A Functional Description of the Canine Choledochoduodenal Flutter Valve MARTIN F. TANSY, PhD, DAVID L. INNES, PhD, JOHN S. MARTIN, PhD, and FRANCIS M. K E N D A L L , PhD
Forward- and reverse-opening pressures of the choledochoduodenal junction were measured in anesthetized, vagotomized dogs. Mean reverse-opening pressures were found to be significantly greater in most cases including those following the intraductal administration o f vasoactive agents which are known to significantly influence mean forward-opening pressures. The polypeptides C C K - P Z and CCK--C8 were ineffective in reducing mean forward-opening pressures regardless of the route of administration. Previously published observations have indicated that mean forward-opening pressures are also unaffected by nervous activity. It is concluded that the canine choledochoduodenal junction possesses the physical and functional properties o f a passive flutter valve during duodenal relaxation.
During the course of the past two years a series of reports from our laboratories have appeared in this journal which have described the course of our investigations into the function of the choledochoduodenal junction (1-3). We have chosen to base our conclusions upon the results of physical measurements which employed the opening-pressure technique and we have sought to support the feasibility of these conclusions with descriptions of the anatomical structures which appear to be responsible for the effects that we observed. In summary, we have concluded that the occlusive competencies of the choledochoduodenal junctions of cats and dogs are due to the physical arrangements of the mucosa of the terminal common bile ducts of these animals. Ductal-opening pressures may be markedly altered by duodenal contractions, by the localized intraductal administration of vasoactive agents, as well as by changes in central arterial, central venous, and portal venous From the Department of Physiology and Biophysics, Temple University Health Sciences Center, Philadelphia, Pennsylvania. Address for reprint requests: Dr. Martin F. Tansy, Department of Physiology and Biophysics, Temple University, 3223 N. Broad Street, Philadelphia, Pennsylvania 19140. Digestive Diseases, Vol. 21, No. 3 (March 1976)
blood pressures. It appears that ductal-opening pressures in these species are not remarkably altered by peripheral-nerve stimulation sufficiently discrete to prevent large changes in systemic vascular pressures. The purposes of this report are to present further observations with respect to the hydraulic behavior of the terminal common bile duct as well as to describe the effects of cholecystokinin preparations injected into the caudal pancreaticoduodenal artery upon junctional-opening pressures. MATEI~IALS AND METHODS Acute experiments were performed on 18 adult mongrel dogs of both sexes. All dogs were fasted for 24 hours prior to experimentation. Anesthesia was induced and maintained by the intravenous administration of a mixture of a-chloralose (5 g/100 ml in polyethylene glycol200) and urethan (50 g/100ml in 0.9% saline) mixed in equal volumes. Each animal was individually titrated to a surgical plane of anesthesia. Surgery was preceded by cannulation of ipsilateral femoral artery and vein and the establishment of a tracheostomy for positive pressure ventilation. Both vagosympathetic trunks were exposed and severed at the cervical level. A midline thoracotomy-laparotomy was performed
233
T A N S Y ET A L
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Digestive Diseases,
Vol. 21, No. 3 (March 1976)
CANINE CHOLEDOCHODUODENAL FLUTTER VALVE
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Digestive Diseases, Vol. 21, No, 3 (March 1976)
235
TANSY ET AL
TABLE I. COMPARISON OF MEAN FORWARD AND REVERSE DUCTAL-OPENING PRESSURES Dog no.
Forward O P t
Reverse O P t
73542* 75044* 45522* 16056* 14788* 2120" 44599* 74354* Range
31.3 + 5.86(12) 31.8 -+ 6.46(12) 32.5 +- 4.2 (16) 22.8 +- 2.38 (12) 25,8 +- 4.43 (12) 26,3 -+ 4.79(12) 28,1 -+ 2.61 (9) 29.0 +- 4.78(12) 22.8--32.5
49.2 +- 8.33 (12) 47.4 -+ 4.35 (12) 38.1 -+ 4,04(16) 34.6 -+ 5~25 (12) 32.6 +- 4.70 (12) 39.9 -+ 6.58(12) 57.8 + 9.6 (9) 41.4 -+ 4.94(12) 32.6-57.8
*Indicates significant difference in m e a n opening pressures. t O P - - O p e n i n g pressure m e a s u r e m e n t s in centimeters of saline; -+ indicates one standard deviation; p a r e n t h e s e s denote number of observations.
from the pectoral girdle to the pelvic girdle. Cardiovascular hydraulic-pressure measurements were made by means of cannulae which were inserted in a femoral artery, femoral vein, splenic vein, and a mesenteric vein in the jejunal arcade. Jejunal motor effects were monitored by direct visualization and by means of an intraluminal balloon which was introduced through a duodenotomy 2 cm distal to the duodenal papilla, Gallbladder motor activity was monitored by direct visualization and by a balloon which was surgically introduced through the fundus. A convenient hepatic duct was cannulated, according to the standard pattern of bile-duct distribution by Ogawa and his associates (4), in order to monitor relative hepatic secretion by means of a photoelectric drop counter. A lead II electrocardiogram and a continuous measurement of body temperature by a rectal thermistor were routinely made. Drugs were administered intravenously by means of the femoral venous pressure cannula. Intraarterial administration of drugs in the region of the duodenal papilla was performed via a cannula which was inserted into an artery which visually appeared to supply the immediate vicinity of the choledochoduodenal junction. At the end of each experiment this artery was injected with india ink to confirm the original assumption that its contents in fact perfused the region of the choledochoduodenal junction (Figures 1 and 2). Junctional-opening pressures were made with a pressure-ramp generator according to a method which has been previously described (1). The intraductal administration of various vasoactive agents and hormones was made through the cannula of the pressure-ramp generator in a manner which has also been previously described (2). Comparison of forward and reverse ductal-opening pressures were made by means of a modification of the opening-pressure technique. The forward-pressure cannula was inserted via the common duct to the intramural portion of the duct as previously described. A polyethylene cannula of identical length and diameter to the forwardpressure cannula was inserted via the duodenotomy into the orifice of the papilla for at least 2 mm. until it was pos-
236
sible to fix its end in position by means of a ligature tied around the papilla. Fluid was then forced through the forward cannula until both cannulae were full. The output end of the output cannula was then fixed permanently at the same hydrostatic level as the input to the forward cannula. The endpoint for forward-opening pressure was determined by the first detectable flow of fluid from the output cannula. Reverse-opening pressures were determined by applying the pressure ramp to the output catheter and observing the appearance of fluid flow from the forward cannula, lnasmuch as the geometries and hydrostatic heights of both cannulae were identical, differences in observed opening pressures should be primarily determined by the properties of the choledochoduodenal junction. Intraductally administered agents were histamine dihydrochloride, bethanechol chloride, epinephrine hydrochloride, CCK-PZ, and CCK-C8. Agents which were introduced into the arterial supply of the junction were CCK-PZ and CCK-C8. Changes or differences in mean opening pressures were inferred by a statistical comparison of mean values at a significance level of 5%.
RESULTS Table 1 s u m m a r i z e s the results o f a series o f determinations o f m e a n f o r w a r d - and r e v e r s e - o p e n i n g p r e s s u r e s as d e t e r m i n e d in eight separate dogs. In all cases, m e a n r e v e r s e - o p e n i n g p r e s s u r e s were significantly greater than m e a n f o r w a r d - o p e n i n g pressures. T h e s e o b s e r v e d differences persisted in all but one instance following the intraductal administration o f v a s o a c t i v e agents s h o w n in Table 2. A n o t h e r series o f e x p e r i m e n t s was designed with the objective o f determining w h e t h e r it could be inferred that either o f two f o r m s o f c o m m e r c i a l l y
TABLE 2 COMPARISON OF MEAN FORWARD AND REVERSE DUCTAL-OPENING PRESSURES AFTER INTRADUCTAL DRUG ADMINISTRATION Dog no.
73542* 2120" 75044* 14788* 44599 74354* 72013* 72686* 74082*
Forward O P t Histamine diHCl (0.65 mg/ml) 37.0 -+ 7.6 (8) 34.0 -+ 4.98 (6) 49.2 + 3.06 (6) Bethanechol C1 (5 mg/ml) 74.3 -+ 6.47 (6) 80.7 + 8.94(7) Epinephrine HCI (0.45 mg/ml) 11.8 + 1.30(5) 35.0 + 3.46 (9) 24.4 • 3.61 (19) 21.9 -+ 1.88(12)
Reverse O P t
86.8 + 14.4 (8) 41.2 +- 5.0 (6) 67.8 +- 17.7 (6) 90.8 -+ 11.3 (8) 79.1 -+ 14.9(7) 20,1 42,3 43.0 47.0
-+ 1.86(7) +- 3.81 (9) -+ 7.05 (19) • 10.4(12)
*Indicates significant difference in m e a n opening pressures. t O P - - O p e n i n g pressure m e a s u r e m e n t s in centimeters of saline; -+ indicates one standard deviation; p a r e n t h e s e s denote n u m ber of observations. Digestive Diseases, Vol. 21, No:3 (March 1976)
CANINE
CHOLEDOCHODUODENAL
FLUTTER
VALVE
12 IDU/Kg - IA, CCK-PZ Femoral Arterial Pressure
200 mm Hg-
~ ~'~ Portal Venous Pressure
20 mg Hg-
Mesenteric Venous Pressure
20 mm Hg-
0 mm Hg-
Sphincteric Opening Pressure (Cm H~O) 27
29
32
38
ii 9 Mean Femoral
"
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28
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27
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29
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'
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...... ,
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Fig 3. Polygram showing the course of events following the intraarterial administration of a 2.5 minute infusion of a total dosage of 12 IU/kg of CCK-PZ. Femoral arterial pressure exhibits a transient fall, tone and motor activity of the gallbladder are markedly augmented, portal venous pressure rises slightly (generally following the course of gallbladder activity), and small-bowel tone and segmenting motor activities are increased, There are no evident changes in forward ductal-opening pressures.
available cholecystokinin produced significant changes in mean junctional opening pressures when these agents were administered via various routes. These peptides were infused into the femoral vein (IV), a mesenteric artery (IA), over 2--4-minute periods, or a bolus was introduced into the terminal duct via the measurement cannula and held in stasis for approximately 1.5 minutes, after which the measurement cannula was flushed and post-treatment mean opening pressures determined. In addition to junctional-opening pressures, the following parameters were monitored during these experiments: femoral-arterial pressure, gallbladder-pressure activity, splenic-venous pressure (as an indication of portal pressure), hepatic-bile flow, jejuDigestive Diseases, Vol. 2I, No. 3 (March I976)
hal-pressure activity (motor activity was monitored by direct visualization), and pressure in the mesenteric artery which was used for drug administration. Figure 3 is a typical polygram which occurred following the timed injection of 12 IU/kg of CCK-PZ into a mesenteric artery. It can be seen that a slight decrease in femoral-arterial pressure occurred during the period of administration. Portal venous pressure was slightly elevated after a short latency. Blood pressure in a nearby mesenteric vein did not show any remarkable changes when compared to control recordings. Hepatic-duct-flow rate tended to fall transiently following either intravenous or intraarterial administration of either form of C C K . 237
TANSY ET AL
200 mm Hg-
6 IDU/Kg- IA, CCK-C8
Femoral Arterial Pressure
0 mm Hg-
Gall Bladder Motility
Portal Venous Pressure
20 mm Hg-
Mesenteric Venous Pressure
0 mm Hg-
20 mm Hg-
Sphincteric Opening Pressure (Cm H20) 17
17
15
0 mm Hg16
23
33
23
16
19
20
Hepatic Duct Bile Flow (Drops) Mean Femoral Arterial Pressure
200 mm Hg-
+ .
.
.
.
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0
- -+
'~+-7"-'---~-
i i 1 minute
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------
~:
--
Fig 4. Events observed following the intraarterial administration of a 4.3 minute infusion of a total dosage of 6 IU/kg of CCK-C8. Femoral arterial pressure is depressed for several minutes during which time there is a slight rise in both portal venous and mesenteric venous pressures, and an elevation in gallbladder tone. Segmentingjejunal motor activity is markedly but transiently increased. There are no evident changes in forward ductal-opening pressures.
There was also a marked increase in jejunal motor activity following intravenous or intraarterial administration of these peptides. In all cases, the observed increases in both jejunal and duodenal motor activities were observed to be of a segmenting nature. No detectable changes in any of these parameters were observed following the intraductal administration of either peptide. Figure 4 is a polygram which depicts the time course of the previously described parameters following the timed intraarterial administration of CCK-C8. Essentially the same results were obtained as with the administration of C C K - P Z , except that the C C K - C 8 appeared to produce a greater and more prolonged decrease in femoral-arterial pressure. Jejunal motor activity was recorded and
238
observed to be much more vigorous following intraarterial or intravenous administration of CCK-C8. The observed effects of C C K - P Z and C C K - C 8 , administered intravenously, are summarized in Table 3. In all cases except three we were obliged to accept our null hypothesis that either agent administered by any of the three routes was not significantly associated with a change in mean junctional forward-opening pressures. In the three instances where significant results were noted, the mean forward-opening pressures increased. It should be noted that duodenal motor activity was constantly visualized during opening-pressure determinations. The presence of duodenal contractions during any opening-pressure measurement was indicated directly on the polygram. Opening-pressure values Digestive Diseases, Vol. 21, No. 3 (March 1976)
CANINE CHOLEDOCHODUODENAL FLUTTER VALVE
TABLE 3. OBSERVEDMEAN DUCTAL-OPENING PRESSURESPRIORTO AND SUBSEQUENTTO THE ADMINISTRATION OF TWO FORMS OF CHOLECYSTOKININ BY VARIOUSROUTES D o g no.
75161 75161 75161 75161 75161 74492 74492* 74492 74492 74492 75304 75304 75304* 75304 74877* 74877 74877 74877
Pretreatrnent O P t
25.0 26.7 25.9 27.7 26.7 30.4 26.3 23.7 25.0 28.5 17.2 20.0 18.2 20.3 26.0 26.0 29.0 26.3
-+ 4.86 (12) -+ 6.26(12) -+ 4.67 (8) -+ 6.50(6) -+ 4.97 (6) -+ 2.07 (7) -+ 2.43 (7) -+ 2.60 (8) -+ 1.67 (6) • 2.43 (6) -+ 9.82(11) • 1.90 (11) -+ 2.64 (6) -+ 2.73 (6) -+ 1.60 (12) -+ 8.19 (10) -+ 2.71 (7) • 3.27 (6)
Treatment~
IA, CCK-PZ IA, CCK-PZ IV, CCK-PZ ID, CCK-PZ ID, CCK-PZ IA, CCK-PZ IA, CCK-PZ IV, CCK-PZ ID, CCK-PZ ID, CCK-PZ IA, CCK-C8 IA, CCK-C8 ID, CCK-C8 ID, CCK-C8 IA, CCK-C8 IA, CCK-C8 IV, CCK-C8 ID, CCK-C8
Dose
10 IU/kg 10 IU/kg 10 IU/kg 2IU 2 IU 6 IU/kg 12 IU/kg 12 IU/kg 2 IU 2 IU 6 IU/kg 6 IU/kg 2 IU 2 IU 7.5 IU/kg 7.5 IU/kg 7.5 IU/kg 6 IU
Post-treatment O P t
25.5 29.1 24.6 27.8 32.7 30.5 30.7 28.5 25.8 29.0 17.4 19.8 21.6 20.8 29.5 28.1 29.2 27.0
• 5.6 (12) m 5.53 (12) • 1.84 (8) + 5.42(6) -+ 7.37 (6) +- 2.82 (7) • 3.90 (7) -+ 7.34 (6) -+ 2.8 (6) -+ 4.94 (6) -+ 5.18(12) -+ 3.49 (12) -+ 2.51 (5) -4- 2.14 (6) + 3.14(10) + 2.85 (10) -+ 1.75 (8) -+ 2.45 (6)
*Indicates significant difference in mean opening pressures. tOP Opening pressure measurements in centimeters of saline; • indicates one standard deviation; parentheses denote number of observations. 1:[A represents intraarterial; IV represents intravenous; ID represents intraductal.
which were determined during periods of duodenal contraction were excluded from the computation of mean values by virtue of the experimental protocol. This procedure did not result in the elimination of more than two observed values from any single series of measurements. DISCUSSION An historical appreciation of the literature which pertains to the choledochoduodenal junction eventually has led us to conclude that the basic intent of both structural and functional studies has been to provide evidence in support of an apriori belief that this junction exerts an active effector role as a component in an overall controlled mechanism of bile flow. Both lines of investigation should ideally support each other: a physically quantifiable phenomenon should be supported by a structure which can reasonably be inferred to be responsible for producing the effects which were observed. An almost dogmatic devotion to the postulated existence of a choledochoduodenal sphincteric effector mechanism certainly has ample precedent in the literature, in which such entities have been described and accepted as operational mechanisms in both the digestive and circulatory systems. Indeed, Digestive Diseases, Vol. 21, No. 3 (March 1976)
the well-known instability of sphincters and the equally accepted fact that their opening and closing pressures can be altered by the tone of their smooth-muscle component constitutes the fundamental physical description of these biological effectot mechanisms. Unfortunately, in the case of the choledochoduodenal junction in general, and the so-called "sphincter of Oddi" in particular, the almost universal disagreement in opinion which surrounds the operational definition of this entity is entirely attributable to a fundamental and original failure to first determine whether this structure can be inferred to operate as a sphincter or as a valve. It is our opinion that this fundamental failure is attributable to at least three factors: 1. the implicit assumption that a sphincter existed (which has only seriously been questioned on anatomical grounds within the last few years); 2. the inherent difficulty in actually assessing the physical behavior of this entity when it is immersed in its anatomical surroundings; and 3. a fundamental and by no means restricted lack of appreciation of the necessity of methodically determining the nature of the parameters of an assumed system which can render it formally observable on onehand and amenable to modeling on the other. Thus, the purposes of this report are both limited and explicit: to present the results
239
TANSY ET AL
of a series of experiments which were designed to provide a physical description of the canine choledochoduodenal junction and to test the null hypothesis that the mean forward-opening pressures of this junction are unaffected by the administration of cholecystokinin by various routes. As we have previously reported (1, 2) we have been unable to conclude that mean forward-opening pressures of the canine junction are subject to nervous influence. We were able to infer that alterations of systemic arterial and venous pressures and portal venous pressures could influence mean forward-opening pressures. We then investigated the local effects of intraductally administered vasoactire agents upon mean forward-opening pressures and were able to conclude that these pressures were significantly influenced by mechanisms which were local in character and probably located either within the intramural terminal duct or in its immediate vicinity. We were thus obliged to conduct a series of microanatomical studies to account for the effects of vasoactive agents upon opening pressure which we observed (3). Reference to the literature produced an excellent perspective description of the valvular structure of the junction (in which the mucosal folds which we described are denoted as valves), contained in the classic text on the morphology of the liver by Elias and Sherrick (5). Thus, the results of our forward- and reverse-opening pressures support a description of these structures as constituting an unstable valve with pronounced one-way properties, which is characteristic of a flutter valve. We performed these latest experiments as a direct result of the valvular description. We have reason to believe that the presence of the forward valve is in fact necessary to insure gallbaldder filling (6). The reverse character of the valve is of probable significance in preventing the reflux of duodenal contents into the common bile duct. In this connection, it should be noted that our experimental protocols have restricted our consideration of experimental data to those opening pressures which were observed in the absence of observable duodenal contractions. We were obliged to do this because we had no way of insuring that such spontaneous and uncontrolled activity could be quantified and thus describable as part of the observed system. To attempt to do otherwise would have required us to make an assumption of stationarity which we could not support. We do offer the observation that solitary opening pressures that were fortuitously oh-
240
served during bouts of duodenal contractions were always greater than during duodenal quiescence. Thus it is possible that any antireflux properties which are attributable to the one-way nature of this structure are enhanced by the very contractile events which would be necessary to provide the necessary pressure head. Conversely, it is not unreasonable to suspect that duodenal spasm might elevate junctional forward-opening pressures. However, now that alternative nonmuscular mechanisms have been shown to exist which will significantly elevate ductal-opening pressures, it is no longer justifiable to consider the presence of biliary dyskinesias of unknown etiology as being automatically indicative of spasmolytic therapy unless duodenal spasm is definitely known to exist. The model builder is also faced with an unfortunate consequence of our inability to quantitate the effects of duodenal contractions upon forwardopening pressures. We believe that he can legitimately make a one-way assumption but he will still be left to his own devices with respect to the role which he assigns to duodenal contractions in a model of biliary dynamics. Furthermore, under the conditions of our measurements, visceromotor and respiratory effects upon the extramural portion of the duct due to shear forces at the extramural point of entrance were minimized by virtue of the fact that fluid coupling through this region was essentially maintained by the presence of the intraluminalmeasurement cannula. Inasmuch as respiratory movements themselves are still widely regarded to either influence or to be part of the mechanism of gallbladder-bile release, the model builder must assign a role to these other factors. For this reason, we believe that a detailed model of biliary dynamics is still a long way from practical realization. A classical description of bile release indicates that bile flow and gallbladder contraction are accompanied by an opening of the so-called "sphincter." The histochemical literature indicates that the intrinsic nerve supply to this junction and the contiguous duodenal areas is primarily perivascular. Thus, on this basis, and in view of our consistent lack of results with a large number of experiments, we feel that a direct nervous control of junctional forward-opening pressures, either by virtue of an innervated sphincteric mechanism or an effect upon the vasculature of the ductal mucosa, is highly unlikely. This leaves the matter of a postulated hormonal mechanism for a proposed reciprocal relationship Digestive Diseases, Vot. 2l, No. 3 (March 1976)
CANINE CHOLEDOCHODUODENAL
FLUTTER VALVE
between gallbladder contraction and junctional "relaxation." Thus, the final series of experiments was designed to determine whether cholecystokinin could be inferred to produce changes in mean junctional forward-opening pressures. The problems associated with this experimental design involve the facts that the commonly accepted active peptides produce changes in duodenal motor activity, relaxation in the vicinity of the junctional aperature as shown by Persson and Ekman (7), and more recently, alterations in arterial-blood pressures and portal venous blood flow (8, 9). In view of our past experience with both duodenal motor activity and vascular influences, we had reason to believe that CCK-PZ and CCK-C8 should produce some effect upon mean opening pressures even though the actual measurements themselves were made during periods of observed duodenal quiescence. Our experimental data from the CCK-peptide experiments indicated that intravascular administration produced pronounced gallbladder and jejunal motility. These observations are in agreement with the literature. Our cardiovascular observations indicated that intravascular peptide administration was followed by some degree of arterial hypotension and, in the case of a high intravascular dose of CCK, a slight rise in portal venous pressure. Therefore, on the basis of expected motor and vascular effects, we assumed that our intravascular peptide administrations should produce changes in mean forward-opening pressures. The only significant resuits which we observed consequent to peptide administration in any dose, and by any route, were in the wrong direction to be consistent with a proposed reciprocal model. Our tests were, in fact, two-tailed because we simply did not have sufficient faith in the reciprocal model to justify the rather formidable assumption that would underly a one-tailed test. It is thus our conclusion that the choledochoduodenal junction is a passive, nonlinear, essentially one-way valve. Forward opening-pressures may be influenced by respiration, duodenal motor activity, and the vascular status of the mucosal lining of the terminal intramural portion. Any stimulus that will influence these factors will influence mean opening
Digestive Diseases, Vol. 21, No. 3 (March 1976)
pressure in response to a pressure-ramp-forcing function. We believe that this physical and structural definition of this junction is clearly inconsistent with a description of the sphincter of Oddi as a sphincter. With the exclusion of the well-established role of this valve in gallbladder filling (6), we shall regard any assertion that the influences which we have cited ptay any role other than pathophysiological (10), or within the definition of noise in controlled processes, must be accompanied by a necessary and sufficient demonstration of proof. ACKNOWLEDGMENTS The authors appreciate the technical assistance of Mr. Harold Perrong. The authors wish to thank the Squibb Institute of New Jersey for their generous supply of CCKC8. This work was supported in part by a grant-in-aid from Temple University. REFERENCES 1. Tansy MF, Innes DL, Martin JS, Kendall FM: An evaluation of neural influences on the sphincter of Oddi in the dog. Am J Dig Dis 19:423-437, 1974 2. Tansy MF, Innes DL, Martin JS, Kendall FM: Vascular influences on the dynamic stability of the choledochoduodenal junction. Am J Dig Dis 19:1124-1137, 1974 3. Tansy MF, Salkin L, Innes DL, Martin JS, Kendall FM, Litwack D: The mucosal lining of the intramural common bile duct as a determinant of ductal opening pressure. Am J Dig Dis, 20:613-625, 1975 4. Ogawa T, Jefferson NC, Nechles H: Comparative study of bite drainage in dog and man. Am J Surg 99:57-62, 1960 5. Elias H, Sherrick JC: The extrahepatic biliary system. Morphology of the Liver. New York, Academic Press, 1969, Chap 5. 6. Tansy MF, Innes DL, Martin JS, Kendall FM: The role of the intramural common bile duct in the filling of the canine gallbladder. Surg Gynecol Obstet 139:585-592, 1974 7. Persson CGA, Ekman M: Effect of morphine, cholecystokin in and sympathomimetics on the sphincter of Oddi and intramural pressure in cat duodenum. Scand J Gastroenterol 7:345-351, 1972 8. Thulin L, Olsson P: Effects of pure natural cholecystokinin on splanchnic circulation in the dog. Acta Chir Scand 139:681-686, 1973 9. Thulin L: Effects of the C-terminal octapeptide of cholecystokinin on splanchnic circulation in dog. Acta Chit Scand 139:687690, 1973 10. Juvara I, Vereanu I, Huch Ai t~tude du relief endocholeducien. J Chir (Paris) 106:599--608, 1973
241
Forward- and reverse-opening pressures of the choledochoduodenal junction were measured in anesthetized, vagotomized dogs. Mean reverse-opening pressures were found to be significantly greater in most cases including those following the intraductal administration o f vasoactive agents which are known to significantly influence mean forward-opening pressures. The polypeptides C C K - P Z and CCK--C8 were ineffective in reducing mean forward-opening pressures regardless of the route of administration. Previously published observations have indicated that mean forward-opening pressures are also unaffected by nervous activity. It is concluded that the canine choledochoduodenal junction possesses the physical and functional properties o f a passive flutter valve during duodenal relaxation.
During the course of the past two years a series of reports from our laboratories have appeared in this journal which have described the course of our investigations into the function of the choledochoduodenal junction (1-3). We have chosen to base our conclusions upon the results of physical measurements which employed the opening-pressure technique and we have sought to support the feasibility of these conclusions with descriptions of the anatomical structures which appear to be responsible for the effects that we observed. In summary, we have concluded that the occlusive competencies of the choledochoduodenal junctions of cats and dogs are due to the physical arrangements of the mucosa of the terminal common bile ducts of these animals. Ductal-opening pressures may be markedly altered by duodenal contractions, by the localized intraductal administration of vasoactive agents, as well as by changes in central arterial, central venous, and portal venous From the Department of Physiology and Biophysics, Temple University Health Sciences Center, Philadelphia, Pennsylvania. Address for reprint requests: Dr. Martin F. Tansy, Department of Physiology and Biophysics, Temple University, 3223 N. Broad Street, Philadelphia, Pennsylvania 19140. Digestive Diseases, Vol. 21, No. 3 (March 1976)
blood pressures. It appears that ductal-opening pressures in these species are not remarkably altered by peripheral-nerve stimulation sufficiently discrete to prevent large changes in systemic vascular pressures. The purposes of this report are to present further observations with respect to the hydraulic behavior of the terminal common bile duct as well as to describe the effects of cholecystokinin preparations injected into the caudal pancreaticoduodenal artery upon junctional-opening pressures. MATEI~IALS AND METHODS Acute experiments were performed on 18 adult mongrel dogs of both sexes. All dogs were fasted for 24 hours prior to experimentation. Anesthesia was induced and maintained by the intravenous administration of a mixture of a-chloralose (5 g/100 ml in polyethylene glycol200) and urethan (50 g/100ml in 0.9% saline) mixed in equal volumes. Each animal was individually titrated to a surgical plane of anesthesia. Surgery was preceded by cannulation of ipsilateral femoral artery and vein and the establishment of a tracheostomy for positive pressure ventilation. Both vagosympathetic trunks were exposed and severed at the cervical level. A midline thoracotomy-laparotomy was performed
233
T A N S Y ET A L
M.
o
=_, e= G Q x-.
x'.
.=. e~
0 eao
0
"a e~
r e.
234
Digestive Diseases,
Vol. 21, No. 3 (March 1976)
CANINE CHOLEDOCHODUODENAL FLUTTER VALVE
o~
o~
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r~
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~
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~
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%
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'=~
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Digestive Diseases, Vol. 21, No, 3 (March 1976)
235
TANSY ET AL
TABLE I. COMPARISON OF MEAN FORWARD AND REVERSE DUCTAL-OPENING PRESSURES Dog no.
Forward O P t
Reverse O P t
73542* 75044* 45522* 16056* 14788* 2120" 44599* 74354* Range
31.3 + 5.86(12) 31.8 -+ 6.46(12) 32.5 +- 4.2 (16) 22.8 +- 2.38 (12) 25,8 +- 4.43 (12) 26,3 -+ 4.79(12) 28,1 -+ 2.61 (9) 29.0 +- 4.78(12) 22.8--32.5
49.2 +- 8.33 (12) 47.4 -+ 4.35 (12) 38.1 -+ 4,04(16) 34.6 -+ 5~25 (12) 32.6 +- 4.70 (12) 39.9 -+ 6.58(12) 57.8 + 9.6 (9) 41.4 -+ 4.94(12) 32.6-57.8
*Indicates significant difference in m e a n opening pressures. t O P - - O p e n i n g pressure m e a s u r e m e n t s in centimeters of saline; -+ indicates one standard deviation; p a r e n t h e s e s denote number of observations.
from the pectoral girdle to the pelvic girdle. Cardiovascular hydraulic-pressure measurements were made by means of cannulae which were inserted in a femoral artery, femoral vein, splenic vein, and a mesenteric vein in the jejunal arcade. Jejunal motor effects were monitored by direct visualization and by means of an intraluminal balloon which was introduced through a duodenotomy 2 cm distal to the duodenal papilla, Gallbladder motor activity was monitored by direct visualization and by a balloon which was surgically introduced through the fundus. A convenient hepatic duct was cannulated, according to the standard pattern of bile-duct distribution by Ogawa and his associates (4), in order to monitor relative hepatic secretion by means of a photoelectric drop counter. A lead II electrocardiogram and a continuous measurement of body temperature by a rectal thermistor were routinely made. Drugs were administered intravenously by means of the femoral venous pressure cannula. Intraarterial administration of drugs in the region of the duodenal papilla was performed via a cannula which was inserted into an artery which visually appeared to supply the immediate vicinity of the choledochoduodenal junction. At the end of each experiment this artery was injected with india ink to confirm the original assumption that its contents in fact perfused the region of the choledochoduodenal junction (Figures 1 and 2). Junctional-opening pressures were made with a pressure-ramp generator according to a method which has been previously described (1). The intraductal administration of various vasoactive agents and hormones was made through the cannula of the pressure-ramp generator in a manner which has also been previously described (2). Comparison of forward and reverse ductal-opening pressures were made by means of a modification of the opening-pressure technique. The forward-pressure cannula was inserted via the common duct to the intramural portion of the duct as previously described. A polyethylene cannula of identical length and diameter to the forwardpressure cannula was inserted via the duodenotomy into the orifice of the papilla for at least 2 mm. until it was pos-
236
sible to fix its end in position by means of a ligature tied around the papilla. Fluid was then forced through the forward cannula until both cannulae were full. The output end of the output cannula was then fixed permanently at the same hydrostatic level as the input to the forward cannula. The endpoint for forward-opening pressure was determined by the first detectable flow of fluid from the output cannula. Reverse-opening pressures were determined by applying the pressure ramp to the output catheter and observing the appearance of fluid flow from the forward cannula, lnasmuch as the geometries and hydrostatic heights of both cannulae were identical, differences in observed opening pressures should be primarily determined by the properties of the choledochoduodenal junction. Intraductally administered agents were histamine dihydrochloride, bethanechol chloride, epinephrine hydrochloride, CCK-PZ, and CCK-C8. Agents which were introduced into the arterial supply of the junction were CCK-PZ and CCK-C8. Changes or differences in mean opening pressures were inferred by a statistical comparison of mean values at a significance level of 5%.
RESULTS Table 1 s u m m a r i z e s the results o f a series o f determinations o f m e a n f o r w a r d - and r e v e r s e - o p e n i n g p r e s s u r e s as d e t e r m i n e d in eight separate dogs. In all cases, m e a n r e v e r s e - o p e n i n g p r e s s u r e s were significantly greater than m e a n f o r w a r d - o p e n i n g pressures. T h e s e o b s e r v e d differences persisted in all but one instance following the intraductal administration o f v a s o a c t i v e agents s h o w n in Table 2. A n o t h e r series o f e x p e r i m e n t s was designed with the objective o f determining w h e t h e r it could be inferred that either o f two f o r m s o f c o m m e r c i a l l y
TABLE 2 COMPARISON OF MEAN FORWARD AND REVERSE DUCTAL-OPENING PRESSURES AFTER INTRADUCTAL DRUG ADMINISTRATION Dog no.
73542* 2120" 75044* 14788* 44599 74354* 72013* 72686* 74082*
Forward O P t Histamine diHCl (0.65 mg/ml) 37.0 -+ 7.6 (8) 34.0 -+ 4.98 (6) 49.2 + 3.06 (6) Bethanechol C1 (5 mg/ml) 74.3 -+ 6.47 (6) 80.7 + 8.94(7) Epinephrine HCI (0.45 mg/ml) 11.8 + 1.30(5) 35.0 + 3.46 (9) 24.4 • 3.61 (19) 21.9 -+ 1.88(12)
Reverse O P t
86.8 + 14.4 (8) 41.2 +- 5.0 (6) 67.8 +- 17.7 (6) 90.8 -+ 11.3 (8) 79.1 -+ 14.9(7) 20,1 42,3 43.0 47.0
-+ 1.86(7) +- 3.81 (9) -+ 7.05 (19) • 10.4(12)
*Indicates significant difference in m e a n opening pressures. t O P - - O p e n i n g pressure m e a s u r e m e n t s in centimeters of saline; -+ indicates one standard deviation; p a r e n t h e s e s denote n u m ber of observations. Digestive Diseases, Vol. 21, No:3 (March 1976)
CANINE
CHOLEDOCHODUODENAL
FLUTTER
VALVE
12 IDU/Kg - IA, CCK-PZ Femoral Arterial Pressure
200 mm Hg-
~ ~'~ Portal Venous Pressure
20 mg Hg-
Mesenteric Venous Pressure
20 mm Hg-
0 mm Hg-
Sphincteric Opening Pressure (Cm H~O) 27
29
32
38
ii 9 Mean Femoral
"
'
0 mm Hg-
28
ii "
" .....
27
:;: i
28
29
!
i
! i
Arterial Pressure
'
t
33
I
!
I minute
200 mm Hg,, i
...... ,
i
.... /i
,
' I
J
9
Fig 3. Polygram showing the course of events following the intraarterial administration of a 2.5 minute infusion of a total dosage of 12 IU/kg of CCK-PZ. Femoral arterial pressure exhibits a transient fall, tone and motor activity of the gallbladder are markedly augmented, portal venous pressure rises slightly (generally following the course of gallbladder activity), and small-bowel tone and segmenting motor activities are increased, There are no evident changes in forward ductal-opening pressures.
available cholecystokinin produced significant changes in mean junctional opening pressures when these agents were administered via various routes. These peptides were infused into the femoral vein (IV), a mesenteric artery (IA), over 2--4-minute periods, or a bolus was introduced into the terminal duct via the measurement cannula and held in stasis for approximately 1.5 minutes, after which the measurement cannula was flushed and post-treatment mean opening pressures determined. In addition to junctional-opening pressures, the following parameters were monitored during these experiments: femoral-arterial pressure, gallbladder-pressure activity, splenic-venous pressure (as an indication of portal pressure), hepatic-bile flow, jejuDigestive Diseases, Vol. 2I, No. 3 (March I976)
hal-pressure activity (motor activity was monitored by direct visualization), and pressure in the mesenteric artery which was used for drug administration. Figure 3 is a typical polygram which occurred following the timed injection of 12 IU/kg of CCK-PZ into a mesenteric artery. It can be seen that a slight decrease in femoral-arterial pressure occurred during the period of administration. Portal venous pressure was slightly elevated after a short latency. Blood pressure in a nearby mesenteric vein did not show any remarkable changes when compared to control recordings. Hepatic-duct-flow rate tended to fall transiently following either intravenous or intraarterial administration of either form of C C K . 237
TANSY ET AL
200 mm Hg-
6 IDU/Kg- IA, CCK-C8
Femoral Arterial Pressure
0 mm Hg-
Gall Bladder Motility
Portal Venous Pressure
20 mm Hg-
Mesenteric Venous Pressure
0 mm Hg-
20 mm Hg-
Sphincteric Opening Pressure (Cm H20) 17
17
15
0 mm Hg16
23
33
23
16
19
20
Hepatic Duct Bile Flow (Drops) Mean Femoral Arterial Pressure
200 mm Hg-
+ .
.
.
.
t. . . . .
0
- -+
'~+-7"-'---~-
i i 1 minute
mmHg---+
------
~:
--
Fig 4. Events observed following the intraarterial administration of a 4.3 minute infusion of a total dosage of 6 IU/kg of CCK-C8. Femoral arterial pressure is depressed for several minutes during which time there is a slight rise in both portal venous and mesenteric venous pressures, and an elevation in gallbladder tone. Segmentingjejunal motor activity is markedly but transiently increased. There are no evident changes in forward ductal-opening pressures.
There was also a marked increase in jejunal motor activity following intravenous or intraarterial administration of these peptides. In all cases, the observed increases in both jejunal and duodenal motor activities were observed to be of a segmenting nature. No detectable changes in any of these parameters were observed following the intraductal administration of either peptide. Figure 4 is a polygram which depicts the time course of the previously described parameters following the timed intraarterial administration of CCK-C8. Essentially the same results were obtained as with the administration of C C K - P Z , except that the C C K - C 8 appeared to produce a greater and more prolonged decrease in femoral-arterial pressure. Jejunal motor activity was recorded and
238
observed to be much more vigorous following intraarterial or intravenous administration of CCK-C8. The observed effects of C C K - P Z and C C K - C 8 , administered intravenously, are summarized in Table 3. In all cases except three we were obliged to accept our null hypothesis that either agent administered by any of the three routes was not significantly associated with a change in mean junctional forward-opening pressures. In the three instances where significant results were noted, the mean forward-opening pressures increased. It should be noted that duodenal motor activity was constantly visualized during opening-pressure determinations. The presence of duodenal contractions during any opening-pressure measurement was indicated directly on the polygram. Opening-pressure values Digestive Diseases, Vol. 21, No. 3 (March 1976)
CANINE CHOLEDOCHODUODENAL FLUTTER VALVE
TABLE 3. OBSERVEDMEAN DUCTAL-OPENING PRESSURESPRIORTO AND SUBSEQUENTTO THE ADMINISTRATION OF TWO FORMS OF CHOLECYSTOKININ BY VARIOUSROUTES D o g no.
75161 75161 75161 75161 75161 74492 74492* 74492 74492 74492 75304 75304 75304* 75304 74877* 74877 74877 74877
Pretreatrnent O P t
25.0 26.7 25.9 27.7 26.7 30.4 26.3 23.7 25.0 28.5 17.2 20.0 18.2 20.3 26.0 26.0 29.0 26.3
-+ 4.86 (12) -+ 6.26(12) -+ 4.67 (8) -+ 6.50(6) -+ 4.97 (6) -+ 2.07 (7) -+ 2.43 (7) -+ 2.60 (8) -+ 1.67 (6) • 2.43 (6) -+ 9.82(11) • 1.90 (11) -+ 2.64 (6) -+ 2.73 (6) -+ 1.60 (12) -+ 8.19 (10) -+ 2.71 (7) • 3.27 (6)
Treatment~
IA, CCK-PZ IA, CCK-PZ IV, CCK-PZ ID, CCK-PZ ID, CCK-PZ IA, CCK-PZ IA, CCK-PZ IV, CCK-PZ ID, CCK-PZ ID, CCK-PZ IA, CCK-C8 IA, CCK-C8 ID, CCK-C8 ID, CCK-C8 IA, CCK-C8 IA, CCK-C8 IV, CCK-C8 ID, CCK-C8
Dose
10 IU/kg 10 IU/kg 10 IU/kg 2IU 2 IU 6 IU/kg 12 IU/kg 12 IU/kg 2 IU 2 IU 6 IU/kg 6 IU/kg 2 IU 2 IU 7.5 IU/kg 7.5 IU/kg 7.5 IU/kg 6 IU
Post-treatment O P t
25.5 29.1 24.6 27.8 32.7 30.5 30.7 28.5 25.8 29.0 17.4 19.8 21.6 20.8 29.5 28.1 29.2 27.0
• 5.6 (12) m 5.53 (12) • 1.84 (8) + 5.42(6) -+ 7.37 (6) +- 2.82 (7) • 3.90 (7) -+ 7.34 (6) -+ 2.8 (6) -+ 4.94 (6) -+ 5.18(12) -+ 3.49 (12) -+ 2.51 (5) -4- 2.14 (6) + 3.14(10) + 2.85 (10) -+ 1.75 (8) -+ 2.45 (6)
*Indicates significant difference in mean opening pressures. tOP Opening pressure measurements in centimeters of saline; • indicates one standard deviation; parentheses denote number of observations. 1:[A represents intraarterial; IV represents intravenous; ID represents intraductal.
which were determined during periods of duodenal contraction were excluded from the computation of mean values by virtue of the experimental protocol. This procedure did not result in the elimination of more than two observed values from any single series of measurements. DISCUSSION An historical appreciation of the literature which pertains to the choledochoduodenal junction eventually has led us to conclude that the basic intent of both structural and functional studies has been to provide evidence in support of an apriori belief that this junction exerts an active effector role as a component in an overall controlled mechanism of bile flow. Both lines of investigation should ideally support each other: a physically quantifiable phenomenon should be supported by a structure which can reasonably be inferred to be responsible for producing the effects which were observed. An almost dogmatic devotion to the postulated existence of a choledochoduodenal sphincteric effector mechanism certainly has ample precedent in the literature, in which such entities have been described and accepted as operational mechanisms in both the digestive and circulatory systems. Indeed, Digestive Diseases, Vol. 21, No. 3 (March 1976)
the well-known instability of sphincters and the equally accepted fact that their opening and closing pressures can be altered by the tone of their smooth-muscle component constitutes the fundamental physical description of these biological effectot mechanisms. Unfortunately, in the case of the choledochoduodenal junction in general, and the so-called "sphincter of Oddi" in particular, the almost universal disagreement in opinion which surrounds the operational definition of this entity is entirely attributable to a fundamental and original failure to first determine whether this structure can be inferred to operate as a sphincter or as a valve. It is our opinion that this fundamental failure is attributable to at least three factors: 1. the implicit assumption that a sphincter existed (which has only seriously been questioned on anatomical grounds within the last few years); 2. the inherent difficulty in actually assessing the physical behavior of this entity when it is immersed in its anatomical surroundings; and 3. a fundamental and by no means restricted lack of appreciation of the necessity of methodically determining the nature of the parameters of an assumed system which can render it formally observable on onehand and amenable to modeling on the other. Thus, the purposes of this report are both limited and explicit: to present the results
239
TANSY ET AL
of a series of experiments which were designed to provide a physical description of the canine choledochoduodenal junction and to test the null hypothesis that the mean forward-opening pressures of this junction are unaffected by the administration of cholecystokinin by various routes. As we have previously reported (1, 2) we have been unable to conclude that mean forward-opening pressures of the canine junction are subject to nervous influence. We were able to infer that alterations of systemic arterial and venous pressures and portal venous pressures could influence mean forward-opening pressures. We then investigated the local effects of intraductally administered vasoactire agents upon mean forward-opening pressures and were able to conclude that these pressures were significantly influenced by mechanisms which were local in character and probably located either within the intramural terminal duct or in its immediate vicinity. We were thus obliged to conduct a series of microanatomical studies to account for the effects of vasoactive agents upon opening pressure which we observed (3). Reference to the literature produced an excellent perspective description of the valvular structure of the junction (in which the mucosal folds which we described are denoted as valves), contained in the classic text on the morphology of the liver by Elias and Sherrick (5). Thus, the results of our forward- and reverse-opening pressures support a description of these structures as constituting an unstable valve with pronounced one-way properties, which is characteristic of a flutter valve. We performed these latest experiments as a direct result of the valvular description. We have reason to believe that the presence of the forward valve is in fact necessary to insure gallbaldder filling (6). The reverse character of the valve is of probable significance in preventing the reflux of duodenal contents into the common bile duct. In this connection, it should be noted that our experimental protocols have restricted our consideration of experimental data to those opening pressures which were observed in the absence of observable duodenal contractions. We were obliged to do this because we had no way of insuring that such spontaneous and uncontrolled activity could be quantified and thus describable as part of the observed system. To attempt to do otherwise would have required us to make an assumption of stationarity which we could not support. We do offer the observation that solitary opening pressures that were fortuitously oh-
240
served during bouts of duodenal contractions were always greater than during duodenal quiescence. Thus it is possible that any antireflux properties which are attributable to the one-way nature of this structure are enhanced by the very contractile events which would be necessary to provide the necessary pressure head. Conversely, it is not unreasonable to suspect that duodenal spasm might elevate junctional forward-opening pressures. However, now that alternative nonmuscular mechanisms have been shown to exist which will significantly elevate ductal-opening pressures, it is no longer justifiable to consider the presence of biliary dyskinesias of unknown etiology as being automatically indicative of spasmolytic therapy unless duodenal spasm is definitely known to exist. The model builder is also faced with an unfortunate consequence of our inability to quantitate the effects of duodenal contractions upon forwardopening pressures. We believe that he can legitimately make a one-way assumption but he will still be left to his own devices with respect to the role which he assigns to duodenal contractions in a model of biliary dynamics. Furthermore, under the conditions of our measurements, visceromotor and respiratory effects upon the extramural portion of the duct due to shear forces at the extramural point of entrance were minimized by virtue of the fact that fluid coupling through this region was essentially maintained by the presence of the intraluminalmeasurement cannula. Inasmuch as respiratory movements themselves are still widely regarded to either influence or to be part of the mechanism of gallbladder-bile release, the model builder must assign a role to these other factors. For this reason, we believe that a detailed model of biliary dynamics is still a long way from practical realization. A classical description of bile release indicates that bile flow and gallbladder contraction are accompanied by an opening of the so-called "sphincter." The histochemical literature indicates that the intrinsic nerve supply to this junction and the contiguous duodenal areas is primarily perivascular. Thus, on this basis, and in view of our consistent lack of results with a large number of experiments, we feel that a direct nervous control of junctional forward-opening pressures, either by virtue of an innervated sphincteric mechanism or an effect upon the vasculature of the ductal mucosa, is highly unlikely. This leaves the matter of a postulated hormonal mechanism for a proposed reciprocal relationship Digestive Diseases, Vot. 2l, No. 3 (March 1976)
CANINE CHOLEDOCHODUODENAL
FLUTTER VALVE
between gallbladder contraction and junctional "relaxation." Thus, the final series of experiments was designed to determine whether cholecystokinin could be inferred to produce changes in mean junctional forward-opening pressures. The problems associated with this experimental design involve the facts that the commonly accepted active peptides produce changes in duodenal motor activity, relaxation in the vicinity of the junctional aperature as shown by Persson and Ekman (7), and more recently, alterations in arterial-blood pressures and portal venous blood flow (8, 9). In view of our past experience with both duodenal motor activity and vascular influences, we had reason to believe that CCK-PZ and CCK-C8 should produce some effect upon mean opening pressures even though the actual measurements themselves were made during periods of observed duodenal quiescence. Our experimental data from the CCK-peptide experiments indicated that intravascular administration produced pronounced gallbladder and jejunal motility. These observations are in agreement with the literature. Our cardiovascular observations indicated that intravascular peptide administration was followed by some degree of arterial hypotension and, in the case of a high intravascular dose of CCK, a slight rise in portal venous pressure. Therefore, on the basis of expected motor and vascular effects, we assumed that our intravascular peptide administrations should produce changes in mean forward-opening pressures. The only significant resuits which we observed consequent to peptide administration in any dose, and by any route, were in the wrong direction to be consistent with a proposed reciprocal model. Our tests were, in fact, two-tailed because we simply did not have sufficient faith in the reciprocal model to justify the rather formidable assumption that would underly a one-tailed test. It is thus our conclusion that the choledochoduodenal junction is a passive, nonlinear, essentially one-way valve. Forward opening-pressures may be influenced by respiration, duodenal motor activity, and the vascular status of the mucosal lining of the terminal intramural portion. Any stimulus that will influence these factors will influence mean opening
Digestive Diseases, Vol. 21, No. 3 (March 1976)
pressure in response to a pressure-ramp-forcing function. We believe that this physical and structural definition of this junction is clearly inconsistent with a description of the sphincter of Oddi as a sphincter. With the exclusion of the well-established role of this valve in gallbladder filling (6), we shall regard any assertion that the influences which we have cited ptay any role other than pathophysiological (10), or within the definition of noise in controlled processes, must be accompanied by a necessary and sufficient demonstration of proof. ACKNOWLEDGMENTS The authors appreciate the technical assistance of Mr. Harold Perrong. The authors wish to thank the Squibb Institute of New Jersey for their generous supply of CCKC8. This work was supported in part by a grant-in-aid from Temple University. REFERENCES 1. Tansy MF, Innes DL, Martin JS, Kendall FM: An evaluation of neural influences on the sphincter of Oddi in the dog. Am J Dig Dis 19:423-437, 1974 2. Tansy MF, Innes DL, Martin JS, Kendall FM: Vascular influences on the dynamic stability of the choledochoduodenal junction. Am J Dig Dis 19:1124-1137, 1974 3. Tansy MF, Salkin L, Innes DL, Martin JS, Kendall FM, Litwack D: The mucosal lining of the intramural common bile duct as a determinant of ductal opening pressure. Am J Dig Dis, 20:613-625, 1975 4. Ogawa T, Jefferson NC, Nechles H: Comparative study of bite drainage in dog and man. Am J Surg 99:57-62, 1960 5. Elias H, Sherrick JC: The extrahepatic biliary system. Morphology of the Liver. New York, Academic Press, 1969, Chap 5. 6. Tansy MF, Innes DL, Martin JS, Kendall FM: The role of the intramural common bile duct in the filling of the canine gallbladder. Surg Gynecol Obstet 139:585-592, 1974 7. Persson CGA, Ekman M: Effect of morphine, cholecystokin in and sympathomimetics on the sphincter of Oddi and intramural pressure in cat duodenum. Scand J Gastroenterol 7:345-351, 1972 8. Thulin L, Olsson P: Effects of pure natural cholecystokinin on splanchnic circulation in the dog. Acta Chir Scand 139:681-686, 1973 9. Thulin L: Effects of the C-terminal octapeptide of cholecystokinin on splanchnic circulation in dog. Acta Chit Scand 139:687690, 1973 10. Juvara I, Vereanu I, Huch Ai t~tude du relief endocholeducien. J Chir (Paris) 106:599--608, 1973
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