GASTROENTEROLOGY

1992;103:1215-1220

Effect of Loxiglumide on Basal and Gastrinand Bombesin-Stimulated Gastric Acid and Serum Gastrin Levels MAX C. W. JEBBINK, CORNELIS B. H. W. LAMER& LUCIO C. ROVATI, and JAN B. M. J. JANSEN Departments of Gastroenterology and Hepatology, University The Netherlands: and Rotta Laboratories: MO&~, Italy

The effect of the specific cholecystokinin-receptor antagonist loxiglumide on basal and bombesin-, and gastrin 17-I-stimulated gastric acid secretion and serum gastrin levels was studied in 12 healthy subjects. Loxiglumide (10 mg * kg-’ * h-‘) significantly augmented basal gastric acid output from 1.8+ 0.3to 3.9 + 0.8mmol H+/h (P < 0.005) but did not significantly influence integrated basal serum gastrin concentrations (2 f 21 vs. 32 + 21 pmol L-l - h-l). Both gastric acid secretion and integrated serum gastrin concentrations stimulated by bombesin infusion (92.8 pmol- kg-‘. h-l) were significantly augmented by loxiglumide [from 4.0 f 0.3 to 10.0 +- 1.3mmol H+/h (P c 0.005) and from 1251 f 93 to 2558 f 208 pmol . L-l+ h-’ (P < 0.005), respectively]. Gastric acid output and serum gastrin concentrations during infusion of 5 pmol - kg-’ h-l of synthetic human gastrin 17-I (9.8 + 2.9 mmol H+/h and 1045 + 177 pmol - L-’ - h-‘) and during infusion of 15 pmol - kg-’ - h-l of gastrin 17-I (14.5 + 3.1 mmol H+/h and 2412 f 312 pmol - L-’ . h-l) were not significantly influenced by loxiglumide (10.3 + 2.3 mmol H+/h and 1291 + 257 pmol- L-’ -h-’ for the 5pmol . kg-’ * h-l gastrin 17-I infusion dose with loxiglumide and 13.8 f 3.4 mmol H+/h and 2811 + 305 pmol . L-l - h-’ for the 15-pmol - kg-’ * h-’ gastrin 17I infusion dose with loxiglumide). These data indicate that endogenous cholecystokinin inhibits gastric acid secretion under basal conditions and gastrin release and gastric acid secretion during infusion of bombesin in humans and suggest that the augmented effect of loxiglumide on bombesin-stimulated gastric acid secretion may be explained largely by enhanced gastrin release. ??

R

egulation of gastric acid secretion is a complex interplay between neurocrine [e.g., cholinergic, adrenergic, peptidergic (bombesin)], paracrine (e.g., somatostatin, histamine), and endocrine [e.g., gastrin, enterogastrones (cholecystokinin)] mechanisms. The role of cholecystokinin (CCK) in the regulation of gastric acid secretion is of particular interest because CCK and gastrin share an identical penta-

DIANA

M. MOOY,

Hospitals of Leiden and Nijmegen,

peptide in the biologically active part of the molecule.lw3 Indeed, CCK is a competitive gastrin agonist when tested in vitro, stimulating gastric acid secretion from isolated parietal cells.* In vivo, however, CCK inhibits stimulated gastric acid secretion.5-g Previous studies have emerged that CCK occupies at least two subtypes of receptors10-‘2: the type B receptor, which is nonselective because gastrin is also able to bind to this type of receptor,13*‘* and the specific type A receptor, by which CCK stimulates gallbladder contraction and pancreatic enzyme secretion.‘5-‘8 Specific CCK type A receptors have also been shown on somatostatin (SS)-producing D cells in the gastric mucosa. *‘JOBecause CCK inhibits stimulated gastric acid secretion in vivo, it has been hypothesized that this inhibition is achieved by stimulating SS release from these D cells in the gastric mucosa.lg In previous studies we have shown that the amphibian peptide bombesin (BBS), of which the mammalian counterpart gastrin-releasing peptide (GRP) is present in nerves of human gastric tissue, stimulates gastrin release and subsequently gastric acid secretion.21-23 In addition, we have shown that BBS stimulates not only gastrin release but also CCK secretion into the systemic circulation.24~25 In the present study we have investigated the interaction of basal and BBS-stimulated gastrin and CCK on gastric acid secretion and gastrin release by infusing saline and BBS with and without the specific CCK type Areceptor antagonist loxiglumide into healthy subjects. We compared these results with those obtained during infusion of synthetic human gastrin 17-Iwith and without a background infusion of loxigumide, resulting in circulating gastrin levels comparable to those obtained during the BBS-infusion experiments. Materials and Methods Twelve healthy volunteers (6 women, 6 men; mean participated in this study. In each sub-

age, 23 + 2 years)

0 1992 by the American

Gastroenterological 0016-5065/92/$3.00

Association

1216

JEBBINK ET AL.

ject, two tests were performed in random order at different days separated by at least 1 week. After an overnight fast, the volunteers presented at the laboratory at 8:30 AM. A polyvinyl nasogastric tube and a thin polyethylene perfusion catheter were placed with the tips in the most dependent part of the stomach. The position of the tube was checked by the water-recovery test,26 then the polyethylene perfusion catheter was pulled back about 10 cm. During the experiments, the stomach was continuously perfused through this catheter with a phenol red solution (3 mg/L in 0.9% NaCl) at a rate of 220 mL/15 min to correct for pyloric losses.27 Gastric contents were aspirated continuously during the experiments using a suction pump, which provided intermittent negative pressure. The aspirate was separated into ‘15-minute portions. After an equilibration period, four 15-minute samples were collected under unstimulated conditions. Subsequently, an intravenous infusion of loxiglumide (a loading dose of 2.5 mg. kg-‘- 10 min-‘, followed by 10 mg -kg-’ - h-’ for 110 minutes) or saline was started in random order. Sixty minutes after the start of the infusion of loxiglumide or saline, BBS (92.6 pmol-kg-‘-h-‘) was infused intravenously for 60 minutes. Blood samples for measurement of serum gastrin levels were drawn every 15 minutes during these two experiments. Six of the 12 subjects participated in a second study in which two additional experiments were carried out in random order, separated by at least 1 week. In this second study the synthetic unsulfated heptadecapeptide of human gastrin was infused in a dose of 5 pmol - kg-’ - h-‘, followed by 15 pmol - kg-’ - h-’ against a background infusion of saline or loxiglumide (a loading dose of 2.5 mg *kg-‘. 10 min-*, followed by 10 mg- kg-’ - h-’ for 170 minutes). Loxiglumide infusion began 60 minutes before gastrin 17-I was infused. Gastric contents were aspirated according to the same protocol. Blood samples for measurement of serum gastrin were collected at 15-minute intervals during these studies. Blood samples were collected on ice in glass tubes and centrifuged (10 minutes at 4OOOg), and the serum was stored at -20T until assayed. Serum gastrin levels were measured by a sensitive and specific radioimmunoassay as previously described. 28,2gIn brief, antibody 2604, used in the gastrin assay had equal affinity for component-I gastrin and sulfated and nonsulfated forms of gastrin 34 and gastrin 17. Binding of gastrin 14 to the antiserum was 60% compared with gastrin 17. However, because gastrin 14 constitutes only a small percentage of total circulating gastrin, the serum concentration measured with antiserum 2604 closely reflects the total amount of gastrin present. The normal range of basal serum gastrin in our laboratory is 10-40 pmol/L. Integrated serum gastrin concentrations were calculated using the trapezoidal rule as area under the serum concentration/time curves after subtraction of basal values. The volume and pH of each 15-minute gastric sample was recorded and the acid concentration determined by titration to pH 7.0 with O.lN NaOH using an automatic

titrator (Radiometer, Copenhagen, Denmark). The phenol red concentrations in the gastric samples were determined spectrophotometrically at 560 nm after filtration and alka-

GASTROENTEROLOGY Vol. 103, No.4

linization of the samples with 2.5N NaOH. Recoveries were calculated by the equation (AV x ABSJ/(PV x ABS,), in which AV represents the aspirated volume, ABS, the phenol red absorption of the aspirated volume, PV the perfused volume, and ABS, the phenol red absorption of the perfused volume. The amount of acid in the gastric samples was corrected according to the equation (Acid Concentration Measured X AV)/Recovery and expressed as millimoles of H+ per 15 minutes or as basal acid output (BAO; mmol H+/h) or peak acid output (PAO; mmol H+/ h). The experiments were approved by the local ethical committee. Informed consent was obtained from all subjects.

Statistical

Analysis

Differences were tested for statistical significance by the analysis of variance and subsequently by Student’s t test for paired and unpaired results. A P value of ~0.05 was considered

significant.

Results Compared with saline infusion, loxiglumide infusion resulted in a significant increase in mean BAO from 1.8 f 0.2 mmol H+/h to 3.9 + 0.6 mmol H+/h (P < 0.005). Integrated basal serum gastrin concentrations during saline infusion (2 it 21 pmolL-’ - h-l) were not significantly affected by loxiglumide (32 + 21 pmol - L-’ - h-l). Against a background infusion of saline, infusion of BBS significantly (P < 0.001) increased gastric acid output from 1.8 f 0.2 mmol H+/h to 4.0 f 0.3 mmol H+/h and integrated serum gastrin concentrations from 41 +- 22 pmol-L-l-h-’ to 1251 + 93 pmol-L-‘-h-l (P < 0.001). Against a background infusion of loxiglumide, BAO (3.9 + 0.6 mmol H+/h) and integrated basal serum gastrin concentrations (32 + 21 pmolL-’ 0h-‘) were significantly increased by BBS to values of 10.0 + 1.3 mmol H+/h (P < 0.005) and 2558 + 206 pmol- L-’ +h-l (P < 0.005), respectively. BBSstimulated gastric acid output and integrated serum gastrin concentrations were significantly higher against a loxiglumide background infusion than against a saline background infusion (P < 0.05). Separated 15-minute values of these experiments are shown in Figure 1. Infusion of 5 and 15 pmol. kg-‘. h-’ of synthetic human gastrin 17-I resulted in a dose-dependent increase in serum gastrin concentrations and gastric acid output (Figure 2). Infusion of 5 pmol. kg-’ - h-’ of gastrin 17-I resulted in increases in integrated serum gastrin concentration from -39 +- 32 pmol- L-’ -h-l to 1045 f 177 pmol -L-‘- h-’ (P < 0.01). These serum gastrin concentrations were not significantly different from those obtained during BBS infusion against a saline background. Infusion of

EFFECT OF LOXIGLUMIDEON GASTRICACID SECRETION

October1992

100 80

.A

nificant increase in BAO without significant alterations in basal circulating gastrin concentrations. Second, BBS-stimulated gastric acid secretion and circulating gastrin concentrations are significantly augmented by loxiglumide infusion. Third, gastric acid secretion and circulating gastrin concentrations during infusion of synthetic human gastrin 17-Iare not affected by.loxiglumide. And fourth, BBS infusion, resulting in serum gastrin concentrations in the same range as those seen during gastrin 17-Iinfusion, stimulates gastric acid secretion distinctly less than gastrin 17-Iinfusion. In contrast to previous studies in dogs,30 we have shown a twofold increase in gastric acid secretion over basal values during loxiglumide infusion in humans. These findings cannot be explained by interference of loxiglumide with unstimulated gastrin release, because basal serum gastrin concentrations are not augmented by loxiglumide. In vitro studies have shown that loxiglumide is highly specific for

SALINE OR LOXIGLUMIDE

-

80 -

-30

0

30 TIME

60

90

1217

120

(min)

Figure1. Serum gastrin concentrations (A) and gastric acid output (B) in response to bombesin infusion (92.6pmol . kg-’ - h-l) against a background infusion of saline or loxiglumide (2.5 mg . kg-’ -10 min- I, followed by 10 mg. kg-’ - h-‘) in 13 healthy volunteers. Closed bars (E) and closed squares (A) indicate BBS infusion against a saline background, hatched bars (B) and solid dots (A) indicate BBS infusion against a background infusion of loxiglumide.

15 pmol - kg-l - h-’ of gastrin 17-Iresulted in a further increase in integrated serum gastrin levels to 2412 f 312 pmol- L-’ -h-l. These levels were in the same range as those obtained during BBS infusion against a loxiglumide background. Infusion of loxiglumide did not significantly influence serum gastrin concentrations obtained during gastrin 17-Iinfusion with a saline background (1291f 257 pmol - L-’ - h-’ for the 5-pmol . kg-’ * h-’ dose and 26llk 305 pmol . L-’ - h-l for the 15-pmol - kg-’ - h-’ dose). Separated 15-minute values are presented in Figure 2. BBS and gastrin 17-Iinfusions giving comparable serum gastrin concentrations resulted in significantly different (P < 0.05) gastric acid outputs (Tables 1 and 2). Discussion The present study has several interesting findings. First, blockade of CCK receptors by the specific CCK-receptor antagonist loxiglumide results in a sig-

6 iI

_

-30

0

30

60

90

TIME

(min)

120

150

I

180

Figure 2. Serum gastrin concentrations (A) and gastric acid output (B) in response to two different doses of gastrin 17-I (5 pmol - kg-‘. h-l, followed by 15 pmol -kg-’ *h-‘) against a background infusion of saline or loxiglumide (2.5 mg . kg-’ *10 min-‘, followed by 10 mg - kg-’ - h-‘) in six healthy volunteers. Closed bars (B) and solid squares (A) indicate gastrin infusion against a saline background; hatched bars and solid dots indicate gastrin infusion against a background infusion of loxiglumide.

1218

JEBBINK ET AL.

Table 1. Gastric

GASTROENTEROLOGY Vol. 103,No. 4

Acid Output

in Response to BBS and Gastrin

17-I Infusion

With a Background

Infusion

of Loxiglumide

or

Saline Acid output (mmol H+/h) Basal Saline Loxiglumide

1.8 * 0.2 3.9 + 0.6d

BBS

Gastrin 17-I (5 pmol/L)

4.0+ 0.3O 10.0+ 1.3O.d

Gastrin 17-I (15 pmol/L)

9.6It2.90,b 10.3+ 2.3'

14.5+ 3.1OJ 13.6f 3.4a

NOTE. BBS infusion, 92.6 pmol. kg-‘. h-‘, n = 12;gastrin 17-Iinfusion, 5 and 15 pmol. kg-‘. h-‘, n = 6;loxiglumide for 10 minutes, followed by 10 mg. kg-‘. h-‘. “P < 0.005 compared with basal. bP < 0.05 compared with BBS with saline. “P < 0.005 compared with BBS with saline. dP < 0.05 compared with saline.

type A CCK receptors,“-” and the present study confirms this finding in vivo by showing that loxiglumide does not affect gastrin 17-I-stimulated gastric acid secretion; therefore, these data indicate that blockade of the effects of CCK under basal conditions directly or indirectly stimulates gastric acid secretion in humans by a gastrin-independent mechanism. Specific type A CCK receptors have been shown on D cells in the gastric mucosa of rats and humans.20s31 Previous studies have also shown that CCK stimulates the release of SS from these D cells,‘g*32 which are found in the vicinity of gastrin-producing cells and parietal cells. Microvilli or small processes that come into contact with the gastric lumen (open-type D cells) are believed to provide the means by which changes in stomach contents can be sensed by antral D cells, thereby regulating SS secretion. In the gastric fundus, however, D cells are not in direct contact with the gastric lumen (closed-type D cells). With the knowledge that SS exerts a powerful inhibition on both gastrin release and gastric acid secretion,33 it is suggested that loxiglumide augments BAO indirectly by inhibiting CCK-stimulated SS secretion from closed-type D cells present in the vicinity of parietal cells.34 The stimulating effect of the CCK-receptor antago-

Table

2. Serum Gastrin Concentrations Loxiglumide or Saline

in Response

Basal Saline Loxialumide

2 + 21 32 * 21

nist loxiglumide on BAO in humans was unexpected because previous studies have shown that infusion of CCK under basal conditions stimulates gastric acid secretion.* However, the dose of CCK required for this effect was probably in the supraphysiological range, whereas in the loxiglumide experiments basal plasma CCK concentrations are not affected.25 Therefore, under basal conditions, low endogenous concentrations of CCK may preferentially bind to specific type A CCK receptors on SS-producing D cells, resulting in inhibition of gastric acid secretion, whereas high circulating concentrations of CCK may also result in binding to less specific type B receptors present on parietal cells. This eventually results in the observed stimulation of gastric acid secretion during infusion of CCK.8 Although the effect of loxiglumide on basal gastric acid secretion cannot be explained by augmented circulating gastrin concentrations, the effect of loxiglumide on BBS-stimulated gastric acid secretion may be explained largely by augmented gastrin release. This is concluded because infusion of 15 pmolkg-’ - h-’ of gastrin 17-1, resulting in plasma gastrin concentrations in the same range as during BBS infusion with loxiglumide, stimulates gastric acid secretion to values not significantly different from those obtained during BBS infusion with loxiglumide. This

to BBS and Gastrin Integrated

BBS 1251+ 93' 2558 + 206asc

infusion, 2.5mg. kg-’

17-I lnfusion

With a Background

Infusion

of

serum gastrin (pm01 - L-’ - h-‘) Gastrin 17-I (5pmol/L)

Gastrin 17-I (15 pmol/L)

1045 * 1770rb 1291 k 257",b

NOTE. BBS infusion, 92.6 pmol- kg-‘. h-l, n = 12;gastrin 17-I infusion, 5 and 15 pmol *kg-’ - h-‘, n = 6; loxiglumide for 10 minutes, followed by 10 mg. kg-‘. h-‘. “P < 0.005 compared with basal. bP < 0.05 compared with BBS with saline. “P < 0.005 compared with BBS with loxiglumide.

2412 f 312",' 2611 + 305"sc infusion, 2.5 mg *kg-’

EFFECT OF LOXIGLUMIDE ON GASTRIC ACID SECRETION

October 1992

conclusion seems justified because previous studies have shown that the synthetic molecular equivalents of circulating gastrin under stimulated conditions have similar acid stimulating potencies35 and bind to antibody 2604 with almost equal affinity.28*2g Because stimulated but not basal circulating gastrin levels are augmented by loxiglumide, it is suggested that loxiglumide not only augments gastric acid secretion by an indirect effect via inhibition of CCKstimulated SS release from closed-type D cells but also augments BBS-stimulated gastrin release via inhibition of CCK-stimulated SS release from opentype D cells in the antral part of the stomach.34 SS from D cells in the intestinal mucosa is believed to act locally and is not released into the circulation.37 Because of difficulties in studying paracrine mechanisms, there is no in vivo information about the effects of CCK on D cells present in the gastric mucosa. However, evidence from in vitro studies showing that CCK stimulates SS release from D cells in the gastric mucosa is so overwhelming’g’31-33 that we propose the following model to illustrate the effect of loxiglumide on basal and BBS-stimulated gastric acid secretion in humans (Figure 3). Under unstimulated conditions, gastric acid output is inhibited by a stimulatory effect of basal CCK concentrations on SS release from closed-type D cells. The augmented gastric acid output that results from blockade of CCK receptors on these closed-type D cells might subsequently overrule the effect of CCK-receptor blockade on open-type D cells, by which the expected augmented gastrin release under basal conditions is prevented (Figure 3). BBS infusion selectively stimulates gastrin release from the antrum and has no direct stimulating effect on gastric acid secretion in

vivo because BBS infusion into antrectomized patients does not result in stimulation of gastric acid secretion.36 In addition, BBS infusion stimulates the release of CCK,*’ which subsequently stimulates the release of SS from both closed-type and open-type D resulting in attenuation of BBS-stimucells, 1g*31-33 lated gastrin release and gastric acid output. Whether a similar mechanism is also involved in the effects of loxiglumide on meal-stimulated serum gastrin concentrations in humans remains to be established. In conclusion, the present study shows that the specific CCK-receptor antagonist loxiglumide stimulates basal and BBS-stimulated gastric acid secretion but only augments BBS-stimulated gastrin concentrations, without influencing basal gastrin levels. Loxiglumide does not affect gastric acid output and serum gastrin concentrations during infusion of synthetic gastrin 17-1, resulting in circulating gastrin concentrations in the physiological range. These studies support the idea that CCK is an enterogastrone. References 1. Larsson LI, Rehfeld

2.

3.

4

5.

GASTRIN

6.

7.

8.

9. ( SST

(

I producing

10.

11. Figure 3. Proposed model to illustrate the regulation of basal and BBS-stimulated gastric acid secretion by gastrin, CCK, and SS in humans. Asterisks indicate type A-specific CCK receptors. For details, see Discussion.

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JF. Evidence for a common evolutionary origin of gastrin and cholecystokinin. Nature 1977;269:335338. Calam J, Ellis A, Dockray GJ. Identification and measurement of molecular variants of cholecystokinin in duodenal mucosa and plasma. J Clin Invest 1982;69:218-225, Walsh JH, Lamers CBHW, Valenzuela JE. Cholecystokinin octapeptide immunoreactivity in human plasma. Gastroenterology 1982;82:438-444. Sol1 AH, Amiran DA. Thomas LP, Reedy JD, Elashoff JD. Gastrin receptors on isolated canine parietal cells. J Clin Invest 1984;73:1434-1447. Stening FG, Grossman MI. Gastrin-related peptides as stimulants of pancreatic and gastric secretion. Am J Physiol 1969;217:262-266. Johnson LR, Grossman MI. Analysis of inhibition of acid secretion by cholecystokinin in dogs. Am J Physiol 1970; 218:550-554. Brooks AM, Grossman MI. Effect of secretin and cholecystokinin on pentagastrin-stimulated gastric acid secretion in man. Gastroenterology 1970;59:114-119. Corazziari E, Solomon TE, Grossman MI. Effect of ninety-five percent pure cholecystokinin on gastrin-stimulated acid secretion in man and dog. Gastroenterology 1979;77:91-95. Mayer EA, Elashoff J, Mutt V, Walsh JH. Reassessment of gastric acid inhibition by cholecystokinin and gastric inhibitory polypeptide in dogs. Gastroenterology 1982;83:1047-1050. Makovec F, Chistb R, Bani M, Pacini MA, Setnikar I, Rovati LA. New glutaramic acid derivatives with potent competitive and specific cholecystokinin-antagonistic activity. Arzneimittelforsch Drug Res 1985;35:1048-1051. Makovec F, Bani M, Chisth R, Revel L, Rovati LC, Rovati LA. Differentiation of central and peripheral cholecystokinin receptors by new glutaramic acid derivatives with cholecystokinin-antagonist activity. Arzneimittelforsch Drug Res 1986;36:98-102. Jensen RT, Zhon ZC, Murphy RB, et al. Structural features of

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various proglumide-related cholecystokinin antagonists. Am J Physiol 1986;251:G839-G846. Menozzi D, Gardner JD, Jensen RT, Maton PN. Properties of receptors for gastrin and CCK on smooth muscle cells. Am J Physiol 1989;257:G73-G79. Grider JR, Makhlouf GM. Distinct receptors for cholecystokinin and gastrin on muscle cells of stomach and gallbladder. Am J Physiol 1990;259:G184-G190. Douglas BR, Jebbink MCW, Tjon a Tham RTO, Jansen JBMJ, Lamers CBHW. The effect of loxiglumide (CR-1505) on basal and bombesin stimulated gallbladder volume in man. Eur J Pharmacol1989;166:307-310, Jebbink MCW, Jansen JBMJ, Mooy DM, Rovati LC, Lamers CBHW. Effect of the specific cholecystokinin-receptor antagonist loxiglumide on bombesin stimulated pancreatic enzyme secretion in man. Regul Pept 1991;32:361-368. Liddle RA, Gertz BJ, Kanayama S, Becazzia L, Coker LD, Twinbull TA, Morita ET. Effects of a novel cholecystokinin (CCK) receptor antagonist, MK-329, on gallbladder contraction and gastric emptying in humans. Implications for the physiology of CCK. J Clin Invest 1989;84:1220-1225. Hildebrand P, Beglinger C, Gyr K, Jansen JBMJ, Rovati L, Zuercher M, Lamers CBHW, Setnikar I, Stalder GA. Effects of a cholecystokinin receptor antagonist on intestinal phase of pancreatic and biliary responses in man. J Clin Invest 1990;85:640-646. Sol1 AH, Amirian DA, Park J, Elashoff JD, Yamada T. Cholecystokinin potently releases somatostatin form canine fundic mucosal cells in short-term culture. Am J Physiol 1985; 248:G569-G573. Eissele R, Koop I, Schaar M, Koop H, Arnold R. Role of cholecystokinin in the control of gastric somatostatin in the rat: in vivo and in vitro studies. Regul Pept 1991;32:333-340. Jansen JBMJ, Lamers CBHW. The effect of somatostatin on bombesin-stimulated serum gastrin and gastric acid secretion in man. Digestion 1981;21:193-197. Jansen JBMJ, Lamers CBHW. Serum gastrin responses to bombesin and food in patients with hypergastrinaemia. Dig Dis Sci 1982;27:303-307. Varner AA, Modlin MI, Walsh JH. High potency of bombesin for stimulation of human gastrin release and gastric acid secretion. Regul Pept 1981;1:289-296. de Jong AJL, Klamer M, Jansen JBMJ, Lamers CBHW. Effect of atropine and somatostatin on bombesin-stimulated plasma gastrin, cholecystokinin and pancreatic polypeptide in man. Regul Pept 1987;17:285-293. Jansen JBMJ, Jebbink MCW, Douglas BR, Lamers CBHW. Effect of loxiglumide [CR-1505) on bombesin and meal stimu-

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lated plasma cholecystokinin in man. Eur J Clin Pharmacol 1990;38:367-370. Hassan MA, Hobsley M. Positioning of subject and of nasogastric tube during a gastric secretion study. Br Med J 1970;1:458-460. Jansen JBMJ, Lundborg P, Baak LC, Greve J, Ohman M, Stiiver C, ROhss K, Lamers CBHW. Effect of single and repeated intravenous doses of omeprazole on pentagastrin-stimulated gastric acid secretion and pharmacokinetics in man. Gut 1988;29:75-81. Rehfeld JF, Stadil F, Rubin B. Production and evaluation of antibodies for the radioimmunoassay of gastrin. Stand J Clin Lab Invest 1972;30:221-232. Jansen JBMJ, Lamers CBHW. Effect of changes in serum calcium on secretin-stimulated serum gastrin in patients with Zollinger-Ellison syndrome. Gastroenterology 1982;83:173176. Hildebrand P, Beglinger C, Kohler C, Setnikar I, Gyr K. Biological effects of a proglumide derivative as cholecystokinin antagonist in conscious dogs. Regul Pept 1987;18:213-220. Buchan AMJ, Curtis SB, Meloche RM. Release of somatostatin immunoreactivity from human antral D-cells in culture. Gastroenterology 1990;99:690-696. Buchan AMJ, Meloche RM. CCK stimulates somatostatin release from human antral D-cells via the type A receptor subtype (abstr). Gastroenterology 1991;100:A632. Makhlouf GM, Schubert ML. Gastric somatostatin: a paracrine regulator of acid secretion. Metabolism 1990;39:138142. Larsson LI, Golterman H, de Magistris L, Rehfeld JF, Schwartz TW. Somatostatin cell processes as pathways for paracrine secretion. Science 1979;205:1393-1395. Eysselein VE, Maxwell V, Reedy T, Wtinsch E, Walsh JH. Similar acid stimulatory potencies of synthetic human big and little gastrins in man. J Clin Invest 1984;73:1284-1290. Basso N, Lezoche E, Giri S, Percolo M, Speranza V. Acid and gastrin levels after bombesin and calcium infusion in patients with incomplete antrectomy. Am J Dig Dis 1977;22:125-128. Liddle RA, Ensinck JW. Cholecystokinin does not stimulate prosomatostatin derived peptides in man. J Clin Endocrinol Metab 1990;70:1403-1407.

Received August 29, 1989. Accepted April 29, 1992. Address requests for reprints to: Jan B. M. J. Jansen, M.D., Ph.D., Department of Gastroenterology and Hepatology, University Hospital Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Supported by a grant from The Netherlands Digestive Diseases Foundation (grant: WS 8g-07).

Effect of loxiglumide on basal and gastrin- and bombesin-stimulated gastric acid and serum gastrin levels.

The effect of the specific cholecystokinin-receptor antagonist loxiglumide on basal and bombesin-, and gastrin 17-I-stimulated gastric acid secretion ...
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