphia,
Bull. N.Y. Acad. Med.
VOL. 54, No. 3
MARCH 1978
MODELING THE GASTROINTESTINAL SYSTEM* STANLEY M. FINKELSTEIN, Ph.D., DAVID A. DREILING, M.D., AND WILLIAM B. BLESSER, Sc. D. Department of Surgery The Mount Sinai School of Medicine of the City University of New York New York, New York Division of Bioengineering, Polytechnic Institute of New York Brooklyn, New York
W E have developed a basic block diagram model to describe the gastrointestinal system and to study the interaction between the various organs of the system during digestion. The primary blocks of the system represent the stomach, duodenum, pancreas, and gallbladder. Excitation signals for the system are the neural (vagus) responses to the intake of food and the volume effects of the constituents of food, particularly fat, carbohydrate, and protein. The initial study proposes that both the concentration of hydrogen ions (or pH) and the volume of the ingested foodstuff stimulate the primary system blocks. The model describes the acid and gastrin responses of the stomach wall, the duodenal hormonal response to the concentration of secretin, and the gallbladder response to cholecystokinin in a total closed-loop configuration. *Presented before the Section on Biomedical Engineering of the New York Academy of Medicine September 14, 1976.
S. M. FINKELSTEIN AND OTHERS 2522S2.FNESENADOHR 25
Once the model has been validated and quantitative values have been assigned to the various blocks, the model can be simulated on a digital computer and then can be used to study the interactive effect of each subsystem on total system function and the sensitivity of the system's response to variations in parameters. OBJECTIVES
The composite block diagram attempts to consolidate various isolated characteristics of the gastrointestinal system into a unified operating system. The project's purpose is twofold: to describe the overall operation of the gastrointestinal system and to serve as an educational tool for surgical residents in their training program. This program includes animal studies in gastrointestinal physiology and function and the application of modeling techniques to physiological systems. The modeling effort requires an application of analytic procedures to experimental and clinical observations, and thereby expands and reinforces their knowledge of both areas. Moreover, the development of models forces an integration of each student's experimental efforts with the overall function and interaction of the system. As a further advantage of this approach, when quantitative descriptions of each block are developed it will be possible to simulate the model on a computer so that specific quantitative and parametric studies which are not easily performed in vivo or by direct analytic methods can be pursued. The configuration described below is a preliminary attempt to represent the functioning parts of the gastrointestinal system and their interdependence. Some of the specifics of the model will be questioned, and suggestions for adding or deleting blocks are anticipated and welcome. The successful development of a physiologically valid and clinically useful model can be achieved only with feedback from experts in all areas related to the investigation. THE SYSTEM: PHYSIOLOGY
AND MODELING
The gastrointestinal system transfers ingested foodstuffs from the external to the internal environment, where they can be distributed throughout the body by the circulatory and lymphatic systems. Food, consisting primarily of proteins, carbohydrates, and fats, taken into the mouth must be broken down into small molecules which can cross the cell membranes Bull. N.Y. Acad. Med.
253
GASTROINTESTINAL SYSTEM
r
f,(SoIuv,
;;,Rr)
HL
H(free)IHC
VOL H (bound)
CH
-
AC}
-
VOL
VOI, VAGUS FAT
X
HT-DUDEU
-
FOD PARIETAL-
-L-
FET
ANTRUM
H+TO DUODENUM BL A" i|
STOMACH
_ DUODENUM
~~~~I L
DUODENUM
B
I JEJUM-|
Fig. 1. The gastrointestinal system. Reproduced by permission from A. G. Guyton: Textbook of Medical Physiology. Philadelphia, Saunders, 1966, p. 875.
Vol. 54, No. 3, March 1978
254
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MOUTHH
GLAND
SALIVARY GLANDS
ESOPH AGUS *STOMACH LIVER GALLBLADDER PANCREA m y DUODENUM ASC EN 91 FIG ~--o ..........41tlJEJUNJUM ILEUM COLON -SOACH
-ANUS Fig. 2. Block diagram model for the gastrointestinal system. See text for explanation of abbreviations. Points "B", " C", " D", and " E" indicate the connection points between the upper and lower portions of the overall block diagram in this figure.
of the intestinal tract (digestion) to enter the circulatory and lymphatic systems (absorption). Digestion and absorption are made possible by specific secretions and muscular contractions within the gastrointestinal system, and are regulated by both neural and hormonal activity. '2'3 The gastrointestinal system is detailed in Figure 1. Of particular interest is the portion of the system involved in basic digestion and absorption, consisting of the stomach, small intestine (duodenum, jejunum, and ileum), and those portions of the pancreas and liver which contribute to these functions. The model we have developed is shown in Figure 2. It describes interactions between these organs and does not include details of the predigestive (mouth through esophagus) or postdigestive (large intestine) portions of the gastrointestinal system. Gastrointestinal motility also is not discussed specifically; it is assumed that the contents of the stomach and intestine move forward at a rate sufficient for proper digestion and absorption to occur. The block diagram of this system, shown in Figure 2, details the effect of ingested foodstuffs on the acidity of the contents of the
Bull. N.Y. Acad. Med.
GASTROINTESTINAL SYSTEM
GASTROINTESTINAL
SYSTEM
255
255
gastrointestinal tract. The volume and hydrogen ion content of the ingested and digested material, it is assumed, are primary stimuli to the system. The specific blocks of this diagram represent potential operational functions between system variables. At present exact quantitative descriptions of each block are not available, so that an analytical study of the system cannot be undertaken. Blocks have been included where it is thought that significant interactions occur; many of these blocks may be omitted from a final quantitative model if the functions ascribed to these blocks turn out to be of negligible importance to the overall function of the system. Beginning at the left of the model, protein (PROT), carbohydrates (CHO), and fat inputs to the system are considered. In each case the constituent will have a particular volume (VOL) and contain an amount of available hydrogen ions (H+).* Only the protein pathway has been detailed, but the path of carbohydrate or fat would follow a similar pattern with different specific quantitative descriptions for each block. The saliva's function in freeing hydrogen ions from proteins is indicated by the fl (saliva) function. A similar function exists for carbohydrate and fat. The difference between the available and saliva-freed hydrogen ions is indicated as "H+ bound" on the diagram. Free H+, bound H+, and volume from each food constituent enter the stomach. Saliva volume adds to food volume entering the stomach. The stomach has been divided into parietal and antral portions to indicate the functional difference between the different glands of the stomach wall. Gastric glands located on the walls of the body and fundus of the stomach contain mucus, chief, and parietal cells. These cells secrete mucus, the digestive enzyme pepsin, and hydrochloric acid, respectively. Digestion requires the combined action of pepsin and hydrochloric acid. The antral portion of the stomach contains pyloric glands which contain the mucous cells (but almost no cells producing pepsin or acid). These cells provide the mucus lining which protects the stomach wall from self-digestion by gastric enzymes. In addition, the hormone gastrin (GAST) originates from the antral portion of the stomach mucosa. Gastrin, as will be described, has a feedback effect on gastric secretions. The hydrochloric acid (and its volume) secreted into the stomach by the parietal cells add to the stomach contents from the ingested foodstuff. The digestive action of the gastric juices on separating additional H+ from the *That hydrogen content of the inputs which may be contributory to the acidity of the stomach and intestinal contents.
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bound hydrogen within the foodstuff is indicated by the functions f2 (HCl). Again, a similar effect would be expected from the carbohydrate and fat pathways. At this point a concentration of hydrogen ion exists because of the sum of ingested and secreted effects, as does a volume consisting of ingested food volume, saliva, and gastric secretions. As indicated by the blocks labeled "stomach wall" in the upper left portion of Figure 2, parietal cells secrete acid in response to hormonal and neural stimuli. The sight and smell of food causes the vagus nerve to excite the acid-secreting gastric cells. Circulating levels of secretin (SEC), glucagon (GLU C), and enterogastrone-like hormones-gastric inhibitory polypeptide (GIP) and vasoactive inhibitory polypeptide (VIP)-inhibit the release of gastric acid, while gastrin provides a stimulus for the secretion of acid. Inhibitory hormones active in this feedback path are secreted downstream from the stomach, primarily from the upper intestinal mucosa and pancreas. Gastrin, in contrast, is secreted by the mucosa of the antral portion of the stomach and the intestinal mucosa.4 There appears to be a desired operating level or set point for stomach acidity which is internally generated, and the difference between desired and actual acid levels within the antral portion of the stomach provides one of the activating signals for the release of gastrin from the stomach mucosa into the circulation. A positive actuating signal indicates a lower acidity than desired and stimulates the release of gastrin, while a negative actuating signal indicates a high acid level and inhibits this release. Thus, high levels of stomach acidity reduce gastrin secretion, which, in turn, reduce gastric acid secretion and eventually lower stomach acidity to a desired level. In addition to this direct effect of acid level on the secretion of gastrin, there are hormonal, neural, and purely mechanical stimuli to such function. Food mass and volume, which causes distention of the stomach walls, stimulate the secretion of gastrin, as does direct vagal stimulation of the parietal cells. Circulating levels of secretin, glucagon, and possibly gastric and vasoactive inhibitory polypeptides each inhibit gastrin output. The rate of gastrin secretion caused by hormonal excitation (generally inhibition) is added to the rate of gastrin secretion from direct acid effects and the combined neural and mechanical effects to produce a total rate of gastrin release into the circulation by the stomach. This then is added to the rate of intestinal secretion of gastrin. This total is divided by a volume flow rate (the cardiac output) to give a circulating concentration of gastrin. In the gastrin loop additional interactions occur; these are indicated in Bull. N.Y. Acad. Med.
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Figure 2 by the blocks just below the summing junctions (encircled x) along the gastrin-concentration pathway to the stomach wall. Secretin, glucagon, and the enterogastrones, in addition to their direct inhibitory effect on gastrin secretion, attenuate the stimulatory effect of gastrin concentration on the secretion of gastric acid. Thus, in Figure 2 the point called "gastrin" entering the stomach-wall block is really the effective gastrin concentration. Note that the gastrin pathway does not proceed into the duodenum, but enters the circulatory feedback pathway with the other hormones released by the stomach and intestinal mucosa into the circulation. Pathway "A" is the flow direction for chyme as it passes the pylorus into the upper intestine and carries with it the instantaneous acid level of the stomach contents. The duodenum has been divided into two sections at the papilla of Vater, where the common bile duct and the pancreatic duct deliver bile and pancreatic juices to the duodenum. Upstream from this point the acidity of the chyme, which is the same as in the stomach, and its mass and volume (together indicated as food effect, FD on the diagram) regulate hormal secretions of the upper duodenum. These include intestinal gastrin, secretin, glucagon, and the gastric and vasoactive inhibitory polypeptides. The secretory rates of secretin and glucagon are regulated mostly by the acidity of duodenal chyme and much less by the mechanical properties of the chyme. Gastric and vasoactive inhibitory polypeptides are stimulated by the alkalinity, volume, and composition (especially fat) of intestinal chyme. These hormones inhibit the secretion of gastric acid by the stomach wall. They also inhibit gastric and intestinal motility so that a particularly fatty load remains in the stomach longer, allowing digestion to occur;5 this effect is not exhibited in our model. The acidity of chyme plays an almost negligible role in the secretion of intestinal gastrin, but the mass, volume, and composition of chyme are important. At the papilla of Vater the duodenal contents are augmented by bile and pancreatic juices, so that the chyme beyond this point has an alkaline level of hydrogen ion. Further secretions of intestinal hormone into the circulation, primarily from the lower duodenum and jejunum, are regulated by the mass and volume of chyme. However, the possibility of further hydrogen ion regulation of these hormones is accounted for by the blocks of the flow diagram, which represent possible relations between the input and output of each block. (The magnitude of each functional relation can be controlled by the quantitative description of each block, but the quantification Vol. 54, No. 3, March 1978
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of each component of the system will not be developed in this discussion.) Cholecystokinin (CCK) originates in the duodenal mucosa. Its appearance in the circulation is somewhat stimulated by the acidity and volume of the chyme, but the primary stimulant is the fat content of the chyme. The cholecystokinin controls release of bile from the gallbladder (GALL BLAD), where the continuous hepatic output of bile is collected and concentrated. Cholecystokinin stimulates the muscle of the gallbladder wall to contract, forcing the contents through the bile duct and into the duodenum where bile salts aid in the digestion and absorption of fat. Thus, in Figure 2 the input of cholecystokinin ("M") to the gallbladder results in an output of some volume of bile with some level of free hydrogen ion, and these variables enter the system at the appropriate summing junction. Pancreatic juices enter the system at the same junction. Again, the variables of interest for this model are volume and level of hydrogen ion. The pancreatic juices are the output variables of the pancreatic (PANC) block, which is excited by three inputs: secretin (from the upper and lower duodenum and the jejunum), intestinal gastrin (" N"), and cholecystokinin. These originate in the intestinal mucosa and enter the circulation under the regulation of the intestinal contents. Secretin stimulates pancreatic secretions which contain large quantities of sodium bicarbonate but almost no digestive enzymes. The bicarbonate reacts with and neutralizes the acid emptied into the duodenum along with the content from the stomach. In addition, the duodenal concentration of hydrogen ion is brought to a level at which the pancreatic digestive enzymes can function. The release of these enzymes is stimulated by cholecystokinin in the pancreatic circulation. This discussion, although omitting many of the quantitative details and chemical reactions, traces the ingestion of food by means of the block diagram describing gastrointestinal function. Additional hormonal secretions from the mucosa of the ileum can be included by using a scheme similar to that shown for the jejunum. However, we have assumed that these add little to the major secretions of the upper intestinal mucosa. Because digestion and absorption are completed within the small intestine, additional considerations of large intestinal function have been omitted from the diagram. DISCUSSION AND CONCLUSION
This model was developed to bring together the many functions of the Bull. N.Y. Acad. Med.
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gastrointestinal system. In particular, it demonstrates the effect of direct neural and mechanical stimuli on the function of the system and the feedback function of hormonal stimuli. The concept of our model agrees with the accepted functions of the gastrointestinal system, and the individual operations and functional blocks of the model are comparable to descriptions in the literature. For example, Kline describes stimuli to gastric acid secretion and divides these stimuli into three phases: cephalic, gastric, and intestinal;6 this is equivalent to the blocks within the stomach section of Figure 2. Kline also presents a block diagram of each phase. The cephalic stimuli in Figure 2 are represented by direct vagal input to the stomach-wall block within the parietal-cell region and by the vagus component of inputs to the gastrin-secreting antral region of the stomach. Kline's diagram and Figure 2 both indicate that a combination of gastrin and direct neural stimuli to the parietal cells excites the release of hydrochloric acid into the stomach. A similar correspondence exists between Kline's representation and Figure 2 for the other two phases of gastric secretion. Quantitative descriptions of each block of the model are needed if detailed quantitative and parameter studies are to be performed. Such descriptions must relate stimulus and response for each block of the system. For example, the gallbladder block of Figure 2 would be described by experimental results showing the effect of various rates of cholecystokinin secretion (input) on volume and concentration of hydrogen ion (outputs) of bile entering the duodenum. Such data, when available, generally describe steady-state relations and often are presented as characteristic curves plotting constant cholecystokinin rates against the total collected output of bile from the gallbladder. However, if data could be obtained which show the dynamic changes in bile flow that occur from an initial flow of zero with zero collected volume to the final flow of zero with a total collected volume, the differential equations describing gallbladder response to the stimulus of cholecystokinin could be determined. These equations would represent gallbladder function (between cholecystokinin and bile flow) at every instant of time. The coefficients of the terms within these equations could be related to specific characteristics of the gallbladder, such as filling volume, wall compliance, and sphincter and duct resistance. After such relations are obtained for every block of the model, a computer simulation could be generated and used for educational, clinical, Vol. 54, No. 3, March 1978
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and research activities. Again, using the gallbladder as an example, a student could be presented with a computer representation of a patient with gallstones; this might be represented by an increased duct resistance on the model. Activating the model, the student could observe the effect of this abnormality on both the overall behavior of the system and the functions of each component of the model. It would be a simple exercise to modify the quantity of gallstones-increasing resistance as the situation deteriorates or decreasing resistance as it improves-and observe the differing effects in each case. This would provide a clearer illustration of system behavior than a qualitative textual description, and would be easier to implement and less costly than actual laboratory experiments. Thus, the block diagram representation is a first step in the overall development of such a useful simulation of gastrointestinal dynamics.
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REFERENCES Guyton, A. C.: Textbook of Medical Saunders, 1974, chap. 20. Physiology, 3d ed. Philadelphia, Saun- 5. Rudick, J., Chapman, N. D., and Nyhus, L. M.: Gastroduodenal Physiology. In: ders, 1966, chap. 60, 61. Surgery of the Stomach and Duodenum, Maklouf, G. M.: The neuroendocrine Harkins, H. N. and Nyhus, L. M., design of the gut. Gastroenterology 67: editors. Boston, Little, Brown, 1969, 159-84, 1974. chap. 3. Rudick, J. and Pertsmilides, D.: Personal 6. Wiener, D.: The Gastrointestinal System. communication. In: Biological Foundations of Biomedical Rudick, J. and Janowitz, H. D.: Gastric Engineering, Kline, J., editor. Boston, Gastroenterology, In: Physiology. Little, Brown, 1976, chap. 47. Bockus, H., editor. Philadelphia,
Bull. N.Y. Acad. Med.
