Rat Atrial Natriuretic Polypeptide Increases Net Water, Sodium and Chloride Absorption Across Rat Small Intestine In Vivo

Japan. J . Pharmacol. 4 5 , 7 - 1 3 ( 1 9 8 7 )

7

Rat Atrial Natriuretic Polypeptide Increases Net Water, Sodium and Chloride Absorption Across Rat Small Intestine In Vivo Yasushi K A N A I , Norio 0 H N U M A and Hisayuki

MATSUO*

Suntory Institute for Biomedical Research, S h i m a m o t o , M i s h i m a , Osaka 618, Japan ' D e p a r t m e n t of Biochemistry, Miyazaki Medical College, Kiyotake, Miyazaki 8 8 9 - 1 6 , Japan Accepted May 13, 1987

A b s t r a c t — L o c a l i z a t i o n o f b i n d i n g sites f o r s y n t h e t i c rat atrial n a t r i u r e t i c (a-rANP) vivo

perfused

demonstrated base

of

polypeptide

and t h e effect of the peptide on net w a t e r and electrolyte m o v e m e n t small

intestine

that specific

epithelia

and

of

the

binding

lamina

rat

were

sites w e r e

propria

of the

studied.

Autoradiographic

localized small

on

a space

intestine.

between

Alpha-rANP

/ ¿ g / m i n ) i n f u s e d i n t o t h e s u p e r i o r m e s e n t e r i c artery of rats increased net of w a t e r (70%

( 4 6 % i n c r e a s e in c o m p a r i s o n w i t h c o n t r o l s ) ,

increase)

These

across the small

increases

employed.

were

also

T h u s it w o u l d

intestinal tract

observed

when

circulating

glucose-free

water-electrolyte

Ringer's

Ringer's

Na-glucose

and

through

solution

cotransport

regulating

not

CI

solution. was

system

These observations suggest that

balance

the (0.25

absorption

( 8 4 % increase)

perfused w i t h

be c o n c l u d e d t h a t t h e

is n o t i n v o l v e d i n t h e a c t i o n o f a - r A N P . controls

Na

in

study

a-rANP

only

renal

f u n c t i o n b u t a l s o i n t e s t i n a l w a t e r , N a a n d CI a b s o r p t i o n .

Atrial seses

natriuretic

potent

polypeptide

diuretic

and

(ANP)

pos-

Dawley

natriuretic

acti-

[

vities ( 1 - 3 ) . Koseki et al. ( 4 , 5) h a v e that in

specific the

lecting

as

the

small

on

of

inner

and

Furthermore,

localized

the

sites

glomerulus, tubule

kidneys. were

binding

ANP

extra-renal

intestine,

heart, liver a n d brain In

this

study,

localization [

1 2 5

of

l]a-rANP

we

have

in t h e

39

at 4

min

following

col-

tion.

For

whole

rat

cording

ug

to

of

a-rANP

and

intravenous

body

50

jum

lung,

Japan)

eye,

effects

investigated

binding

f o r 4 w e e k s at 4 ° C . For

autoradiography,

10

jum

semi-micro

frozen

sites

perfused

the

room

for

apposed

temperature.

the

microscopic

rat

These

sections

tighly to the X-ray

the

films.

autoradiography,

the

the

To

complete

dissected

organs

the

a-rANP

lactoperoxidase

was

sists a-rANP:

radioiodinated

method

as

by

described

previously ( 4 ) . The specific activity of

[

1 2 5

l]-

studies:

9

mM

91

mM

picric 16

Na HP0 2

mM 4

( p H 7.2)

20

NaH P0 2

12H 0.

sections were washed saline

acid,

2

in

Ten

4

were

solution fixation

were

kept

which

con-

mg/l

para-

2H 0 2

um

Male

Sprague-

and

frozen

phosphate-buffered

and dipped into the

nuclear

track emulsion ( N T B - 2 , Kodack, U.S.A.)

a - r A N P w a s 0.65 mCi//¿g. Autoradiographic

of

formaldehyde,

light

rats

the

f o r 2 4 hr in Z a m b o n i ' s s o l u t i o n Methods

were

For

1 0 0 ml of Z a m b o n i ' s

aorta.

process,

monoiodinated

sections

w e r e m o u n t e d o n t o glass slides a n d d r i e d at

small intestine.

Synthetic

ac-

freeze-dried

s e c t i o n s w e r e p r e p a r e d a n d p l a c e d in c o n t a c t

perfused w i t h

of

sacrificed administra-

autoradiography,

(7),

of

w i t h X - r a y f i l m s ( N o . 1 5 0 , Fuji F i l m C o . , L t d . ,

via

Materials and

ng

sites

movement

Preparation

39

combination

such

clarified.

in v i v o

given

organs

small intestine and

applying

cold

Ullberg

effect of a - r A N P on net w a t e r and electrolyte by

were

binding

adrenal,

specific

g)

either a l o n e or in

with

of

(6), while A N P

in t h e s e o r g a n s are n o t y e t

(350

were

medullary recta

rats

l]a-rANP

shown

a-rANP

vasa

1 2 5

and

exposed for 2 weeks. After the sections were

Copyright 1987. Production and Hosting by Elseiver B.V. On behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND License (http://creativecommons.org/licenses/by-nc-nd/ ).

8

Y. Kanai, Ν. Ohnuma & Η. Matsuo

developed and fixed, they were stained haematoxylin-eosin and Small

intestine

performed small

the

Seeber

of et

Dawley

with

al.(9).

rats

weighing i.p.)

performed. After and

distal

small

end

intestine

of

a

ileum.

perfused

peristatic

pump

for

10

min

solution

contained

K C l , 1.4

mM

ml,

specific

solution

activity

was of

3.4

MgCI ,

5

2

mM mM

(10,000 d p m /

at

the

peristatic Sweden). at

was

37°C.

measured (Model

LS-7500,

and

Beckman,

U.S.A.).

Na

concentrations were determined flame

photometer

Japan).

CI

was

titration

(Model

750,

measured

by

/¿moles/min/m intestine.

using

of

Positive

absorption

and

secretion. All mean±S.E.

a

Hitachi, Potentio­

chloridimeter

Hiranuma, Japan). the

expressed length

of

numbers negative

results w e r e Statistical

Κ

b y use of a

Water

as ß\ the

represent

net

numbers, expressed

analysis

or

small net

as

the

was

per-

f o r m e d by S t u d e n t ' s r-test.

mCi/mmol, the

osmotic

Localization [

1 2 5

of

l]a-rANP:

specific

When

binding

rats w e r e

sites

given

39

for ng

of [

( M o d e l 3 W 2 , A d v a n c e d Instruments, U.S.A.).

at 4

The

localized on the kidney and the lung (Fig. 1 ) .

mesenteric

nulated from the femoral

275

Results

Ringer's

replacing

mosmol/l

superior

was

col­

a

by a liquid scintillation spectrometer

and electrolyte flux w a s

D-mannitol. The

perfusate

samples

ml/min,

11.4 by

in t h e

(Chloride counter,

Ringer's

infused

maintained

metrie

P-1,

was

Pharmacia,

was

washed

Glucose-free

prepared

P-3,

temperature

circulation

/¿g/min w i t h

warmed

NaCI,

C-inulin

England).

glucose w i t h 5 m M pressure

1 4

a-rANP

/¿I/0.25

Radioactivity

the this

The

The

mM

2

(Model

in

confirmed. Through

with

effluent w a s

mM

C a C I , 0.1

g l u c o s e a n d 6 0 juM Amersham,

137

or

Body

tubes

(Model

periods.

saline

pump

duodenum

at t h e rate of 0.5

Pharmacia, S w e d e n ) . The lected

the

tube,

the

was

blood

intestine w a s

and were

of bile d u c t ,

normal

small

25

pentobarbital

both

the

was

Ringer's solution by using

into

g

operation,

rate of

rat

Sprague-

tracheotomy

ligation

cannulated

male

200-300 a

of

et al. ( 8 )

sodium and

We

of

modification

Fasting

with

mg/kg,

were

a

studies:

experiment

Dharmsathphorn

anesthetized (50

perfusion

perfusion

intestine

methods

with

photographed.

artery

was

artery w i t h

tubes (Clay Adams, U.S.A).

can­ PE-10

Completing

this

Lu^,

ZMk'!

On

1 2 5

l]a-rANP

min, the

shown

high

other in t h e

intravenously and density organs,

small

sacrificed

radioactivities radioactivities

intestine,

liver,

were were

adrenal,

A k

J?

Fig. 1 . Whole body autoradiography of the rat given 39 ng of [ l ] a - r A N P intravenously. The animal was sacrificed at 4 min after injection. Ey, eye; Lu, l u n g ; En, endocardium; Li, liver; S, small intestine; A , adrenal; K, kidney. 1 2 5

Effect of A N P in Small Intestine

9

Fig. 2. Semi-micro autoradiography of the small intestine f r o m rat given 39 ng of [ l ] a - r A N P either alone (A) or in combination w i t h 39 /¿g of cold or-rANP ( B ) . The animal was sacrificed at 4 min after injection. Microautoradiogram superimposed on a histological image of the small intestine from a rat given 39 ng [ l ] a - r A N P ( C ) . 1 2 5

1 2 5

e n d o c a r d i u m and eye ball.

and D ) .

To determine whether the small 39

intestine

ng

of

[

was

specific

l]a-rANP

1 2 5

binding or

was

in

the

nonspecific,

injected

either

a l o n e ( F i g . 2 , A a n d C ) or in c o m b i n a t i o n 39

/ig

of

cold

grains w e r e 2A)

a-rANP

observed

and were

along

displaced

a-rANP

(Fig.

obtained

autoradiogram

histological were

(Fig.

2B).

image

distributed

the

with

Figure

of

on

2B). villus

an

of

electrolyte

2C

shows

superimposed

the

the

villus. The

space

a-rANP

on

movement:

i n t e s t i n e o f rats w a s

(Fig.

excess on

net

When

and

the

small Ringer's

s o l u t i o n in v i v o , t h e r e w a s n e t w a t e r a b s o r p tion

across

absorption

the was

small nearly

intestine constant

and

from

solution,

(126±7

of

(60-180

min

W h e n the

small

perfused

with

rats w e r e a-rANP

(0.25

/¿g/min)

with in

to

a

statistical

comparison 183±8

significance

with

the

//l/min/m).

controls

Significant

increases w e r e also o b s e r v e d

in n e t

absorp-

tion

70%

increase,

of

Na and

CI

(84% and

respectively). The net m o v e m e n t of Κ across the intestinal tract c h a n g e d f r o m secretion to a b s o r p t i o n ; h o w e v e r , t h e d i f f e r e n c e in n e t Κ flux

was

only

1/40-1/44

of that

observed

in N a a n d C I .

this

When

to

modified

60

state

c a u s e d a 4 6 % i n c r e a s e in t h e m e a n n e t w a t e r (P<0.01)

propria.

perfused w i t h

tracts

Ringer's

absorption

a

steady

(Table 1).

intestinal

an

the

water

at t h e

of the perfusion)

of

grains

between

base of t h e epithelia a n d t h e lamina Effects

with Dense

M e a n n e t f l u x e s o f w a t e r , N a a n d CI w e r e calculated

the

intestine

was

perfused

R i n g e r ' s s o l u t i o n , in w h i c h

with

a

glucose

1 8 0 m i n a f t e r t h e s t a r t o f p e r f u s i o n in c o n t r o l

was

animals that

w a t e r absorption w a s l o w e r e d to 5 3 % of that

received

saline

(Fig. 3A,

open

c i r c l e ) . I n c r e a s e in n e t w a t e r f l u x a c r o s s intestinal tract w a s d e m o n s t r a t e d w h e n /¿g/min

of

a-rANP

superior

mesenteric

the

from

displaced the

with

original

D-mannitol,

Ringer's

change was

also n o t e d

the

under these

conditions, w h e n

was

infused

into

artery

during

perfusion

( F i g . 3 A , c l o s e d c i r c l e ) . I n c r e a s e s in t h e

net

infused, significant

compared

5 7 % increase, respectively).

When with

the

modified

glucose

was

small

controls

( F i g . 3,

intestine

Ringer's displaced

was

solution with

B-D).

net

Similar

CI.

Even

α-rANP

was

observed

i n t h e n e t a b s o r p t i o n o f w a t e r , N a a n d CI as compared

the

Na and

increases w e r e

f l u x e s o f N a , Κ a n d CI w e r e a l s o o b s e r v e d as with

solution.

0.25

in

basal

to

the

controls

(47%,

85%

and

perfused in

Discussion

which

D-mannitol,

after 6 0 m i n , α - r A N P t e n d e d t o increase n e t f l u x e s o f w a t e r , N a a n d CI ( F i g . 4 , A ,

the Β

It h a s b e e n d e m o n s t r a t e d t h a t

autoradio­

graphy provides a useful tool to identify distribution

of A N P

receptors

in t h e

the

kidney

10

Y. Kanai, Ν. Ohnuma & H. Matsuo 220·

24-

ç165E ö χ 3 Li­ ra ζ

LU

<

12·

I

=> 110-

55"

6-

LJ Ζ

Ζ 60

120

0-

180

0

PERFUSION TIME (min)

1

1

60

120

—ι 180

PERFUSION TIME (min]

0.4-

30-

1 I

ε 1 20Ε

0.2¬

1

χ

χ 3

10-

ZD •-0.2-

r ~T— 120

-1— 60

—1 180

-r— 60

PERFUSION TIME (min)

120

180

PERFUSION TIME (min)

Fig. 3. Time course of net water ( A ) , Na ( Β ) . Κ (C) and CI ( D ) flux across the w a l l of rat intestinal tracts perfused w i t h Ringer's solution. A l p h a - r A N P ( # ) or saline ( O ) (0.25 ¿¿g/25 μ Ι / m i n ) was infused into the superior mesenteric artery during the perfusion of the small intestine. Each point represents the mean±S.E. of 6 determinations. (4-6,

1 0 ) , brain

other organs

( 1 1 , 1 2 ) , eye

( 6 ) . It h a s b e e n

(6, 11) also

t h a t t h e r e c e p t o r s f o r A N P e x i s t in t h e lateral

membranes

cortex

(13)

and

isolated

vascular

Our autoradiographic between

the

base

from

rat

systems

and

reported basokidney

(14-16).

study w a s of the

of

the

epithelia

area

and

the

o b s e r v e d specific b i n d i n g has n o t been characterized, receptors

are

they

suggest

that

present

in t h e

small

a n d m a y p l a y a role in w a t e r a n d

intestine electrolyte

h a n d l i n g in t h e s m a l l i n t e s t i n e . In

the

α-rANP

present

study,

0.25

/¿g/min

infused into the superior

lamina propria (Figs. 1 and 2 ) . H o w e v e r , the

artery increased net absorption of w a t e r , and

resolution for determining sites

for

α-rANP

membrane laries

in

of

the

exist

the lamina

had

insufficient

if s p e c i f i c in

epithelia propria.

the or

binding

CI

with

across

Ringer's

the

small

solution

intestine

in v i v o . T h e

mecha­

nisms by w h i c h α - r A N P increased w a t e r

the

solute

Although

the

absorption

in t h e

small

intestine

u n k n o w n at p r e s e n t . H o w e v e r , t h e

Na

perfused

basolateral capil­

of

mesenteric

obtained

autoradiogram

well

a-rANP

and are

following

11

Effect of A N P in Small Intestine 22024 165-

18-

Q 12 Ε

110'

=5

Ft

55 •

6

τ

0—J— 60

I 120

- 1 — —Γ 120 60 PERFUSION TIME (min) -

180

PERFUSION TIME (min)

180

30-

0.4 π

0.2·

20-

o 10-

χ

¥

LU

2

- ι — 120

~"r~~ 60

o -

180

"Ί 180

120

60

PERFUSION TIME (min)

PERFUSION TIME (min)

Fig. 4. Time course of net water ( A ) , Na ( Β ) , Κ (C) and CI (D) flux across the w a l l of rat intestinal tracts perfused w i t h glucose-free Ringer's solution. A l p h a - r A N P ( • ) or saline ( • ) (0.25 /¿g/25 /¿l/min) w a s infused into the superior mesenteric artery during perfusion of the small intestine. Each point represents the mean±S.E. of 6 determinations.

three possibilities deserve t o be c o n s i d e r e d : 1 )

fluid

α-rANP,

capillaries,

p r e s e n c e or a b s e n c e

acting

on

might increase w a t e r , by

decreasing

pressure

which

submucosal Na and

Ci

intracapillary regulates

paracellular

fluid

through

the

shunt

α-rANP

m i g h t stimulate active Na

on

Na-K-ATPase

activity

observed

in e i t h e r

of glucose to the

the

same

absorption

e x t e n t , it is l i k e l y t h a t t h e N a - g l u c o s e p o r t s y s t e m is n o t i n v o l v e d i n t h e

absorption

o f f l u i d a b s o r p t i o n b y α - r A N P . In v i e w o f t h e

pathway.

3)

2)

transport. because

has n o

(17).

was

hydrostatic

H o w e v e r , t h i s p o s s i b i l i t y is u n l i k e l y it h a s b e e n r e p o r t e d t h a t A N P

absorption

effect

a-rANP

cotrans-

stimulation

general effect of A N P o n the vascular system (14-16), Our effect

the

first

finding expected

possibility

is s e e m i n g l y from

of A N P . Recently,

the

is m o s t contrary

natriuretic

Seeber et al. ( 9 )

likely. to

the

action reported

m i g h t i n c r e a s e t h e e n t r y o f N a a n d CI a c r o s s

t h a t rat atrial e x t r a c t s u p r e s s e d t h e N a - g l u c o s e

the brushborder

c o t r a n s p o r t across t h e rat

membrane. Since

enhanced

intestine

perfused

12

Y. Kanai, N. Ohnuma & H. Matsuo Table 1 .

Effect of α - r A N P on net fluxes of water, Na, Κ and CI across the rat small intestine Water (μΙ/min/m)

Na (¿¿nnoles/min/m)

(/¿moles/min/m)

(//moles/min/m)

126±7

11.0±1.7

-0.029±0.043

14.7±1.8

183±8**

20.2±1.8**

CI

Ringer's solution control (n = 6) α-rANP (n = 6)

0.259±0.077**

24.9*1.7"

Glucose free Ringer's solution control (n=6) a-rANP (n=6)

6.4±1.2

-0.009±0.038

9.7±1.2

11.9±1.5*

-0.024±0.087

15.2±1.1**

66±7 97±3**

A l p h a - r A N P (0.25 /¿g/25 μΙ/rnin) or saline was infused through the superior mesenteric artery. Glucosefree Ringer's solution contains D-mannitol instead of glucose. Net absorption of water, Na, Κ and CI was calculated from the data (from 60 min to 180 min) in Figs. 3 and 4. Each value represents the mean±S.E. Significant difference from the controls, P < 0 . 0 5 ( * ) , P < 0 . 0 1 ( * * ) .

in

vivo.

However,

this

work

evaluate for the f o l l o w i n g used

crude

extract

is

difficult

reasons:

instead

of

1)

to

They

synthetic

a-

r A N P , w h i c h h a s b e e n i d e n t i f i e d as t h e n a t i v e circulating

ANP

in rats

( 1 8 ) . 2)

In v i e w

of

t h e e x t r e m e l y s h o r t b i o l o g i c a l half life o f A N P in t h e rat ( t

1 / 2

= 26.5 sec)

(19), the

duration

of c o l l e c t i o n period seems to be t o o

long to

detect the acute effect of A N P . O'Grady peptin

et al.

III

(20)

inhibited

reported

Na-K-2CI

that

cotransport

in s h o r t c i r c u l a t e d t e l e o s t i n t e s t i n e . it

is q u e s t i o n a b l e

plicable

to

whether

mammals.

It

this

has

atrio-

However,

is a l s o

been

ap­

reported

i n r a b b i t s t h a t A N P d i d n o t a f f e c t CI t r a n s p o r t across the thick loop,

where

ascending

Na-K-2CI

limb

of

Henle's

cotransport

is

also

operating (21 ). Since

we

administered

α-rANP

directly

i n t o t h e m e s e n t e r i c a r t e r y , it is p o s s i b l e

that

the

this

vascular

maneuver.

effect

is

Although

exaggerated our

by

autoradiographic

study s h o w e d that the specific binding for

α-rANP

between lamina

were

the

base

localized of

propria, w e

the

on

the

epithelia

sites space

and

the

can not exclude a possi­

bility that A N P directly acts, on the epithelia, leading

to

a

different

the experimental Our

observations

that A N P intestine

result

depending

reported

here

suggest

has a d i s t i n c t t a r g e t o n t h e and

on

conditions.

may

modulate

fluid

balance, although the underlying

and

small salt

mechanisms

which

a c c o u n t for the action of α - r A N P

on

the small intestine remain t o be e l u c i d a t e d . A c k n o w l e d g m e n t s : We are grateful to Y. Minami¬ take and Y. Hayashi (Suntory Institute for B i o ­ medical Research) for providing synthetic a - r A N P and [ l ] a - r A N P . We also thank Dr. M . Imai of the National Cardiovascular Center Research Institute for reviewing this article. 1 2 5

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