Konar Center for Digestive and Liver Diseases, University of Rochester Medical Center, Rochester, New York 14642
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ABSTRACT |
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We investigated the mechanism of action of methionine enkephalin (MEK) on HCl-stimulated secretin release and pancreatic exocrine secretion. Anesthetized rats with pancreatobiliary cannulas and isolated upper small intestinal loops were perfused intraduodenally with 0.01 N HCl while bile and pancreatic juice were diverted. The effect of intravenous MEK on acid-stimulated secretin release and pancreatic exocrine secretion was then studied with or without coinfusion of naloxone, an anti-somatostatin (SS) serum, or normal rabbit serum. Duodenal acid perfusate, which contains secretin-releasing peptide (SRP) activity, was collected from donor rats with or without pretreatment with MEK, MEK + naloxone, or MEK + anti-SS serum, concentrated by ultrafiltration, and neutralized. The concentrated acid perfusate (CAP), which contains SRP bioactivity, was infused intraduodenally into recipient rats. MEK increased plasma SS concentration and inhibited secretin release and pancreatic fluid and bicarbonate secretion dose-dependently. The inhibition was partially reversed by naloxone and anti-SS serum but not by normal rabbit serum. In recipient rats, CAP increased plasma secretin level and pancreatic secretion. CAP SRP bioactivity decreased when it was collected from MEK-treated donor rats; this was partially reversed by coinfusion with naloxone or anti-SS serum. These results suggest that in the rat, MEK inhibition of acid-stimulated pancreatic secretion and secretin release involves suppression of SRP activity release. Thus the MEK inhibitory effect appears to be mediated in part by endogenous SS.
naloxone; anti-somatostatin serum; rats; fluid; bicarbonate secretion
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INTRODUCTION |
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METHIONINE ENKEPHALIN (MEK), a pentapeptide with methionine as the COOH-terminal amino acid, was originally isolated from the pituitary and identified in 1975 (11). It has been demonstrated through immunocytochemistry that MEK is widely distributed in the gastrointestinal tract and the pancreas (26). It has a powerful opiate-like effect and participates in the control of a wide variety of motor and secretory functions in the gastrointestinal tract (21). MEK has been shown to exert an inhibitory action on pancreatic exocrine secretion stimulated by duodenal acidification, exogenous secretin, and CCK in the dog (4). The inhibition by MEK appears to be caused, at least in part, by a direct effect on the exocrine pancreas. In addition, the release of secretin, and perhaps CCK, was also reduced by MEK in the dog (4). Konturek et al. (12) reported that MEK inhibited pancreatic secretion elicited by sham feeding or exogenous secretin and CCK in humans that was reversed by naloxone. Gullo et al. (8), however, found that MEK enhanced secretin- and CCK-stimulated exocrine pancreatic secretion in humans. This discrepancy may be due to the different doses of MEK used in the studies (8, 12).
We (18) reported that HCl-stimulated pancreatic exocrine secretion and secretin release are mediated by a secretin-releasing peptide (SRP), which is trypsin sensitive and heat stable. The release of SRP is regulated by a neural mechanism, particularly through mediation by capsaicin-sensitive afferent sensory neurons (17). Both MEK (26) and somatostatin (SS) (23) are found in the upper small intestine. Matsumura et al. (22) observed that duodenal acidification increased plasma endorphin-like immunoreactivity. Lucey et al. (20) reported that duodenal perfusion with acid elevated peripheral plasma levels of SS in humans. Thus it is quite possible that both MEK and SS are involved in the acid-stimulated release of SRP and secretin as well as in pancreatic exocrine secretion. The relationship of MEK and SS in acid-stimulated pancreatic exocrine secretion and release of SRP and secretin has not been studied.
The aim of the present study was to investigate in anesthetized rats the effect of MEK on pancreatic secretion and the release of secretin and SRP bioactivity in response to duodenal acidification and the role of endogenous SS in the inhibitory effect of MEK.
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MATERIALS AND METHODS |
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Materials. The agents used in the present study were from the following sources. MEK was obtained from Bachem (Torrance, CA), and naloxone was from Du Pont Pharmaceuticals (Manati, PR). Synthetic porcine secretin was a gift from Dr. David Coy (Tulane University, New Orleans, LA), and goat anti-SS serum was a gift from Dr. A. Arimura (Tulane University). A rabbit anti-secretin serum with a titer of 1:1,000,000 and a rabbit anti-SS serum with a titer of 1:150,000 were both produced in our laboratory.
Animal preparation. Adult male Sprague-Dawley rats weighing 230-280 g were fasted for 24 h with free access to drinking water before surgery. Anesthetized rats with pancreatobiliary cannulas and isolated upper small intestinal loops were prepared as described previously (17, 18).
Preparation of concentrated acid perfusate in donors.
The upper small intestinal loop of each donor rat was washed with 40 ml
of 0.15 M NaCl to remove the remaining pancreatic juice and bile. HCl
(0.01 N) was then perfused into the loop at a rate of 0.3 ml/min for
1.5 h while bile and pancreatic juice were continuously diverted
(17, 18). The perfusate was collected from the distal end
of the loop with an ice-chilled beaker and centrifuged. The supernatant
solution was concentrated by ultrafiltration as described previously
(17, 18). The concentrate of the acid perfusate (CAP) was
adjusted to pH 7.0 and reinfused into recipient rats via the duodenal
cannula of the upper small intestinal loop to test for SRP bioactivity.
NaCl (0.15 M) was also infused into the upper small intestinal loop of
each donor rat, and the perfusate was collected and treated in the same
way as CAP. The concentrated saline perfusate (CSP) was adjusted to pH
7.0 and reinfused into recipient rats as a control group. MEK (40 µg · kg1 · h
1), MEK plus
naloxone (20 µg · kg
1 · h
1), MEK plus
rabbit anti-SS serum (1 ml/rat), or MEK plus normal rabbit serum (1 ml/rat) was administered intravenously 30 min before intraduodenal
perfusion with 0.01 N HCl. The perfusate was collected and concentrated
as described above.
Experimental procedure. After the upper small intestine was washed with 40 ml of 0.15 M NaCl administered intraduodenally, each animal was infused intraduodenally with 0.15 M NaCl at 0.3 ml/min for 1 h as the basal period. Various treatments were administered intravenously after the basal period. Pancreatic juice was continuously collected in 30-min intervals through the entire experiment period for determination of fluid volume and bicarbonate output while bile was diverted. In some rats, blood was drawn from the abdominal aorta at the end of the experiments to determine plasma concentrations of secretin and SS.
To study the effect of MEK on acid-stimulated release of secretin and pancreatic secretion, we infused 42 rats with 0.01 N HCl for 2 h. During the second hour of HCl infusion, MEK was administered intravenously at 5, 10, 20, 40, or 80 µg · kgMeasurement. Pancreatic juice was collected by inserting the pancreatic cannula into a glass micropipette. The volume of pancreatic juice collected in 30-min intervals was determined by measuring the length of pancreatic juice in the micropipette. A 10-µl aliquot of pancreatic juice was immediately taken for measurement of bicarbonate concentration by a CO2 analyzer (Beckman Instruments, Fullerton, CA) as described previously (17, 18). Plasma secretin and SS levels were measured by the corresponding specific RIA as described previously (3, 27).
Statistical analysis. All data are presented as means ± SE. The percent increase over basal pancreatic secretion was calculated by comparing pancreatic secretion including flow volume and bicarbonate output measured during the 1-h basal period with that during the last hour in the treatment period. The differences in responses among experimental groups were analyzed using ANOVA. The difference between two treatment means was determined by Tukey's post hoc test. Statistical significance was established at P < 0.05.
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RESULTS |
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Effect of MEK on pancreatic secretion and plasma
secretin in response to duodenal acidification.
Intraduodenal infusion of 0.01 N HCl significantly increased pancreatic
juice volume (36.9 ± 4.6 vs. 17.8 ± 1.8 µl/30 min, P < 0.01), bicarbonate output (2.02 ± 0.31 vs.
0.85 ± 0.20 µeq/30 min, P < 0.01), and plasma
secretin level (8.8 ± 1.5 vs. 1.7 ± 0.3 pM,
P < 0.01) compared with the basal period. MEK, given
intravenously at graded doses (5-80
µg · kg1 · h
1),
dose-dependently suppressed the increases in pancreatic exocrine secretion and plasma secretin concentration in response to duodenal acidification (Fig. 1). MEK at 10 µg · kg
1 · h
1 was the
minimal dose that significantly inhibited the acid-induced pancreatic
exocrine secretion. On the other hand, a significant inhibition of
plasma secretin level occurred at 40 µg · kg
1 · h
1 MEK or
above (Fig. 1).
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Plasma concentration of SS in response to acid or
MEK administration.
The basal plasma level of SS was 14.6 ± 4.1 pM. After
intraduodenal administration of 0.01 N HCl, plasma SS level rose to 29.8 ± 7.3 pM (P < 0.05). Intravenous infusion
of MEK in graded doses ranging from 10 to 80 µg · kg1 · h
1 also
increased plasma concentration of SS in a dose-related manner. However,
MEK significantly increased plasma SS concentration over the basal
level only when 40 µg · kg
1 · h
1 or a larger
dose was given (Fig. 2).
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Effect of naloxone on acid-stimulated pancreatic secretion and
release of secretin.
Naloxone (20 µg · kg1 · h
1) alone did
not influence basal pancreatic secretion and the release of secretin or
SS. Dooley et al. (5) also observed that naloxone had no
effect on basal pancreatic secretion of fluid and bicarbonate in the
dog. However, naloxone partially reversed inhibition by MEK (40 µg · kg
1 · h
1) of
acid-stimulated pancreatic secretion (53.8% in flow volume and 55.2%
in bicarbonate output) and secretin release (7.1 ± 0.6 vs. 5.3 ± 0.5 pM) (Fig. 3).
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Effect of anti-SS serum on inhibitory effect of
MEK.
Intravenous injection of rabbit anti-SS serum (1 ml/rat) did not
influence basal pancreatic exocrine secretion and the release of
secretin. However, the anti-SS serum significantly reversed the
inhibitory effect of MEK on acid-stimulated pancreatic secretion and
the release of secretin (7.7 ± 0.8 vs. 5.3 ± 0.5, P < 0.05) (Fig. 4,
right). The inhibition by MEK of pancreatic exocrine secretion including flow volume and bicarbonate output was completely reversed by the anti-SS serum (Fig. 4). In contrast, normal rabbit serum did not influence the effect of MEK (Fig. 4).
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Effect of MEK on acid-induced release of
SRP bioactivity.
Infusion of CAP into the small intestinal loop of recipient rats (Fig.
5) markedly increased the volume of
pancreatic juice by 79.4 ± 7.3% and bicarbonate output by
146.9 ± 11.1% (P < 0.01). Plasma secretin level
also increased from 1.2 ± 0.4 to 4.7 ± 0.7 pM
(P < 0.05). These effects were shown to be caused by
the release of SRP activity in duodenal acid perfusate (17,
18). In contrast, CSP did not influence the release of secretin
or pancreatic exocrine secretion (data not shown). Infusion of CAP from
MEK-pretreated donor rats produced 44% less pancreatic fluid and
68.1% less bicarbonate secretion (Fig. 5). The plasma secretin level
was also reduced to 2.3 ± 0.4 pM (Fig. 5, right).
These results indicated decreased SRP activity in MEK-pretreated CAP.
However, the reduction of SRP activity by MEK was partially reversed by
pretreatment of donor rats with MEK in the presence of naloxone (51.3%
in fluid volume, 79.4% in bicarbonate output, and 4 ± 0.3 pM in
plasma concentration of secretin). This result suggested that an opiate receptor or receptors are involved in regulation of the acid-stimulated release of SRP activity.
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Effect of anti-SS serum on inhibition of
SRP release by MEK.
As shown in Fig. 6, CAP obtained from the
donor rats pretreated with MEK in the presence of the anti-SS serum
produced a greater pancreatic secretion than the MEK-pretreated CAP
(68.4 ± 16.2% in volume flow and 74.0 ± 18.1% in
bicarbonate output). In addition, plasma secretin
concentration (4.8 ± 0.7 pM) was restored to the same level as
that produced by control CAP. These results indicated that the anti-SS
serum reversed the MEK inhibition of acid-elicited release of SRP
activity in donor rats. On the other hand, pretreatment of donor rats
with MEK in the presence of a normal rabbit serum did not affect
reduction by MEK of SRP activity in CAP (data not shown).
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DISCUSSION |
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In the present study we have demonstrated that MEK
dose-dependently inhibited the release of secretin and pancreatic
secretion of fluid and bicarbonate in response to duodenal
acidification in anesthetized rats. The inhibitory effect of MEK was
significantly reversed by naloxone, indicating mediation by an opiate
receptor or receptors. This observation confirmed previous observations on the same effect of MEK in dogs (4, 13) and humans
(12). In addition, the present results also indicated that
MEK at 40 µg · kg1 · h
1
or higher significantly increased plasma concentration of SS. The role
of SS in MEK-evoked inhibition of acid-stimulated release of secretin
and pancreatic exocrine secretion therefore was tested. The observation
that the anti-SS serum, but not normal rabbit serum, reversed the
inhibitory effect of MEK clearly suggested that endogenous SS mediates
the actions of MEK on acid-stimulated secretin release and pancreatic
exocrine secretion. It should be noted that although plasma
concentration of SS is elevated in anesthetized rats (33),
it does not affect basal pancreatic exocrine secretion
(32). The observation made in the present study, however,
confirmed the previous notion that endogenous SS is involved in
regulation of stimulated pancreatic exocrine secretion
(32).
We reported previously (18) that duodenal acidification-stimulated release of secretin and pancreatic exocrine secretion is mediated through the release of SRP activity in the intestinal lumen. Thus CAP obtained from donor rats was shown to contain a heat-stable and trypsin-sensitive low-molecular-mass (<10 kDa) substance(s) that stimulated secretin release and pancreatic exocrine secretion on infusion into the upper small intestinal lumen of the recipient rats. Administration of a specific anti-secretin serum abolished CAP-stimulated pancreatic exocrine secretion, suggesting that the effect of CAP on the pancreas is mediated through the release of secretin (18). The results of the present study indicated that such a SRP activity in CAP was substantially reduced when CAP was obtained from MEK-pretreated donor rats. Moreover, pretreatment of donor rats with MEK together with naloxone or anti-SS serum partially but significantly reversed the reduction of SRP activity in CAP. Thus it may be concluded that inhibition of acid-stimulated secretin release and pancreatic exocrine secretion by MEK is at least in part mediated through inhibition of the release of SRP activity. This action of MEK involves an opiate receptor-mediated process that is also mediated through the release of endogenous SS.
The mechanism through which SS mediates MEK-elicited inhibition of acid-stimulated release of secretin is not clear at present. Both peptides were shown to inhibit low pH-stimulated secretin secretion from mucosal explants isolated from canine duodenum (24). In addition to its presence in the mucosal endocrine cells (25), SS is also present in the submucosal plexus and nerve fibers projecting to the intestinal mucosa in various mammalian species (1, 7, 9, 19). Similarly, MEK-immunoreactive nerve fibers have been found to innervate the mucosa and submucosal plexus of human duodenum (7). SS is released from human submucosal neurons in vitro (2). Both MEK and SS have been shown to inhibit calcium current in guinea pig submucosal neurons (31) and cholera toxin-induced net fluid secretion and vasoactive intestinal polypeptide release from cat jejunum (6). In addition, SS receptors are expressed in enterocytes and in the submucosal plexus of rat intestine (29). Thus it is possible that exogenous MEK in the present study could act on either mucosal SS-containing nerve fibers or the intestinal D cells to release SS, which in turn inhibit the release of secretin by acting either directly on S cells or through inhibition of SRP release or both. These questions require further study.
The mechanism through which SS mediates MEK-elicited inhibition of acid-stimulated pancreatic exocrine secretion is also unclear. Larsson (14) demonstrated that immmunoreactivity of MEK is located in nerve fibers in the endocrine and exocrine pancreas. In addition, pancreatic extract from guinea pigs was shown to contain peptides eluting with similar characteristics to MEK on HPLC (30). In isolated and perfused rat (28) and dog (10) pancreas, MEK was shown to stimulate SS release, suggesting that SS may mediate the action of MEK on the pancreas. The result of the present study has indicated that inhibition of pancreatic exocrine secretion by MEK is completely reversed by cotreatment with the anti-SS serum. In previous studies using isolated and perfused rat (16) and canine (15) pancreas, we showed that endogenous insulin is required for stimulation of pancreatic exocrine secretion by secretin and CCK. Thus infusion of secretin and CCK in the presence of a specific anti-insulin serum abolished the stimulatory effect of the two gut hormones. Coinfusion of the two gut hormones with the anti-insulin serum resulted in an elevation of SS and pancreatic polypeptide in the portal venous effluent. Coinfusion with the anti-insulin serum together with an anti-SS serum, however, restored secretin, and CCK stimulated pancreatic secretion of fluid and bicarbonate (15, 16), thereby suggesting that endogenous SS from the pancreas plays a negative regulatory role in pancreatic exocrine secretion. Thus it is very likely that MEK inhibits pancreatic secretion through stimulation of SS release from the pancreatic islet. However, we cannot rule out the possibility that MEK acts to elicit SS release through the enteric nerves, which exert an inhibitory effect on the pancreas via an enteropancreatic reflex mechanism. This matter requires further study to be resolved.
In summary, MEK inhibited acid-stimulated pancreatic exocrine secretion and the release of secretin through suppression of the release of SRP bioactivity. The inhibitory effect of MEK appears to be mediated by endogenous SS in the rat. Further study is required to determine whether this regulatory mechanism plays a significant role under normal physiological conditions.
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ACKNOWLEDGEMENTS |
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We thank Norene Buehner, Frank Roth, and Laura Braggins for technical assistance and Pat Faiello for manuscript preparation.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-25962.
Address for reprint requests and other correspondence: W. Y. Chey, Rochester Inst. for Digestive Diseases and Sciences, 222 Alexander St., Suite 3100, Rochester, NY 14607 (E-mail: w.y.chey{at}inetmail.att.net).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 1 March 2000; accepted in final form 13 December 2000.
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