Inhibition of gastric acid secretion by somatostatin and analogs in the rat

Pharmacological

‘NHIBITION

Research Communications,

OF GASTRIC

ACID

SECRETION

W.

5 December

SUMMARY

-

subcutaneously,

the

unanesthetized

while

the

and

inhibited rat.

not

(50

ug/Kg/hr,

(0.05

i.v.)

-

release

1974),

and

min

even

I

hormone),

acid

secretion

34

2 urn/Kg,

secretion

the

min);

urn/

min)

similar

in

in

activity

]-somatostatin

analogs

CD-lysine9]-somatostatin Pentagastrin-induced

S.C.

was

0.6

(77

was 14

][descarboxy

and at

acid

Somatostatin,

of

various

organs,

cell

-*a I

gastric

[desamino (38

gastric

prevented

a tetradecapeptide

bv

’

glucagon et

humans

et

(Brazeau

different

al.,

are

growth

1974;

Mortimer

et

to

gastrointestinal

al.,

-*al and

humans.

hormone

et

Alberti

et -

and

(Siler

1974;

also

systems

animals

thyrotropin

(Gerich al.,

in

preparations, in

1973),

and

hormone

hormones

antagonized

(Mortimer

basal

release-inhibiting

secretlons

RAT

somatostatin

i.v.1.

growth-hormone

Ha I I -et

I-

effective

um/Kg/hr,

isolated

IN THE

Borella

[desaminoll-somatostatin

activities

appreciably

INTRODUCTION

the

ANALOGS

release-inhibiting

the The

14

reduced

was

L.E.

AND

Pharmacology Department Research Laboratories Quebec, Canada

(growth-hormone

[descarboxy

exhibited

SDMATOSTATIN

445

1975

Somatostatin

Kg t

BY

Lippmann

Biochemical Ayerst Montreal, Received

Vol. 8, No. 5, 1976

al.,

1973)

referred

et

-et

i.e., the --al

hormonal 1973;

’

prolactin

(Yen

1974),

gastrin

as

inhibits

species, Among

al.,

and

19731,

’

(Siler

19741,

to

et

al.,

al _*

j

insulin

(Bloom

-et

1974). With the

rise

and

diabetic

1974).

respect in

blood-sugar or

Normal

the

after

acromegalic subjects

and

oral

tract, glucose

patients

(Mortimer

patients

with

somatostatin

acts

administration et acromegalv

al.,

in 1974; receiving

to

delay

normal

subjects

Besser

et

a food

al., stimulus

446

Pharmacological

exhibit

decreased

tion

as

(Bloom

do

plasma-qastrin

patients

--et

al.,

observed

to The

with In

Somatostatin

et

Borg-t

ship,

et

the

a I.,

1974)

Recently,

1973). various

somatostatin

In

the

gastric The

cyclic

present

studies

acid

also

of

been

AND g)

described after

the

-

AMP,

(Kaneko

hormone

been

the

e.g., --et

been

(Kaneko

et

and

unanesthetized

(Kaneko

inhibit al.,

these

rat,

the In

preparation).

analogs

have

gastric

al.,

relation-

to et

with

1973).

structure-activity

(Llppmann

pentagastrin-induced

as

al.,

release

demonstrated

somatostatin

the

has

AMP accumulation

accumulation

and

that

for

mlnute.

The

rats

1971).

which

the

hours

after were

Albino

the

on

been

acid

of

a continuous,

but

the

stomach

through

The

gastric

perfusate

the

collections

the litter

basal

determined.

secretion

has

the

animals

were

perfusing

mild,

fluid

stream forestomach

was

with

collected with

0.01

of

air.

N NaOH

controls.

placed

saline

at

through

and I5 using

of

washed Bollman

the

rate

minutes phenol

out and red

and

0.85 was

ml

their per

facilitated

and

the

the

antral total

as

was were

cages

the

weeks

saline.

of

liquid

rats

animals

stomach

flowed

3-4

with

In

the

previously

the

The

the

Both

as

experiments gain

were

cannula every

for

welght

mate

Laboratories;

cannulas

used

of

stomachs

perfused the

rate

their

wash

the

titrated

time

Breedlng

gastric

were

which

continuously flow

two

Rats

unoperated

after

(Canadian

with

Herr, at

of

I8

stomachs

Male

chronically-implanted

operation,

Immediately

by

cyclic

of

have

in

syndrome

cyclic

vitro

accompanvinq

of

administra-

somatostatin

by --in

determination

on

METHODS

were

to

fasted

in

i.e.,

(Borella

similar

patients,

5, 1976

investigated.

MATERIALS 160-220

increase

a

8, No.

somatostatin

Zollinger-Ellison

mediated

release

effects

somatostatin

be

the

Vol.

secretion.

hormone

AMP

the

secretion,

effect

to

analogs

prostaglandin-induced

of

acid

and In

or

type

appears

antagonizes

al.,

latter

growth

after

anaemia

gastric

release

prostaglandin-induced

1973;

the

antagonize

hormonal

Communications,

concentrations

pernicious

1974). also

Research

an

air

entered cannula.

acid indicator.

in

Pharmacological

In

the

acid

Research

experiments

in

secretion

of

stabilized

ml)

with

were

the

test was

the

for

a

of

vehicle

was after

minutes

and

the

two

gastrin

infusion

percent

of

Included

K.

the

calculation

mined.

The

data

RESULTS

-

tion

control

In

of

Figure

60

Time

Figure

I.

Saline (0.1 deslgnatlon.

Basal ml,

i.v.

the at

rate

of

a dose

50

this

infusion

The

total

solution.

pentagastrin

animal.

The of

with

the

the

the

response test

compound

first

Ayerst

rats

area

from under

utllizinq

values over

hours

Acid

of

a period

the

second

was

expressed

prepared

pentaas

the

Ayerst the

curve

Student’s

basal

gastric

5 hr

time

shown

by

was

deter-

9”

test.

acid

including

the

Drs.

Laboratories.

the

of

by

(Lippmann

Secretlon at the employed.

output

measured

420

was administered were I7 animals

or

acid

Laboratories

was

the

statistically

average

were

Research

output,

ug/Kg/hr

(control).

(Peptavlon)

acid

four

was

to

analoqs

Nelson,

the

infusion

3 ml/hr.

of

to

which

animals

somatostatin

V.R.

360

at

the

(Min)

Gastric s.c.) There

infused

structurally-related

300

output,

the

analyzed

180 240

acid

In

administered;

(saline-treated)

120

experiments

was

each

period (0.5

infusion

each

I depicts

a

gastric

subcutaneously

the

infused

attain

Three

in

of

Injected In

was

was

Pentagastrln

were

then

to

basal

infusion.

of

and

allowed

on

a saline

start

the

Sestanj

preparation).

*

saline

447

compounds

induced-qastric

obtained

and

were

were

administration

response

In

al _-

the

test

1976

by

In

compared

Somatostatin

-et

followed

after

the

Immer,

min

the

vehicle.

and

pentagastrin

were

and

the

vein

5,

animals

saline

for

a tail

45

saline

H.U.

or

8, No.

of

pentagastrin

a second

90

output

employed

later,

for

the

acid

stabilization,

Vol.

effects

determined,

in

period

the

compound

cannulated

After

which

gastric

pentagastrin were

Communications,

arrow

secre-

a saline

448

administration gastric

acid

time

period

at

Z-3/4

output

of

and

the

the

at

gastric decrease

uEq/min)

then

to

that

of The

statin of

the

occurred

the

urn/Kg.

in

lnhlbltion Various

in

acid

for

each

of

I).

34

appreciably

effective; of

similar of

in

the

I,

time

Inhibitory

28).

even

at

to

that rate

shown

at

0.6

of of

2

the

examined similar

effective

return

(e.g.,

[desamino’][descarboxy14]-somatostatin;

min

2A).

(from

50-60

output

returned

of

Table

somato-

I.

to

The

133

output

was

under

similar

in

min

duration at

2.0

similar

with

the

to

activities

with

it

2C).

the

duration

were

high

exhibited

only

Atroplne (0.6

at

urn/kg)

onset

with

of

the

of the

secretory

not

25%

inhibition

active

comparison the

min.

28).

analogs than

62%,

was

The

effective maximal

[D-Iysine’]-somatostatin,

levels Fig.

I5

of

and

was

In

I).

38 67

urn/Kg

each

action

less

’ 4]being

about

(Table

except

somato-

being

0.014

activities,

analogs,

control

to

[D-lysine’]-somatostatin

urn/Kg

an

conditions.

[desamino’][descarboxy

lnhibltions

somatostatin

rapid

(Fig.

of

urn/Kg

acid

antisecretory

of

a more

in

and

somatostatin

each

decrease

activity

is

total

was

The

showed

of

rate

inhibitory

min

were

(Fig.

somatostatin,

to

the

percent

Fig.

of

effect

similar

for

the

less

periods

activities

like

The

period.

urn/Kg)

the

characteristics

agents,

was

two

min.

output.

dose.

were

respectively; (Table

each

uEq/l5

min

somatostatin

urn/Kg)

respectively

for

IO-20

[Descarboxy14]-somatostatin

(0.6 min,

about

this

the

a significant

5,

The

during

affect

injection

60

77

of

(0.6

(Table

and

from

cause

not

8, No.

uEq/min.

altered

after

secretion

inhibition

analogs

somatostatin

30

45-60

15 min of of

Vol.

was

did not

first

a rate

increased

75%

output annreciably

did

a period

[Desamino’l-somatostatin statln

the

to

gastric

of

being

s.c.,

relationship

degree

not

Convwnications,

administration

a subsequent

effect The

was

urn/Kg,

for

basal

inhlbitory

gastric

animals

output

dose-response on

acid

output in

basal

The

hr.

0.6

acid

A marked

Research

saline-vehicle

Somatostatin in

Pharmacological

exhibiting somatostatin

1976

Pharmacological

Research Communications,

Vol. 8, No. 5, 1976

449

B

C

;/y,j*,

120 I-)

Figure

2.

Effect Secretion

of

Somatostatin

60

0

Time

(Min)

and

60

Analogs

120 I+1

on

60

0

60

I20

t-1

the

(+)

Basal

Gastric

Acid

The test compounds: A. somatostatin (0.6um/Kg, s.c.); B [desamlno'][des[D-lysine$somatostatin carboxyl4]-somatostatin (0.6 urn/Kg, s.c.); C. (2 urn/Kg, s.c.) were administered at time shown by arrow designation. There were 21, 7 and 7 animals employed, respectively.

TABLE Effects

of

Somatostatin

and

Analogs

Dose (urn/Kg, S.C.)

Compound

I on

the

Basal

Onset Effect (min)

No. of Animals

Gastric

Duration inhibitory (min f

Acid

Somatostatin

0.6

21

15

2.0

7

I5

[Desamino'l-S

0.6

5

I5

87*

[Descarboxy14]-S

0.6

9

I5

38

*

(S)

0.6

7

15

34

f

0.014

7

I5

735

[Desamin carboxyl'l-S

***p<0.001,

*vO.O5

**p<0.01;

Flgure

hours

of

acid S.E.)

77h 133

*

5

75

f

3

17""

75

f

3

I4

73

f

4

8***

67

f

3

3"""

62

f

5*

8

69

A 5

'][des-

Atropine

gastric

Inhibition total output (percent f

of effect S.E.)

I7

Saline

equal

Secretion

doses acid apart,

3 shows of

the

gastric

pentagastrln secretion was

essentially

vs

somatostatin-treated

acid (50

response

ug/Kg/hr) to

the

output

the same

(0.6

stimulation infused

two (592

after I.v.

for

consecutive f

94

vs.

urn/Kg).

two 45

minutes.

infusions, 882

f

IO1

consecutive The spaced

uEq

f

S.E.;

3-4 pO.05)

450

Pharmacological

(In

experiments

i.e.,

not

vehicle

secretion

for or

Figure

3.

reported the

the

of

(50 and

ug/Kg/hr) repeated

gastrln,

caused

acid

secretion

acid

output

dltion, of

the

second (40

acid

(86

f

f

10%)

(Fig.4B);

0.025

urn/Kg

with

(Fig.

4C).

DISCUSSION of

its

-

The

analogs

of

In basal

by

inhibit

f

13%)

gastric

urn/Kg,

the

affect by

the

basal

on

for

of

the

the

of

inhibition

of

flndings basal

acid

secretion,

relationship analogs

Gastric

saline,

(arrow employed.

of

the

induced-gastric

In the

urn/Kg

the

also

maximal

secretion

the

lower

the

dose 24

*

8%

various

unanesthetized by for

showed

of

and

antagonlzed

determined examlned

the

somatostatin in

ad-

a determination

caused

being

secretion

In

pentagastrin-

basal at

that

penta-

somatostatin,

0.05

is

1976

Acid

with

induced-secretion

secretlon

the

the

(Fig.4A).

decreased

acid

5,

pentagastrin-induced

inhibition

demonstrate

gastric

gastric

of

output

and

the

basal

pentagastrin;

induced-secretion were

of

simultaneously

somatostatin,

inhibitions

injection

for 45 min 6 animals

prevention

acid

8, No.

pentagastrin).

lnhibitlon

of

Vol.

the

were

i.v.

complete

structure-activity acid

not

the

Pentagastrin

marked

by

gastric the

of

administration

present

Pentagastrin-Induced statin.

and

the the

that

induced

0.2

secretlon

9%)

found did

Doses

relatlonship

gastric

inhibition

(30

evidenced

dose-response

induced

Equal

Communications,

was infused intravenously There 3 - 4 hr later.

as

decreased

the

Two

a consistent

of

was

response

administered

Somatostatin,

it tested,

output

Effects Secretion

Pentagastrin designation)

here,

compounds

acid

Research

the that

rat. somatoInhibition

the

Pharmacological

Research Communications,

Vol. 8, No. 5, 1976

A

Figure

4.

Effect Secretion

Pentagastrin designation).

(50

was given number of

0

of

Somatostatin

ug/Kg/hr) Somatostatin

terminal

amlno

group

activity

while

elimination

terminal

groups

causes

the at

center

a

higher With

present

some the

cyclic

AMP

the

to

reduction moiety

not

be

of

importance

carboxyl in

activity.

at

posi

exhibit

9

is

the

or

The

iable

apprec

for group

tion

Acid

for 45 min (arrow urn/Kg; C: 0.025 urn/Kg) The administration.

0.05

pentagastrin 9,respectively.

terminal

specificity

generally with

latter

(Lippmann

et --

al.,

pituitary

and

present

compounds

importance

action

their

the

inhibitory

both

of

these

configuration of

at

importance

inhibitory

was

the

sl rice

activity

examlned

Similar

formation

In

cyclic

AMP

with to the

in

the the

anterior

formation;

analogs were

to

prostaqlandin

inhibit in

the

contrast

even

pharmacokinetics

to of

pltuitary theophylline-induced

vivo. --in

ET-induced present and

vitro

exist the

t he with

specificity

appears

in

the

pituitary

recognition

in

obtained

to

anterior

receptors

difference

examined

activities

although

observed

tract

the

of

ability

rat,

gastrointestinal

respect

actlon relative

preparation).

with

the

to in

In

of similar

regard

accumulation

system,thls

preceding

to

studies,

AMP

appear

lysyl did

respect

analoqs,

cyclic

intravenously B: urn/Kg;

Gastric

dose.

these

of

not of

[D-Lysine']-analog

infused 0.2

C

Pentagastrin-induced

with the second was 5, 8 and

does

of

on

was (A:

simultaneously animals employed

asymmetric

451

in -by

for

being

Somatostatin

formatlon

the

the

compounds

suggesting

vitro

inhibited an was

action also

Pharmacological

452

antagonized

(Borgeat

induced

by

was

inhlbited

tion

(Labrie In

--et

In

to

to

et

differ

to

anaemla

or (Bloom

healthy

rlse

above

when

a The

levels

stimulus

was

ability

secretion

of

could

be

Consistent

with

this

the

i.e.,

in

human,

concomitant

(Bloom

of

et

upon

the

parletal

of

an

inhibitory

findings pentagastrl

n.

recently

been

has

secretion 1975).

In Thus,

the this

are

As

plasma-gastrln

al.,

1974).

observed

reported dog

to

(Barros action

Is

to

the

the

also

inhlblt

D’Sa

et

not

specific

al.,

p lasma-gastri subsequently

acid

gastrin

release.

somatostatin

and

effect

that

could in

there gastric

be

accord

by

studies

in

the

and the

a

the the rat,

a direct present large

level

somatostatin gastric

cat rat

was

to

pentagastrln-induced 1975)

in

acid

due

with

Induced-secretion

for

n

acromegaly

syndrome,

present

pernicious

gastric

with

be

-et

did

Inhibit

findings

would

(Gomez-Pan

with

inhibit

concentrations

of in

In

patients

Zollinger-Ellison

This

effect

to

the

rebound

1974).

ability

Also,

cells.

al.,

no

or

levels in

analog

the

with

in

et

its

cat

occurred

been

species

syndrome

and

an

of

suggestion

the

In has

consideration In

basal

cells

of

latter

rebound

the

rebound

parietal

possibility

the

to a

the

plasma-gastrln

or

a reflection

decrease

production action

somatostatin

forma-

after

somatostatin

on

secretion

(Bloom

AMP

returned

after

the

subjects

employed

barium

secretion

secretion,

effect

to

no

5,

NO.

hormone

cyclic

acid

Zolllnger-Ellison

normal

a patient

acid

the

However, in

growth

following

hormone,

Al so,

subjects.

basal

food

1974).

8,

or

gastric

gastric

regard

with

of

subsequently

acid

patients

al.,

fasting

analog

Induced-gastric

the

et

in

Vol.

1974).

although

respect,

step

basal

Thus,

However,

in

an

a

al., of

on

1974).

thls

In

release

i.e.,growth

al., In

occur

1975)

level

action

levels,

exists.

appeared

this

addition,

at et

or

Communications,

3-isobutyl-I-methylxanthine

action

the

somatostatin

hormone

differences

in

Schofield

studies

(Besser

aJ.,

1974;

contrast

plasma

appears

an

present

In AMP,

indicating

al.,

of

observed

1974). cyclic

thus

the

level.

al.,

N6-monobutyryl

administration

human

et

Research

(Gomez-Pan and

appears

et to

acid al., be

a

1976

Pharmacological basic

Research Communications,

mechanism As

of

pointed

following

out,

cyclic

the

mediation

has

been

1974)

of

and

thus

et

the

action

result

on In

analog

hormonal of

of

various

of

ALBERTI, IVERSEN, (1973).

inhibition

In

ulcers

or

altered

The and

MISS

at

lnhlbitory and

of

the

It

Is

Bennet,

more use

physiologlcal

(Gomezof

of

relevance

and

therapeutic

step

by

the somato-

antlsecretory

of the

calcium

al.,

1974).

gastric

possessing

action

et

secretlon

action

of

In Calcium

the

some

for

acknowledge A.

acid

potentlal

related

authors

of

gastric

(Curry

calcium

(Holtermuller

blndlng

the

analogs,

advantageous

-

or

a step

importance.

secretion

of

for

the

of

at

of

availability

demonstration

offers

action

role

be

acid

processes

its the

may

appropriate

suggested

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