1 Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis 95616; 2 CURE: Digestive Diseases Research Center, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles 90073; and 3 Digestive Diseases Division, School of Medicine, University of California, Los Angeles, California 90024
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ABSTRACT |
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We examined the role of CCK-A receptors in acid
inhibition by intestinal nutrients. Gastric acid and plasma CCK and
gastrin levels were measured in rats with gastric and duodenal fistulas during intragastric 8% peptone and duodenal perfusion with saline, complete liquid diet (CLD; 20% carbohydrate, 6% fat, and 5%
protein), and the individual components of CLD. Acid output was
significantly inhibited (50-60%) by CLD, lipid, and
dextrose. Plasma CCK was significantly increased by CLD (from 2.6 ± 0.3 to 4.8 ± 0.5 pM) and lipid (4.6 ± 0.5 pM). CCK
levels 50-fold higher (218 ± 33 pM) were required to achieve
similar acid inhibition by exogenous CCK-8 (10 nmol · kg1 · h
1 iv).
Intestinal soybean trypsin inhibitor elevated CCK (10.9 ± 2.5 pM)
without inhibiting acid secretion. The CCK-A antagonist MK-329 (1 mg/kg
iv) reversed acid inhibition caused by CLD, lipid, and dextrose.
Peptone-stimulated gastrin (21.7 ± 1.9 pM) was significantly inhibited by CLD (14.5 ± 3.6 pM), lipid (12.3 ± 2.2 pM),
and dextrose (11.9 ± 1.5 pM). Lipid and carbohydrate inhibit acid
secretion by activating CCK-A receptors but not by altering plasma CCK concentrations.
gastric acid secretion; enterogastrone; intestinal phase; cholecystokinin; peptone meal
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INTRODUCTION |
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GASTRIC ACID SECRETION IS regulated by both stimulatory and inhibitory mechanisms that are initiated by the ingestion of food and the presence of nutrients and digestive secretions in the gut lumen. Strong inhibition of acid secretion occurs when certain nutrients enter the small intestine during gastric emptying of a meal. Of the macronutrients comprising a normal mixed meal, carbohydrates (12) and lipids (15) inhibit acid secretion, whereas protein (10, 13) stimulates acid output. Hormonal, paracrine, and neural inhibitory pathways are involved in acid inhibition by luminal nutrients. However, no single regulatory factor (hormone, paracrine agent, or neurotransmitter) has been shown to play a physiological role in inhibition of gastric acid secretion in response to all dietary nutrients.
Dietary lipid has been a carefully defined luminal inhibitor of gastric acid secretion. We have shown that fat in the intestinal lumen of rats causes inhibition of meal-stimulated gastric acid secretion (15). The mechanism of fat-induced inhibition involves a combination of hormonal, paracrine, and neural pathways, including circulating somatostatin (20, 23), somatostatin released from gastric D cells (16, 18), and activation of capsaicin-sensitive vagal afferent nerves (15). The mechanism also appears to depend on CCK, because a CCK-A receptor antagonist blocks inhibition caused by intestinal fat (17). However, whether CCK acts as a hormone, paracrine agent, or neurotransmitter in this mechanism is not clear. Even less is known about the role of CCK in acid inhibition caused by other nutrients.
This study was designed to define the role of CCK-A receptors in mediating inhibition of gastric acid secretion by intestinal nutrients. The contribution and mechanism of CCK-A receptor-mediated inhibition were examined by correlating plasma CCK and gastrin levels and inhibition of acid secretion in response to intestinal nutrients and by quantitating the effect of a specific CCK-A receptor antagonist.
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METHODS |
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Gastric and duodenal cannulation and intravenous catheterization in rats. Gastric and duodenal cannulas were implanted into adult (180-220 g) male Sprague-Dawley rats by modification of a previously described procedure (15). Rats were fasted (except for water) for 18 h before anesthesia was induced with pentobarbital sodium (50 mg/kg ip). The abdomen was opened, and an incision was made in the nonglandular portion of the stomach. A modified two-part Thomas cannula, assembled from an outer stainless steel sleeve and a lightweight delring insert, was inserted into the gastric corpus and sutured in place. The cannula was exteriorized through a stab incision in the ventrolateral aspect of the body wall left of midline and capped. The duodenal cannula was fashioned from a length of polyethylene (PE)-50 tubing. One end of the tubing was flared by gentle heating with a flame and inserted into the duodenum through an enterotomy incision 2 cm distal to the pylorus. The end of the tubing was tunneled subcutaneously to exit between the shoulder blades, where a few centimeters of tubing were exteriorized and secured in place with sutures. The abdomen was sutured closed. The duodenal cannula was flushed daily with saline and plugged with a small amount of petroleum jelly. An intravenous catheter fashioned from PE-50 tubing was secured in a jugular vein through a cervical incision and exited the skin adjacent to the duodenal catheter between the shoulder blades. The catheter was flushed daily with 2 ml saline and plugged with a stainless steel pin.
Rats were returned to their home cages after they had recovered from anesthesia. While recuperating, rats were accustomed to several hours of light restraint in Bollman cages. Rats were used in secretory experiments from 2 to 12 wk after surgery.Experimental protocol.
Rats were fasted for 12-18 h from food but not water and then
placed in Bollman cages. The stomach was rinsed until clean with 0.15 M
saline through the opened cannula. The outer tube of a double-lumen
plastic catheter was attached to the external portion of the gastric
cannula, and the inner tube was advanced into the stomach. During the
basal period, the stomach was rinsed with 10 ml of warm (37°C) saline
every 10 min. Acid output (µmol/10 min) was measured in each basal
sample by back titration with 0.05 M NaOH (Radiometer, Cincinatti, OH).
After 30 min, during which basal acid output stabilized, rats were
administered either MK-329 (1 mg/kg iv in 0.5 ml vehicle) or vehicle
(25 µl DMSO, 10 µl Tween 80, and 465 µl of 0.15 M saline). After
another 30-min period, 5 ml of an 8% solution of peptone (Bacto
Peptone, Difco, Detroit, MI) adjusted to pH 5.5 was infused into the
stomach and gently mixed by an oscillating pump (~20 rpm). After 10 min, the pump was stopped, and the peptone was allowed to drain through the gastric cannula into a reservoir. The stomach lumen was then gently
flushed with 10 ml saline and 5 ml air, and the contents were added to
the reservoir containing the peptone. The contents of the reservoir
(gastric secretions, 5 ml peptone, and 10 ml saline) were back titrated
to pH 5.5 as described above and adjusted each time against a control
sample containing 5 ml peptone plus 10 ml saline. From this
measurement, acid output was recorded as micromoles per 10 min. This
procedure was repeated for the next 2 h. On separate days during
the second hour of intragastric peptone perfusion, the following
substances were infused into the duodenum (0.05 ml/min): saline as
control; complete liquid diet (CLD) (20% dextrose, 5% casein, and 6%
lipid; liquid rat diet AIN-76 control, Bio-Serv, Frenchtown, NJ); 20%
dextrose (dextrose anhydrous granular powder, Fisher Scientific,
Pittsburgh, PA); 5% casein (Sigma Chemical, St. Louis, MO); 6% lipid
emulsion (Intralipid, KabiVitrum, Alameda, CA); or 2% soybean trypsin
inhibitor (STI; Sigma Chemical). At the end of the hour of duodenal
perfusion, blood was drawn from the venous catheter for measurement of
CCK and gastrin. To maintain hydration, rats were given a continuous intravenous infusion of saline (0.05 ml/min) throughout the experiment. In a separate experiment, rats received CCK-8 (10 nmol · kg1 · h
1 iv) during
the second hour of intragastric peptone. This dose was determined in
preliminary studies to produce a similar degree of inhibition of acid
secretion as seen with intestinal nutrients (dose response curve not
shown). In these rats, blood was drawn from a catheter placed in the
aorta to avoid contamination by the exogenously infused CCK-8.
CCK and gastrin RIA.
Blood samples were placed into tubes containing 100 IU heparin. Plasma
was separated by centrifugation and stored at 70°C. Extractions and
assays of plasma CCK (3, 27) and gastrin (5,
19) were performed as described previously.
Chemicals. Peptone was prepared as an 8% (isotonic, 295 mosM) solution in water, adjusted to pH 5.5 with 6 M HCl, and warmed to 37°C before intragastric instillation. CLD was made by blending 1,029 g of the powdered diet in 3,360 ml of cold (<10°C) water for 20-30 s at low speed. A 20% solution of dextrose was made by dissolving 20 g dextrose in 100 ml saline. A 5% solution of casein was made by dissolving 5 g casein in 100 ml of 0.15 M saline. Lipid emulsion was diluted from 20% to 6% with saline to maintain an isotonic solution and pH between 6 and 7. MK-329 (a gift from R. Freidinger, Merck Sharp and Dohme Research Laboratories, West Point, PA) was dissolved in 25 µl DMSO, sonicated briefly after the addition of 10 µl Tween 80, and brought to a total volume of 500 µl with saline before slow intravenous injection.
Data analysis. Acid secretion data is presented as acid output vs. time (in µmol/10 min). For statistical analyses, n was the number of rats in each treatment group (if more than 1 identical experiment was performed with an animal, data were averaged). The average percent inhibition of peptone-stimulated acid output was calculated by dividing stable acid output values during intragastric peptone plus intestinal nutrient perfusion (the last 30 min of hour 2) by stable acid output values during intragastric peptone alone (the last 30 min of hour 1), subtracting the quotient from 1, and multiplying the difference by 100. Plasma gastrin and CCK concentrations are presented as picomoles vs. treatment. The significance of treatment effects (P < 0.05) was assessed by Student's t-test or ANOVA; nonparametric methods were used if preliminary testing for normality of the data failed. Appropriate corrections were made for multiple comparisons.
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RESULTS |
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Peptone-stimulated acid output.
In vehicle-treated rats (Fig.
1B), intragastric peptone
markedly increased acid output to a stable plateau about fourfold higher than basal values. Acid output during the 30- to 60-min period
of intragastric peptone (83 ± 8 µmol/10 min, n = 12) was similar to that in response to a maximal intravenous dose (20 µg · kg1 · h
1) of
pentagastrin (87 ± 6 µmol/10 min, n = 5; Fig.
1A). Acid output fell slightly (8 ± 8%) and
insignificantly to 73 ± 7 µmol/10 min during the 90- to 120-min
period of intragastric peptone. Figure 1B also shows that
administration of MK-329 significantly increased the acid response to
intragastric peptone by 17% (P < 0.05). The volumes
of meal recovered from the stomach before and after MK-329 treatment
did not differ significantly (Table 1).
Basal acid output in 63 rats was 21 ± 1 µmol/10 min and
was not affected by administration of the vehicle used for MK-329
(20 ± 1 µmol/10 min). In a separate group of 39 rats analyzed
for any effects of MK-329 on basal acid output, 1 mg/kg iv MK-329 also
had no statistically significant effect on unstimulated acid output
(21 ± 2 vs. 23 ± 2 µmol/10 min).
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Effect of dietary nutrients alone or with MK-329 on
peptone-stimulated acid output.
Intraduodenal administration of saline (3 ml/h) had no significant
effect on peptone-stimulated acid secretion when values were compared
before and during saline (Fig. 1B) or in separate groups of
rats without saline perfusion (data not shown). In contrast, intraduodenal administration of CLD resulted in a marked decrease in
peptone-induced acid output (Fig. 2),
with acid secretion declining 60 ± 7% from the initial
plateau. This effect was completely reversed by prior treatment
with the CCK-A receptor antagonist MK-329 (Fig. 2). The effects of the
individual nutrient components of CLD on acid secretion are shown in
Fig. 3. Intestinal perfusion with 6%
Intralipid and 20% dextrose elicited acid inhibition similar to that
caused by CLD (Fig. 3); MK-329 also completely reversed the inhibitory
effects of both nutrients. However, intraduodenal administration of 5%
casein did not affect peptone-induced acid output, either alone or with
prior MK-329 (Fig. 3). A summary and statistical analysis of these data
are shown in Fig. 4. Intestinal perfusion
with CLD or its lipid or carbohydrate components strongly (50-60%) and significantly (P < 0.05 and 0.01)
reduced acid secretion stimulated by intragastric peptone.
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Effects of dietary nutrients on plasma CCK and gastrin levels. Intragastric peptone did not alter plasma CCK concentrations compared with values in fasting rats (2.6 ± 0.3 vs. 2.8 ± 0.2 pM, n = 12). Significant (P < 0.05) increases in CCK occurred during intestinal perfusion with CLD (4.8 ± 0.9 pM, n = 9) and lipid (4.6 ± 1.0 pM, n = 7) but not with casein (4.2 ± 1.0 pM, n = 7) or dextrose (2.2 ± 0.6 pM, n = 7). Intragastric peptone significantly (P < 0.05) increased circulating levels of gastrin (21.7 ± 1.9 pM, n = 12) compared with values in fasting rats (4.1 ± 2.1 pM, n = 12). Gastrin levels were significantly lower during intestinal perfusion with CLD (14.5 ± 3.6 pM, n = 9), lipid (12.3 ± 2.2 pM, n = 7), and dextrose (11.9 ± 1.5 pM, n = 7).
Effects of CCK-8 and intestinal perfusion with STI.
Two other conditions were examined to further define the
relationship between circulating CCK levels and inhibition of
peptone-induced acid secretion. Intravenous administration of CCK-8 at
10 nmol · kg1 · h
1
inhibited peptone-induced acid secretion to a similar degree as CLD,
lipid, and dextrose (Fig. 5). Prior
treatment with MK-329 reversed this effect (Fig. 5). CCK-8 at
10 nmol · kg
1 · h
1
increased plasma CCK to 218 ± 33 pM (n = 5).
Intestinal perfusion with STI markedly increased plasma CCK (10.9 ± 2.9 pM, n = 9) but had no effect on acid secretion
(Fig. 6).
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DISCUSSION |
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In awake rats, duodenal perfusion with CLD mimicking the daily diet of the laboratory rat (22, 33) significantly inhibited by approximately one-half the gastric acid response to a peptone meal instilled intragastrically. The acid inhibition was slow in onset, reaching maximum inhibition by 30-40 min after the start of intestinal perfusion. In addition, when nutrient components in concentrations (20% carbohydrate, 6% fat, and 5% protein) similar to those in CLD were administered individually into the duodenum, acid output was variably inhibited compared with CLD. Of the nutrient components tested, lipid and dextrose were the most effective and inhibited acid output by 61% and 51%, respectively. In comparison, casein had no significant effect. Plasma gastrin levels showed the same patterns of response to peptone and intestinal nutrients. Therefore, the acid inhibition by a natural diet depends on the characteristics of individual components. Furthermore, because the inhibitory effects are not additive, these results suggest that the mechanisms mediating acid inhibition share a common pathway.
One such pathway could be mediated by CCK acting as a hormone, paracrine agent, or neurotransmitter. To address this question, we first studied the regulation of gastric acid secretion induced by a meal. Intragastric peptone is a well-characterized stimulant of gastric acid secretion. The stimulatory effects of peptone are primarily mediated through gastrin/CCK-B receptors (2, 28, 29) and neural (21, 25) pathways. However, we now find that there is also an inhibitory component of a peptone meal on gastric acid secretion. We observed that MK-329 enhances peptone-stimulated acid output, consistent with similar studies in dogs (14). Even though experiments were conducted in rats in which the pylorus was patent and not ligated, the effect of MK-329 was not due to emptying of a portion of the peptone meal into the duodenum. Measurement of the residual volume of the peptone meal remaining in the stomach 10 min after intragastic administration indicated that nearly all of the peptone meal was recovered, and there was no significant difference between treatment groups. An important additional finding was that plasma CCK was not increased over basal levels by intragastric peptone in our study. Taken together, these observations enabled us to hypothesize that endogenous CCK acts as a paracrine agent or neurotransmitter, rather than as a hormone, to inhibit peptone-induced acid secretion.
To further test this hypothesis, we used the following two approaches: examining the patterns of acid inhibition by intestinal nutrients and the effects of MK-329 and measuring plasma CCK and gastrin levels in response to the same intestinal nutrients. In earlier studies in dogs (17) and rats (15), we determined that CCK-A receptors are important in mediating lipid-induced inhibition of meal-stimulated acid secretion. In this study, we found that CCK-A receptors play an even broader role in intestinal phase regulation of acid secretion. Acid inhibition caused by CLD was reversed by MK-329. Furthermore, MK-329 reversed acid inhibition caused by individual intraduodenal infusions of lipid and dextrose. This effect was not due to changes in gastric emptying. Therefore, CCK-A receptors play an important physiological role during intestinal phase regulation of gastric acid secretion. Our conclusion is supported by experiments (26) performed in Otsuka Long-Evans Tokushima fatty rats, which do not express CCK-A receptors; in these rats, intestinal perfusion with lipid fails to inhibit gastric acid secretion.
The second aspect of our study was to examine the pathway (hormonal, paracrine, or neural) involved in acid inhibition by CCK. We found no relationship between plasma CCK levels and the degree of acid inhibition caused by intestinal nutrients. Additionally, acid inhibition was not produced by supraphysiological levels of endogenous CCK (in response to intestinal STI) but only by pharmacological levels of exogenously administered CCK. These data provide strong evidence against either a hormonal or paracrine inhibitory pathway for CCK. A peripheral afferent neural pathway is also unlikely to mediate acid inhibition by CCK. In earlier findings in rats (18), capsaicin treatment had no effect on acid inhibition caused by exogenous infusion of CCK but significantly reduced the acid inhibition by intestinal lipid. This line of reasoning suggests that MK-329 blocked the acid inhibitory effects of nutrients by acting on CCK-A receptors in the central nervous system.
Studies (30, 33) have shown that intestinal nutrients, including lipid and dextrose, activate central nervous system neurons, as evidenced by brain stem c-FOS expression. This effect is reversed by MK-329 administration (30). The fact that MK-329 is freely permeable across the blood-brain barrier supports acid inhibition by centrally acting CCK-A receptors (31). Although peripherally administered CCK can also activate brain stem c-FOS expression (6, 7, 34), the doses required to produce this action are likely supraphysiological in terms of acid inhibition. They do not elicit acid inhibition themselves and yet they achieve circulating levels substantially greater than those after intestinal perfusion with lipid or dextrose, which markedly inhibit meal-stimulated acid secretion.
Several other substances, including secretin (23), peptide YY (1, 11), neurotensin (4, 8), and somatostatin (20), can inhibit acid output. However, specific blockade of each of these factors does not reverse the inhibitory effect of intestinal fat on a physiological (i.e., meal stimulation) level of acid secretion as effectively as does blockade of CCK-A receptors. Furthermore, the inhibitory effects of these substances are not blocked by MK-329. Therefore, although CCK is not the sole mediator of acid inhibition induced by intestinal nutrients, it appears to be one of the most important.
In summary, intestinal lipid and dextrose strongly inhibit peptone-stimulated gastric acid secretion. CCK-A receptor antagonism reverses these inhibitory effects of lipid and dextrose. Plasma CCK is not correlated with the degree of acid inhibition. These results suggest that intestinal nutrients inhibit gastric acid secretion through centrally located CCK-A receptors.
Perspectives. Final definition of the location of the CCK-A receptors mediating intestinal nutrient-induced inhibition of gastric acid secretion will require the use of permeant and nonpermeant receptor antagonists, as has been done for regulation of food intake (31). The efferent pathways responsible for inhibition of acid secretion by postulated central CCK-A receptors have not been identified. One possible pathway may involve gastric somatostatin. In an earlier study (18), acid inhibition by exogenous CCK was completely reversed by immunoneutralization of somatostatin. Furthermore, acid inhibition caused by activation of CCK-A receptors depends on somatostatin in rats (18), dogs (9), sheep (32), and humans (24).
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ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant DK-45752 (K. C. K. Lloyd), the Medical Research Service of the Veterans Administration (T. E. Solomon), and NIDDK Animal Models Core Grant DK-41301.
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FOOTNOTES |
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Address for reprint requests and other correspondence: K. C. Kent Lloyd, Center for Comparative Medicine, One Shields Ave., Univ. of California, Davis, CA 95616-8732 (E-mail: kclloyd{at}ucdavis.edu).
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 2 January 2001; accepted in final form 23 May 2001.
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