GastroenterologiaJaponica Copyright~} 1977 by The JapaneseSocietyof Gastroenterology
Vol. 12, No. 5 Printedin Japan
--Case Report--
STUDIES ON E X O G E N O U S AND E N D O G E N O U S INTERACTION OF GASTRIN A N D SECRETIN IN A CASE OF ACHALASIA Nobuo S E K I Y A M A , M.D., Yoshitaka K A K U M O T O , M.D., Susumu N A K A G A W A , M.D. and Takeo WADA, M.D.
First Department of Internal Medicine, Sapporo Medical College (Director: Prof T. Wada)
Summary Studies were carried out in a case of achalasia. Administration of secretin caused relaxation of the spastic condition of LES, and high levels of serum gastrin and lower levels of plasma secretin are suggested to be related with the abnormally spastic condition of LES in the patient.
Key Words: LES, achalasis, secretin, gastrin. Introduction In connection with an interaction between gastrin and secretin ~'~) on the contractility of the lower esophageal sphincter (LES), examinations were carried out in a case of achalasia by estimating the changes of the LES pressure following administration of gastrin-like tetrapeptide (TG) and/or secretin. Determinations of serum gastrin, plasma secretin and LES pressure were also made before and during ingestion loading of test meals and induced intra-duodenal acidification.
Subject and M e t h o d s A 26 year old male patient with achalasia was subjected to the examinations. Intraluminal LES pressure was estimated using an apparatus consisting of three waterfilled balloons to which a catheter was connected as illustrated in Fig. 1. Each balloon was placed at the cardia of the stomach, LES and the upper part close to the LES. The balloons were connected with polyvinyl tubes of 1.6 m m in diameter to transmit the pressures to a transducer, and outputs from the trans-
ducer were recorded on a multichannel recorder (Nihon K6den). The measurements were carried out under fasting conditions overnight in a supine position without any stimulation, and the following morning these were followed under successive administrations of T G at a dose of 4 ~g/kg b.w. intramuscularly, and secretin at a dose of 2 U/kg b.w./2 min. intravascularly. Radioimmunoassays were used for the determinations of gastrin and secretin as reported previously4,5). Maggi-bouillon method 6) and an instillation of 50 ml of 0. t-N HC1 solution into the duodenum were carried for observing the effects of the above agents on the release of gastrin and secretin, and influence ofpre-fed butter on the Maggi-bouillon
Fig. 1. Three balloon-catheter use for measurement of pressures at cardia of the stomach (I), lower esophageal sphincter (II) and at the esophagus (III).
396
N. S E K I Y A M A E T A L .
method was also observed. Daily changes of these levels in serum and/or plasma were also determined from 8 in the morning at 4 hour intervals before each meal and at night for 24 hours.
Vol. 12, No. 5
duodenal acidification (Fig. 5). However, pre-feeding of butter intraduodenally gave rise to a slight suppressive effect on the increase of plasma secretin after duodenal acidification accounting from 75 to 130 pg/ml. Circadian fluctuation 8~ showed serum gastrin
Results 1. LES pressure: A most prominent rhythmical pressure record was obtained from the balloon located around the LES in parallel with the amount of water infused between 10 and 30 m m H g (Fig. 2), and rhythmical contraction of the LES showed but a slight response in its increase after T G administration. However, a remarkable decrease of LES pressure was observed immediately after infusion of secretin, which gradually returned to control level after approximately 13 minutes. The secretin effect on LES contraction was also examined by fluoroscopy (Fig. 3). 2. Gastrin and secretin levels: Following Maggi-bouillon administration, the serum gastrin response was lower compared to that of the control group (Fig. 4), and in contrast, a remarkable increase of plasma secretin from 75 to 225 pg/ml was noted after intra-
Fig. 3(a). X-ray finding of the esophagus in resting condition.
v
Fig. 2. Pressure records of lower esophageal sphincter (upper) and cardia of the stomach (lower) before and after administration of 2 U/kg of secretil~ intravenously.
Fig. 3(b). X-ray finding of the esophagus 5 min. after administration of 2 U/kg of secretin intravenously.
October 1977
397
Gastrin and Secretin Interaction in Aehalasia
Fig. 4. Response in increase of serum gastrin after ingestion of Maggi-Bouillon (O--O)- (Shaded area indicates the mean=SD of normal gastrin responses)
Fig. 6. Circadian fluctuaiion of serum gastrin (O--O). (Shaded area indicates the mean=SD of the normal gastrin fluctuations)
Fig. 7. Circadian fluctuation of plasma secretin.
was 1.614 m E q / h after an intramuscular injection with 4 ~zg/kg of T G .
Discussion
Fig. 5. Response in increase of plasma secretin after instillation of 0.1 N HC1 into the duodenum (O--O). (Shaded area indicates the mean=SD of normal secretin responses) levels of higher values within a normal range (Fig. 6), with a lower pattern of plasma secretin (Fig. 7). Basic gastric acid secretion was 0.855 m E q / h and m a x i m u m acid o u t p u t
Studies were carried out in an a t t e m p t to follow the interaction of gastrin and secretin in the form of pressure of the LES in a case o f achalasia, alternately administrating these exogenously a n d / o r stimulating endogenous release of these by various agents. T h e results showed a remarkable relaxation o f the LES contraction on the pressure m e a s u r e m e n t a n d in X - r a y findings after intravenous injection of secretin. I n contrast, only a slight increase of L E S pressure was seen after gastrin injection 1). It is well known that resting contraction o f
398
Vol. 12, No. 5
N. S E K I Y A M A E T A L .
the smooth muscle increases b y d e n e r v a t i o n 9~,
the etiology o f a c h a l a s i a is still u n k n o w n , a
a n d gastrin a n d / o r secretin effects are the d i r e c t m e c h a n i c a l action o f the smooth muscle10,11>.
lower acid secretion w i t h h i g h serum gastrin levels m a y give rise to a n a b n o r m a l increase of the L E S c o n t r a c t i o n resulting from the
T h e L E S muscle c o n t r a c t i b i l i t y in this case is t h o u g h t to result from the c h a n g e of the inn e r v a t i o n of the L E S . Therefore, in t h e muscle c o n t r a c t i o n after gastrin a d m i n i s t r a t i o n a n d after s t i m u l a t i o n o f gastrin release w i t h M a g g i - b o u i l l o n a slight increase was seen while a r e m a r k a b l e r e l a x a t i o n of the L E S pressure after secretin a d m i n i s t r a t i o n was noted. T h e l a t t e r c a n only be the i n t e r a c t i o n o f secretin to the g a s t r i n action to c o n t r a c t t h e L E S in its resting state. N o d i s c r e p a n c y was d e t e c t e d on the c o m p e t i t i v e i n t e r a c t i o n between gastrin a n d secretin in this case, b e c a u s e as a result of p a t h o h i s t o l o g i c a l e x a m i n a t i o n a t surgery showed a m a r k e d c h a n g e of the n e r v e plexus a r o u n d the L E S . I t is also well k n o w n t h a t p r o t e i n a n d o t h e r stimuli release g a s t r i n l~ into the serum, a n d t h a t acidification b e l o w p H 4.512~ in t h e d u o d e n u m c o m p e t i t i v e l y suppresses the release o f g a s t r i n a c c o m p a n i e d b y a release o f s e c r e t i n 7~ into the blood. F r o m these findings, it m a y be c o n j e c t u r e d t h a t a n y d i s p r o p o r t i o n or d i s t u r b a n c e of the releasing m e c h a n i s m o f these gastrointestinal h o r m o n e s m a y well b e one of the causes o f achalasia. Gastric a c i d secretion in this case was lower t h a n the control, a n d while b e i n g in a n o r m a l range, the s e r u m gastrin levels were higher. A c c o r d i n g l y secretin levels d i m i n i s h e d in a resting state, a n d showed sufficient release after i n t r a d u o d e n a l acidification. I t is, o f course, difficult to a n a l y z e the p a t h o l o g i c a l conditions systematically, a n d the c h a n g e o f the a u t o n o m i c n e r v e system m a y p l a y a role in the h y p e r g a s t r i n e m i c c o n d i t i o n r e l a t e d to G-cell dysfunction. I t m a y further p r e s u m a b l y be said that, a l t h o u g h
decrease of the secretin release. References
l) Cohen S, Lipshutz W: Hormonal regulation of human lower esophageal sphincter competence: interaction of gastrin and secretin. J Clin Invest 50: 449~.54, 1971 2) Lipshutz WI~, Gaskins RD, Lukash WM, Sode J: Hypogastrinemia in patients with lower esophageal sphincter competence. Gastroenterology 67: 423427, 1974 3) Farrel RL, Gastell DO, McGuigan JE: Measurements and comparison of lower esophageal sphincter pressures and serum gastrin levels in patients with gastrointestinal reflux. Gastroenterology 67: 415422, 1974 4) Ohra H, Inabe Y, Yabu-uchi S, Kihara A, Wada T : Radioimmunoassay of secretin. Ig.aku no Ayumi 94(8): 340-342, 1975 5) Yabana T, Abe I-I, Yachi A: Fundamental investigation of radioimmunoassay of gastrin and clinical studies on serum, urine and gastric secretion. Jap J Gastroenterol 69: 244-263, 1972 6) Watanabe K, Yabana T, Kakumoto Y, Sekiyama N, Mitani J, Nakagawa T, Takasu S, Yachi A, Sat6 K: Clinical studies on serum gastrin response to oral ingestion of Bouillon solution. Jap J Gastroenterol 74: 874-882, 1977 7) Sekiyama N, Wada T.: Interaction between gastrin and secretin. The 9th Symposium of GEP hormone, Chitose, August 30- September 1, 1976 8) Uchiya T, Yabana T: Clinical and experimental studies on serum gastrin levels and their circadian fluctuation pattern. Sapporo Med J 46:36-54, 1977 9) Fukuhara T, Sumi T, Kotani S: The role of the ganglion cells in the small intestine taken in the intestinal intrinsic reflex. Jpn J Physiol 11: 281288, 1966 10) Walsh JH, Grossman MI: Gastrin. New Engl J Med 292(25): 1325-1334, 1975 11) Rayford PL, Miller TA, Thompson JC: Secretin, cholecystoklnin and newer gastrointestinal hormones. New Engl J Med 294(20): 1094-1101, 1976 12) Chey WY, Tai t-I, Rhodes R, Lee KY, Hendricks J: A symposium, held at the University of Texas Medical Branch, Galveston, October 9-12, 1976 Edited by JG Thompson, Austin, University of Texas Press, 1975
O c t o b e r 1977
Gastrin and SecretinInteractionin Achalasia
399
These studies were partially supported by Grant-in-Aid for Scientific Researchfrom the Ministry of Education, Science and Culture, Japan. Received June 13, 1977. Accepted August 8, 1977. Address requests for reprints to : Prof. Takeo Wada, The 1st Department of Internal Medicine, Sapporo Medical College, S-l, W-16, Chuoh-ku, Sapporo, 060 Japan.
Vol. 12, No. 5 Printedin Japan
--Case Report--
STUDIES ON E X O G E N O U S AND E N D O G E N O U S INTERACTION OF GASTRIN A N D SECRETIN IN A CASE OF ACHALASIA Nobuo S E K I Y A M A , M.D., Yoshitaka K A K U M O T O , M.D., Susumu N A K A G A W A , M.D. and Takeo WADA, M.D.
First Department of Internal Medicine, Sapporo Medical College (Director: Prof T. Wada)
Summary Studies were carried out in a case of achalasia. Administration of secretin caused relaxation of the spastic condition of LES, and high levels of serum gastrin and lower levels of plasma secretin are suggested to be related with the abnormally spastic condition of LES in the patient.
Key Words: LES, achalasis, secretin, gastrin. Introduction In connection with an interaction between gastrin and secretin ~'~) on the contractility of the lower esophageal sphincter (LES), examinations were carried out in a case of achalasia by estimating the changes of the LES pressure following administration of gastrin-like tetrapeptide (TG) and/or secretin. Determinations of serum gastrin, plasma secretin and LES pressure were also made before and during ingestion loading of test meals and induced intra-duodenal acidification.
Subject and M e t h o d s A 26 year old male patient with achalasia was subjected to the examinations. Intraluminal LES pressure was estimated using an apparatus consisting of three waterfilled balloons to which a catheter was connected as illustrated in Fig. 1. Each balloon was placed at the cardia of the stomach, LES and the upper part close to the LES. The balloons were connected with polyvinyl tubes of 1.6 m m in diameter to transmit the pressures to a transducer, and outputs from the trans-
ducer were recorded on a multichannel recorder (Nihon K6den). The measurements were carried out under fasting conditions overnight in a supine position without any stimulation, and the following morning these were followed under successive administrations of T G at a dose of 4 ~g/kg b.w. intramuscularly, and secretin at a dose of 2 U/kg b.w./2 min. intravascularly. Radioimmunoassays were used for the determinations of gastrin and secretin as reported previously4,5). Maggi-bouillon method 6) and an instillation of 50 ml of 0. t-N HC1 solution into the duodenum were carried for observing the effects of the above agents on the release of gastrin and secretin, and influence ofpre-fed butter on the Maggi-bouillon
Fig. 1. Three balloon-catheter use for measurement of pressures at cardia of the stomach (I), lower esophageal sphincter (II) and at the esophagus (III).
396
N. S E K I Y A M A E T A L .
method was also observed. Daily changes of these levels in serum and/or plasma were also determined from 8 in the morning at 4 hour intervals before each meal and at night for 24 hours.
Vol. 12, No. 5
duodenal acidification (Fig. 5). However, pre-feeding of butter intraduodenally gave rise to a slight suppressive effect on the increase of plasma secretin after duodenal acidification accounting from 75 to 130 pg/ml. Circadian fluctuation 8~ showed serum gastrin
Results 1. LES pressure: A most prominent rhythmical pressure record was obtained from the balloon located around the LES in parallel with the amount of water infused between 10 and 30 m m H g (Fig. 2), and rhythmical contraction of the LES showed but a slight response in its increase after T G administration. However, a remarkable decrease of LES pressure was observed immediately after infusion of secretin, which gradually returned to control level after approximately 13 minutes. The secretin effect on LES contraction was also examined by fluoroscopy (Fig. 3). 2. Gastrin and secretin levels: Following Maggi-bouillon administration, the serum gastrin response was lower compared to that of the control group (Fig. 4), and in contrast, a remarkable increase of plasma secretin from 75 to 225 pg/ml was noted after intra-
Fig. 3(a). X-ray finding of the esophagus in resting condition.
v
Fig. 2. Pressure records of lower esophageal sphincter (upper) and cardia of the stomach (lower) before and after administration of 2 U/kg of secretil~ intravenously.
Fig. 3(b). X-ray finding of the esophagus 5 min. after administration of 2 U/kg of secretin intravenously.
October 1977
397
Gastrin and Secretin Interaction in Aehalasia
Fig. 4. Response in increase of serum gastrin after ingestion of Maggi-Bouillon (O--O)- (Shaded area indicates the mean=SD of normal gastrin responses)
Fig. 6. Circadian fluctuaiion of serum gastrin (O--O). (Shaded area indicates the mean=SD of the normal gastrin fluctuations)
Fig. 7. Circadian fluctuation of plasma secretin.
was 1.614 m E q / h after an intramuscular injection with 4 ~zg/kg of T G .
Discussion
Fig. 5. Response in increase of plasma secretin after instillation of 0.1 N HC1 into the duodenum (O--O). (Shaded area indicates the mean=SD of normal secretin responses) levels of higher values within a normal range (Fig. 6), with a lower pattern of plasma secretin (Fig. 7). Basic gastric acid secretion was 0.855 m E q / h and m a x i m u m acid o u t p u t
Studies were carried out in an a t t e m p t to follow the interaction of gastrin and secretin in the form of pressure of the LES in a case o f achalasia, alternately administrating these exogenously a n d / o r stimulating endogenous release of these by various agents. T h e results showed a remarkable relaxation o f the LES contraction on the pressure m e a s u r e m e n t a n d in X - r a y findings after intravenous injection of secretin. I n contrast, only a slight increase of L E S pressure was seen after gastrin injection 1). It is well known that resting contraction o f
398
Vol. 12, No. 5
N. S E K I Y A M A E T A L .
the smooth muscle increases b y d e n e r v a t i o n 9~,
the etiology o f a c h a l a s i a is still u n k n o w n , a
a n d gastrin a n d / o r secretin effects are the d i r e c t m e c h a n i c a l action o f the smooth muscle10,11>.
lower acid secretion w i t h h i g h serum gastrin levels m a y give rise to a n a b n o r m a l increase of the L E S c o n t r a c t i o n resulting from the
T h e L E S muscle c o n t r a c t i b i l i t y in this case is t h o u g h t to result from the c h a n g e of the inn e r v a t i o n of the L E S . Therefore, in t h e muscle c o n t r a c t i o n after gastrin a d m i n i s t r a t i o n a n d after s t i m u l a t i o n o f gastrin release w i t h M a g g i - b o u i l l o n a slight increase was seen while a r e m a r k a b l e r e l a x a t i o n of the L E S pressure after secretin a d m i n i s t r a t i o n was noted. T h e l a t t e r c a n only be the i n t e r a c t i o n o f secretin to the g a s t r i n action to c o n t r a c t t h e L E S in its resting state. N o d i s c r e p a n c y was d e t e c t e d on the c o m p e t i t i v e i n t e r a c t i o n between gastrin a n d secretin in this case, b e c a u s e as a result of p a t h o h i s t o l o g i c a l e x a m i n a t i o n a t surgery showed a m a r k e d c h a n g e of the n e r v e plexus a r o u n d the L E S . I t is also well k n o w n t h a t p r o t e i n a n d o t h e r stimuli release g a s t r i n l~ into the serum, a n d t h a t acidification b e l o w p H 4.512~ in t h e d u o d e n u m c o m p e t i t i v e l y suppresses the release o f g a s t r i n a c c o m p a n i e d b y a release o f s e c r e t i n 7~ into the blood. F r o m these findings, it m a y be c o n j e c t u r e d t h a t a n y d i s p r o p o r t i o n or d i s t u r b a n c e of the releasing m e c h a n i s m o f these gastrointestinal h o r m o n e s m a y well b e one of the causes o f achalasia. Gastric a c i d secretion in this case was lower t h a n the control, a n d while b e i n g in a n o r m a l range, the s e r u m gastrin levels were higher. A c c o r d i n g l y secretin levels d i m i n i s h e d in a resting state, a n d showed sufficient release after i n t r a d u o d e n a l acidification. I t is, o f course, difficult to a n a l y z e the p a t h o l o g i c a l conditions systematically, a n d the c h a n g e o f the a u t o n o m i c n e r v e system m a y p l a y a role in the h y p e r g a s t r i n e m i c c o n d i t i o n r e l a t e d to G-cell dysfunction. I t m a y further p r e s u m a b l y be said that, a l t h o u g h
decrease of the secretin release. References
l) Cohen S, Lipshutz W: Hormonal regulation of human lower esophageal sphincter competence: interaction of gastrin and secretin. J Clin Invest 50: 449~.54, 1971 2) Lipshutz WI~, Gaskins RD, Lukash WM, Sode J: Hypogastrinemia in patients with lower esophageal sphincter competence. Gastroenterology 67: 423427, 1974 3) Farrel RL, Gastell DO, McGuigan JE: Measurements and comparison of lower esophageal sphincter pressures and serum gastrin levels in patients with gastrointestinal reflux. Gastroenterology 67: 415422, 1974 4) Ohra H, Inabe Y, Yabu-uchi S, Kihara A, Wada T : Radioimmunoassay of secretin. Ig.aku no Ayumi 94(8): 340-342, 1975 5) Yabana T, Abe I-I, Yachi A: Fundamental investigation of radioimmunoassay of gastrin and clinical studies on serum, urine and gastric secretion. Jap J Gastroenterol 69: 244-263, 1972 6) Watanabe K, Yabana T, Kakumoto Y, Sekiyama N, Mitani J, Nakagawa T, Takasu S, Yachi A, Sat6 K: Clinical studies on serum gastrin response to oral ingestion of Bouillon solution. Jap J Gastroenterol 74: 874-882, 1977 7) Sekiyama N, Wada T.: Interaction between gastrin and secretin. The 9th Symposium of GEP hormone, Chitose, August 30- September 1, 1976 8) Uchiya T, Yabana T: Clinical and experimental studies on serum gastrin levels and their circadian fluctuation pattern. Sapporo Med J 46:36-54, 1977 9) Fukuhara T, Sumi T, Kotani S: The role of the ganglion cells in the small intestine taken in the intestinal intrinsic reflex. Jpn J Physiol 11: 281288, 1966 10) Walsh JH, Grossman MI: Gastrin. New Engl J Med 292(25): 1325-1334, 1975 11) Rayford PL, Miller TA, Thompson JC: Secretin, cholecystoklnin and newer gastrointestinal hormones. New Engl J Med 294(20): 1094-1101, 1976 12) Chey WY, Tai t-I, Rhodes R, Lee KY, Hendricks J: A symposium, held at the University of Texas Medical Branch, Galveston, October 9-12, 1976 Edited by JG Thompson, Austin, University of Texas Press, 1975
O c t o b e r 1977
Gastrin and SecretinInteractionin Achalasia
399
These studies were partially supported by Grant-in-Aid for Scientific Researchfrom the Ministry of Education, Science and Culture, Japan. Received June 13, 1977. Accepted August 8, 1977. Address requests for reprints to : Prof. Takeo Wada, The 1st Department of Internal Medicine, Sapporo Medical College, S-l, W-16, Chuoh-ku, Sapporo, 060 Japan.
