effects of h2- receptor antagonist on the cellular

Kitakanto Med.J.

47 ( 5 ) : 291-300, 1997

291

EFFECTS OF H2- RECEPTOR ANTAGONIST

ON THE CELLULAR FUNCTION OF

GASTRIC MUCOSA IN THE RAT

Masahiko Motegi, Yukio Nagamachi, and Shigeru Matsuzaki*

First Department of Surgery, Gunma University School of Medicine, 3-39-22 Showamachi, Maebashi, Gunma , 371, Japan

* Department of Biochemistry, Dokkyo University School of Medicine, 880, Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-02, Japan

Abstract : Hrreceptor antagonists (H2-blockers) block the Hrreceptors on gastric parietal cells and

strongly inhibit acid secretion, resulting in an augmented gastrin secretion by gastrin (G) cells. The

histamine-producing enterochromaffin-like (ECL) cells contain histidine decarboxylase (HDC), a

histamine-forming enzyme, which is controlled mainly by gastrin. HDC has a short biological half-life

and sensitive responses and, therefore, is a good marker for ECL cell function. To investigate the

mechanisms of action of the Hrreceptor antagonists on ECL cells, we examined the changes of gastric

mucosal histamine metabolism and gastrointestinal hormones after administration of five H2-blockers.

Cimetidine, ranitidine and nizatidine increased both the serum gastrin levels and mucosal HDC activity

in a dose-manner. At high doses of famotidine and roxatidine, the gastric pH and serum gastrin levels

were increased, but HDC activity was decreased. In addition, famotidine administration lowered the

mucosal somatostatin levels and increased serum secretin levels. Famotidine and roxatidine may have

acted directly on the ECL cells to lower the sensitivity to gastrin and suppressed HDC activity. The two

H2-receptor antagonists, apart from their pharmacological inhibitory effect on ECL cells, may also affect

cellular function of gastrin of gastric mucosa by regulating secretion of somatostatin and secretin.

Key words : H2-receptor antagonists, Histidine decarboxylase, Gastrin and Acid secretion.

(Kitakanto Med.J. 47 (5) : 291-300, 1997)

INTRODUCTION

H2-receptor antagonists (H2-blocker) discovered in

the 1970s and proton pump inhibitors developed later

are potent inhibitors of gastric acid secretion and have

brought revolutionary progress in the treatment of

peptic ulcers. Since their introduction, conservative treatment for peptic ulcers has changed drastically,

with a dramatic decrease in the number of surgically

treated peptic ulcer cases. Although the availability of

these drugs had led to the anticipation that surgical

treatment might become unnecessary, peptic ulcers

complicated by hemorrhage and perforation still exist.

Analyses of the cases treated with H2-blockers or

proton pump inhibitors have revealed various prob-lems in conservative treatment using these new agents.

Nagamachiu evaluated this from the surgical view

point and concluded that the increase in conservative management resulted from a decrease in selective rela-

tive surgical indications due to expansion of medical

indication to intractable ulcers, and not from a com-

plete disappearance of absolute surgical indication

such as perforation, hemorrhage and pyloric stenosis.

Although peptic ulcers are limited to local, their onset

is related to systemic diseases such as dysfunction of

the autonomic nervous system. Administration of

H2-blockers or proton pump inhibitors may temporar-

ily cure the local lesions without exerting any effect on

the fundamental etiology of the ulcer2). These potent

agents could lead to inappropriate maintenance ther-

apy for ulcers, and the number of surgical indicated

cases may again increase in the future.

Received : Jun 6, 1997

Accepted : Jun 26, 1997

Address : MASAHIKO MOTEGI

First Department of Surgery, Gunma University School of Medicine, 3-39-22 Showamachi, Maebashi, Gunma, 371, Japan

292

Motegi, Nagamachi, Matsuzaki

Even if peptic ulcer is cured by these agents, recur-

rence does occur after termination of treatment.

Although long-term administration of these agents can

prevent recurrence by continuously and strongly sup-

pressing acid secretion, the risks of gastric carcinoid and cancer may increase through long-term suppres-

sion of acid secretion3).

H2-blockers inhibit acid secretion by blocking

H2-receptors on the gastric parietal cells4). As a result,

the pH of the oxyntic mucosa increases and gastrin

secretion from G cells is stimulated. Gastrin stimulates

the histamine-producing enterochromaffin-like (ECL)

cells and increases histamine synthesis and secretion.

Histidine decarboxylase (HDC), a histamine-forming

enzyme, has been demonstrated in ECL cells of the

rats) and appears to be controlled mainly by gastrin6).

Since the HDC activity has a short biological half-life

and responds sensitively to various stimuli, it is a good

indicator of ECL cell function. The present study

aimed at investigating the mechanisms of action of

H2-blockers on ECL cells in the gastric mucosa, espe-

cially their acute effects after single administration.

MATERIALS AND METHODS

1. Experimental Animals

Eight-week-old Wistar male rats weighing 180 to

200g were housed in a room maintained at 25 •} 1•Ž

and a 12-h light-dark cycle (lighting from 7 : 00 to 19 :

00). Food was withdrawn 24 before and water was

withdrawn 8 h before experiment.

2. Drugs and Administration Methods

Five H2-blockers currently used in Japan were

studied ; i.e. cimetidine, ranitidine, famotidine, rox-

atidine and nizatidine.

Time course experiment : Each H2-blocker at 10 or

100mg/kg was suspended in 0.5% methylcellulose and

administered via an intragastric tube. The control rats

received the same amount of methylcellulose. After a

single administration, the rats were sacrificed by decap-

itation at given time intervals.

Dose response experiment : Each H2-blocker at 1,

3, 10, 30 or 100mg/kg was suspended in 0.5% methyl-

cellulose and administered via an intragastric tube.

The control rats were given the same amount of

methylcellulose. After single administration, the rats

were sacrificed by decapitation at a given time.

3. Measurements of Hormones and Mucosal pH

Blood was collected for the determination of serum

gastrin, somatostatin and secretin. The stomach was

removed and opened along the greater curvature.

Gastric mucosal pH was measured using a contact type

electrode. The gastric mucosa was removed and the

wet weight was measured. It was homogenized in 4

volumes of 50mM sodium phosphate buffer (pH 7.2)

containing 5 mM dithiothreitol, and centrifuged at 4•Ž,

12,000rpm for 20min. The supernatants were used as

samples for mucosal histamine and HDC activity

determinations.

1) Mucosal histamine concentrations and HDC

activity

HDC activity was measured according to the

methods of Araki7). Two hundred ,ƒÊ1 of reaction

mixture containing 50mM sodium phosphate buffer

(pH 7.2), 1mM aminoguanidine, 0.05mM pyridoxal

5-phosphate, 1 mM histidine, 0.1mM EDTA and 100,ƒÊ1

of supernatant were allowed to react at 37•Ž for 3h.

The reaction was stopped by adding 0.1,ƒÊ1 of 6 N

perchloric acid. After adding 5900 of 0.34N potas-

sium citrate buffer (pH 5.49), the mixtures were

centrifuged at 3,000rpm for 10min. The supernatants

were passed through MILLIPORE R filter with

0.45,ƒÊ m pores. Histamine in the filtrates was measured

by high performance liquid chromatography (HPLC).

HDC activity was expressed as nmol/g•Eh.

2 ) Serum Gastrin, Secretin and Somatostatin

Determinations

Serum gastrin was assayed using a Gastrin RIA Kit

(Dinabot Co.). Serum secretin was measured using a

Secretin RIA Kit (Daiichi Pharmaceutical Co.), and

serum somatostatin was measured using a Somatostatin

RIA Kit (Incstar Co.).

3 ) Gastric Mucosal Somatostatin Determina-

tion

In order to extract the somatostatin in the gastric

mucosa, the gastric tissues were immediately homogen-

ized in 10volumes of 0.01mM PBS in a teflon

homogenizer and centrifuged at 4•Ž, 1,000rpm for

20min. The supernatants were used as samples for

mucosal somatostatin determination. Mucosal soma-

tostatin was measured using a Somatostatin RIA Kit

(Incstar Co.).

4 ) Statistical analyses

Results are expressed in the mean standard error.

Student's T-test or Cochran-Cox test was used to exam-

ine statistical significance. A p value less than 0.05 was

considered significant.

RESULTS

1) Time Course Response The results of the 10mg/kg dose are described. In

the famotidine group, serum gastrin levels and mucosal HDC activity increased almost in parallel and reached

a peak at 4h, while mucosal histamine concentrations increased significantly at 2h (Table 1). In the

ranitidine group, serum gastrin levels increased rapidly reaching a peak at 1 h and returned to the basal level at

293

FL-Receptor Antagonist and Histidine Decarboxylase

Table. 1 Effects of famotidine (A : 10mg/kg & B : 100mg/kg) on histidine decarboxylase (HDC) activity, histamine concentra-

tion in oxyntic mucosa and serum gastrin levels in the rats. A. Famotidine (10mg/kg)

B. Famotidine (100mg/kg)

All data are shown as the mean •} SEM. Statistical significance vs. control

Table. 2 Effects of ranitidine (A : 10mg/kg & B : 100mg/kg) on histidine decarboxylase (HDC) activity, histamine concentra-tion, intragastric pH in oxyntic mucosa and serum gastrin levels in the rats.

A. Ranitidine (10mg/kg)

B. Ranitidine (100mg/kg)


Table. 3 Effects of roxatidine (A : 10mg/kg & B : 100mg/kg) on histidine decarboxylase (HDC) activity, histamine concentra-tion, intragastric pH in oxyntic mucosa and serum gastrin levels in the rats.

A. Roxatidine (10mg/kg)

B. Roxatidine (100mg/kg)


294


4h. The mucosal HDC activity also increased almost in parallel and returned to basal level at 4h. Mucosal

histamine levels decreased gradually until 4h after administration (Table 2). In the roxatidine group,

serum gastrin levels and mucosal HDC activity in-creased almost in parallel, reached a peak at 2h and returned to basal levels at 12h (Table 3). Similarly, in

the nizatidine group, serum gastrin levels and mucosal HDC activity increased almost in parallel, reached a

peak at 2 h and returned to the basal levels at 12h (Table 4).

The results of the 100mg/kg dose are as follows. In

the famotidine group, serum gastrin levels increased

remarkably, reached a peak at 2 to 4h and were still

significantly increased at 12h, while mucosal HDC

activity increased gradually and was significantly in-

creased at 12h (Table 1). In the ranitidine group,

serum gastrin levels increased markedly reaching a

peak at 4h and returned to the basal level at 12h. The mucosal HDC activity changed almost in parallel to

the gastrin serum levels (Table 2). In the roxatidine

group, serum gastrin level were significantly increased at 2 to 4h, but mucosal HDC activity remained almost

unchanged after 2 h (Table 3). In the nizatidine group,

( A )

( B )

( C )

( D )

Table. 4 Effects of nizatidine (A : 10mg/kg & B : 100mg/kg) on histidine decarboxylase (HDC) activity, histamine concentra-tion, intragastric pH in oxyntic mucosa and serum gastrin levels in the rats.

A. Nizatidine (10mg/kg)

B. Nizatidine (100mg/kg)


Fig. 1 Effects of various dose of famotidine on the oxyntic mucosal HDC activity (A), serum gastrin (B), gastric

histamine levels (C) and intragastric pH (D). All data are shown as the mean± SEM. Statistical significance

vs. control. *p< 0.05, **p < 0.01, ***p < 0.001

295

FL-Receptor Antagonist and Histidine Decarboxylase

(A)

(B)

(C)

(D)

(A)

(B)

(C)

(D)

serum gastrin levels reached a peak at 4 h and returned to the basal levels at 12h. The mucosal HDC activity

changed in parallel to the serum gastrin levels (Table 4). 2 ) Dose Response

Dose response was assessed at the time of peak

gastrin level as shown in the time-related curve. Up to 10mg/kg of famotidine, serum gastrin levels

increased only slightly, while the mucosal HDC activ-ity increased linearly. At doses of 10mg/kg and higher,

serum gastrin levels remained elevated, while the mucosal HDC activity decreased abruptly. The

mucosal histamine levels tended to decrease in a dose-dependent manner (Fig. 1).

In the roxatidine group, serum gastrin levels did not change up to a dose of 3 mg/kg, and increased

significantly only from 10mg/kg with a peak at 30mg/ kg. The mucosal HDC activity increased significantly from 10mg/kg , and decreased at 100mg/kg even

though the serum gastrin levels were still significantly

Fig. 2 Effects of various dose of roxatidine on the oxyntic mucosal HDC activity (A), serum gastrin (B), gastric

histamine levels (C) and intragastric pH (D). All data are shown as the mean •} SEM. Statistical significance

vs. control. *p<0.05, **p<0.01, ***p<0.001

Fig. 3 Effects of various dose of cimetidine on the oxyntic mucosal HDC activity (A), serum gastrin (B), gastric

histamine levels (C) and intragastric pH (D). All data are shown as the mean •} SEM. Statistical significance

vs. control. *p<0.05, **p<0.01, ***p<0.001

296


increased. The mucosal histamine levels remained

unchanged (Fig. 2). In the cimetidine group, the mucosal HDC activity

increased in a dose-dependent manner, but the serum

gastrin level did not differ from that of the control group until 10mg/kg and was significantly increased at a dose higher than 30mg/kg (Fig. 3).

In the ranitidine group, the serum gastrin levels

were essentially the same up to 3 mg/kg and reached a

peak at 30mg/kg. The mucosal HDC activity incre-

ased nearly in parallel to the serum gastrin levels and

reached a maximum at 100mg/kg. The mucosal his-tamine level was significantly decreased at a doses of

100mg/kg (Fig. 4). In the nizatidine group, the serum gastrin levels

increased significantly at doses of 10mg/kg and higher. The mucosal HDC activity increased nearly in parallel to the gastrin levels and reached a peak at 100mg/kg

(Fig. 5).

(A)

( B)

(C)

(D)

(A)

(B)

(C)

(D)

Fig. 4 Effects of various dose of ranitidine on the oxyntic mucosal HDC activity (A), serum gastrin (B), gastric histamine levels (C) and intragastric pH (D). All data are shown as the mean±SEM. Statistical significance

vs. control. *p<0.05, **p < 0.01, ***p < 0.001

Fig. 5 Effects of various dose of nizatidine on the oxyntic mucosal HDC activity (A), serum gastrin (B), gastric

histamine levels (C) and intragastric pH (D). All data are shown as the mean •} SEM . Statistical significance

vs. control. *p<0.05, **p<0.01, ***p<0.00_1

297

H2-Receptor Antagonist and Histidine Decarboxylase

(A)

(B)

(A)

(B)

(A)

(B)

(A)

(B)

Fig. 6 Effects of famotidine (A) and ranitidine (B) on the serum

somatostatin levels. All data are shown as the mean±

SEM. Statistical significance vs. control. *p < 0.05, **p<

0.01, ***p < 0.001. FAM : famotidine, RAN : ranitidine.

Fig. 8 Effects of famotidine (A) and ranitidine (B) on the serum

secretin levels. All data are shown as the mean •} SEM.

Statistical significance vs. control. *p < 0.05, **p < 0.01,

***p < 0 .001. FAM : famotidine, RAN : ranitidine.

Fig. 7 Effects of roxatidine (A) and nizatidine (B) on the serum

somatostatin levels. All data are shown as the mean•}

SEM. Statistical significance vs. control. *p <0.05, **p <

0.01, ***p < 0.001. ROX : roxatidine, NIZ : nizatidine.

Fig. 9 Effects of roxatidine (A) and nizatidine (B) on the serum

secretin levels. All data are shown as the mean •} SEM.

Statistical significance vs. control. *p < 0.05, **p <0.01,

***p < 0.001. ROX : roxatidine, NIZ : nizatidine.

298


(A)

(B)

(C)

(A)

(B)

3 ) Serum Somatostatin Levels The somatostatin levels were not significantly dif-

ferent from those of the control group for all four

agents (famotidine, ranitidine, roxatidine and nizatidine) at 10 and 100mg/kg (Figs. 6 and 7). 4 ) Serum Secretin Levels

A significant increase compared to the control

group was observed at 100mg/kg of famotidine. A significant decrease was observed between ranitidine at 10mg/kg and the control group. A tendency of in-

crease was observed in the roxatidine group although the difference was insignificant. No difference was observed in the nizatidine group (Figs. 8 and 9).

5 ) Mucosal Somatostatin Levels For all the five H2-blockers, the 100mg/kg dose

induced significant increases in gastric mucosal pH and serum gastrin level and a tendency of decrease in

mucosal somatostatin levels although the difference was insignificant (Fig. 10). Famotidine and ranitidine were studied in more detail. No significant difference

in somatostatin levels were observed between ranitidine at 10 or 100mg/kg and the control group.

However, a significant decrease was observed at 10mg/ kg of famotidine, and a tendency of decrease was observed at 100 mg/kg (Fig. 11).

Fig.10 Effects of H2-receptor antagonists on the gastric somatos-

tatin levels (A), serum gastrin levels (B) and intragastric

pH (C). All data are shown as the mean •} SEM. Statisti-

cal significance vs. control. *p<005, **p < 0.01, ***p<

0.001. ROX : roxatidine, NIZ : nizatidine, FAM:

famotidine, RAN : ranitidine, CIM : cimetidine.

Fig.11 Effects of famotidine (A) and ranitidine (B) on the gastric

somatostatin levels. All data are shown as the mean •}

SEM. Statistical significance vs. control. *p < 0.05, **p<

0.01, ***p <0.001. FAM : famotidine, RAN : ranitidine.

Fig.12 Chemical structures of five H2-receptor antagonists.

299

H2-Receptor Antagonist and Histidine Decarboxylase

DISCUSSION

H2-blockers inhibit gastric acid secretion by block-

ing the H2-receptors on gastric parietal cells. As a

result, gastric mucosal pH rises and gastrin secretion by

G cells also increases. Apart from the inhibition of

acid secretion, Maudsley et al.6) and Hakanson et al.8)

have reported stimulation of HDC activity by H2-

blockers. Hakanson et al.8 used rats with resected

antrum of the stomach to investigate gastrin secretion,

and reported that the increased HDC activity by

H2-receptor blockade is due to a secondary increase of

endogenous gastrin as a result of acid secretion inhibi-

tion. Yamauchi et al.9) also reported that the increase

in the mucosal HDC activity by cimetidine is induced

by endogenous gastrin increase. To investigate whe-

ther the endogenous gastrin increase is a reaction

secondary to the inhibition of acid secretion by

cimetidine or a direct action of the blocker on G cell,

a rat model with inhibited endogenous gastrin by

intragastric ingestion was used and the effects of

cimetidine on serum gastrin level and HDC activity

were studied. Even when the antrum was kept at fixed

acidic pH, the cimetidine-induced increases in serum

gastrin was observed. These findings suggested that the increase in endogenous gastrin secretion by cimetidine

is not a secondary reaction induced by gastric pH, but

is a direct action of the drug on G cells6). Ohe et al.10)

and Yagita et al.11) have also reported a direct action of

H2-blockers on G cells and differences in mechanism

of action among various blockers.

In our present study, gastric mucosal pH and serum

gastrin levels were shown to be increased by single administration of H2-blocker. Although there were

variations among the blockers, the increases in

mucosal pH and serum gastrin level were transient and

they were restored almost to the basal values within 12

to 24h.

The histamine-producing ECL cells have been

known to contain HDC, a histamine-forming enzymes).

Determination of HDC activity is important as an

indicator of histamine turnover and a marker of ECL

cell function. The ECL cell is stimulated by gastrin.

Administration of H2-blocker suppresses acid secretion

and increases gastrin secretion. As a result, ECL cells

are expected to be stimulated together with an increase

in HDC activity. Among the H2-blockers investigated

in the present study, low doses of famotidine and

roxatidine induced simultaneous increases of gastrin

and HDC activity. However, a dissociation phenome-

non was observed at high doses with a decrease in

HDC activity despite an increased gastrin level. These

findings suggest that the two blockers may act on the

ECL cells to lower the responsiveness to gastrin. Somatostatin, prostaglandin E and acetylcholine are

known to suppress ECL cells12). Somatostatin-containing endocrine cells (D cells) have cytoplasmic

processes which extend to neighboring G cells in the antrum13) and these cells are in direct contact with the

parietal and chief cells in the body of the stomach. Thus, somatostatin may exert a paracrine action on

these cells. Its main action in the stomach is to sup-

press acid secretion from parietal cells, gastrin secre-tion from G cells and pepsinogen secretion from chief

cells14). To examine whether somatostatin was involved

in the dissociation phenomenon observed in the pres-ent study, we examined the serum and gastric mucosal

somatostatin levels. The serum somatostatin levels were unchanged, but the mucosal levels tended to

decrease after administration of high doses of the five H2-blockers. In the famotidine group, particularly, the mucosal somatostatin levels decreased significantly at a

low dose. This may reflect an increased somatostatin

secretion, and suggests an effect of somatostatin on ECL cells. Serum levels of secretin, another hormone that inhibits acid secretion, were significantly in-

creased by a large dose of famotidine. In addition, a tendency of increase in serum secretin was observed

after roxatidine administration. The chemical structures of the 5 types of H2-

blockers are shown in Fig.12. The H2-blockers possess a common basic structure with an imidazole or heter-

oaromatic ring bearing an extended side chain contain-ing an intermediate chain joining to a terminal

group'5). Because modification of the side chain termi-nal group is closely associated with an increased H2-receptor antagonistic action, many structures have

been reported16,17). Agents with a thiazole ring in the side chain terminal group possess potent antagonistic

action. Our present study has also demonstrated that famotidine, which contains a thiazole ring, is more

potent than the other four H2-blockers in inhibiting

gastric acid secretion. The five H2-blockers have differ-ent structures, and we could not detect any correlation

between the structure and the inhibition of HDC activity. In general, an agent that strongly inhibits

gastric acid secretion is expected to exhibit strong inhibition of HDC activity in ECL cells. Further studies are required to clarify the mechanisms of con-

trol of ECL cell response to gastrin by H2-blockers.

ACKNOWLEDGMENTS

The authors would like to thank Prof. Koei Hamana, Department of Health, Gunma University

School of Medicine, for his guidance and cooperation. The authors would like to thank to Drs.M.Nakamura,

300


T.Kaneko, H.Koitabashi and M.Araki for their coop-

eration.

The authors are indebted to SmithKline Beecham

Pharmaceutical Co. Ltd., Yamanouchi Pharmaceutical

Co. Ltd., Teikokuzouki Pharmaceutical Co. Ltd.,

Zeria Pharmaceutical Co. Ltd. and Sankyo Co. Ltd.

for providing cimetidine, famotidine, roxatidine,

nizatidine and ranitidine, respectively.

REFERENCES

1) Nagamachi Y. Medical and surgical aspects of

indication and limitation of conservative treat-

ment for patients with gastric and duodenal ulcer.

Clinical Surgery 1990 ; 45 : 1367-1379 (in

Japanese).

2) Nagamachi Y. Peptic ulcer - Indication and limi-

tation of conservative treatment-In : Proceedings

of Kanto District Educational Seminar, The

Japanese Society of Gastroenterology 1992 : 1-14

(in Japanese). 3) Larsson H, Carlson E, Mattson H et al. Plasma

gastrin and gastric enterochromaffin-like cell acti-vation and proliferation, Studies with omeprazole

and ranitidine in intact and anterectomized rats.

Gastroenterology 1986 ; 90 : 391-399.

4) Black JW ,Duncan W.A.M., Durnat C.J. Defini-

tion and antagonism of histamine H2-receptor.

Nature 1972 ; 236: 385-390.

5) Kubota H, Taguchi Y, Tohyama M et al. Electron

microscopic identification of histidine decarbox-

ylase containing endocrine cells of the rat gastric mucosa. Gastroenterology 1984 ; 87 : 496-502.

6) Maudsley DV, Kobayashi Y, Bovaird L. et al.

Effects of H2-receptor antagonists on histidine

decarboxylase activity in rat gastric mucosa.

Biochem. Pharmacol. 1974 ; 23 : 2963-2968.

7) Araki M, Nakamura M, Takenoshita S et al.

Effects of dexamethasone on the activity of his-

tidine decarboxylase, ornithine decarboxylase and

DOPA decarboxylase in the rat oxyntic mucosa.

Can. J. Physiol. Pharmacol. 1991 ; 69 : 37-42. 8) Hakanson R, Hedenbro J, Liedberg G et al.

Activation of histidine decarboxylase by H2-

receptor blockade : Mechanism of action. Br. J. Pharmacol. 1975 ; 53 : 127-135.

9) Yamauchi T. The role of mucosal histamine and histidine decarboxylase activity in mechanisms

related to acid secretion in rats. Jpn. J. Gas-troenterol. 1984 ; 81 : 2905-2913 (in Japanese).

10) Ohe K, Nakamura M, Fujiwara T et al. Effects of H2-receptor antagonist, Cimetidine and YM-11170

on serum gastrin levels in lumen perfused rat. Dig. Dis. Sci. 1983 ; 28 : 981-989.

11) Yagita M, Miura Y. Effect of acid secretion inhibitors on humoral background factor of gas-

tric acid secretion-Effect on changes of serum

gastrin level. Proc.Jap.Soc.Gast.Sec.Res. 1987 ; 19 : 65-68 (in Japanese).

12) Imamura I. Histamine H2-receptor and gastric

ulcer. Taisya (Metabolism) 1992 ; 29 : 127-136

(in Japanese). 13) Larsson L I. Distribution and morphology of

somatostatin cells. In : Somatostatin. ed. by Y.C. Patel, and G.S.Tannnenbaum, New York Plenum,

1985 ; pp : 383-402. 14) Sumii K. Somatostatin receptor in gastric mucosa.

G. I. Research 1993 ; 1 : 47-53 (in Japanese).

15) Takei M. H2-receptor antagonists. Taisya (Metab-olism) 1989 ; 26 : 909-917 (in Japanese).

16) Algiri A.A., Luke G.M., Standridge R.T. 1,2,

5-Thiadole 1-oxide and 1,1-dioxide derivatives. A

new class of potent histamine H2-receptor antago-

nist. J. Med. Chem. 1982 ; 25 : 210.

17) LummaW. C . Inhibitor of gastric acid secretion ;

3,4-diamino-1,2,5-thiadine 1-oxides and 1,1-deo-

xides as urea equivalents in a series of histamine

H2-receptor antagonists. J. Med. Chem. 1982 ;

25 : 207.

effects of h2- receptor antagonist on the cellular

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