Electrical activity of the gallbladder and biliary tract in sheep and its relationships with antral and duodenal motility

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Submitted on 1 Jan 1979

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Electrical activity of the gallbladder and biliary tract in

sheep and its relationships with antral and duodenal

motility

Lionel Bueno, Françoise Praddaude, J. P. Serthelon

To cite this version:

Electrical

_activity

of

the

_gallbladder

and

_biliary

tract

in

_sheep

and its

_{relationships}

with

antral and

duodenal

_motility

L. BUENO

_Françoise

PRADDAUDE J. P. SERTHELON

Laboratoire de Physio-Pathologie Digestive, LN.R.A.,

Ecole Nationale Vétérinaire,

23 Chemin des Capelles 31076, Toulouse Cedex, France.

Summary.

The electrical activity of the

_gallbladder,

biliary tract and gastroduodenal junction was recorded in conscious

_{sheep by}

means of

chronically implanted

electrodes

and was related to movements of the wall for both the antrum and duodenum.

Electromyograms

of the

_gallbladder

_presented isolated _{spike potentials}

_lasting

0.5

1.5 sec. and _occurring in series of 40 to 50 in 6-8 min

_{regular periods}

at a mean

_frequency

of 5

_cycles/hr,

correlated with slow contractile changes in the wall, or in

_long

_irregular

periods (50-80 min) independently

of the feeding behaviour.

The presence of

propagated

bursts of _spikes

_along

the _cystic and common bile ducts

was correlated with those of the

_proximal

duodenum. Bile was delivered into the duodenum

just before the arrival of a bolus of

_digesta

at this level.

Cholecystokinine (CCK)

as well as its

_{synthetic octapeptide (CCK-OP) produced}

a

primary

gallbladder

response in the form of

long-burst potentials lasting

20-30 sec and then increasing in

frequency.

The relative _potency was 1 _yg of CCK-OP

_equivalent

to

2.5 ID units ot extracted CCK.

Both

_a-adrenergic

and

_cholinergic

substances

produced

an increase in

_spiking

acti-vity,

whereas

_p-adrenergic

substances inhibited this activity. Concomitant stimulation of

the two _types of receptors

by

adrenaline had an

_inhibitory

action.

Introduction.

The ruminant

_gallbladder

has been considered for a

_long

time to be

_incapable

of

_spontaneous

contraction under

_{physiological}

conditions

_{(Magee, 1965).}

However,

Caple

and Heath

₍₁₉₇₁₎

observed

_spontaneous

variations

_{of gallbladder}

intraluminal pressure which

they

attributed to the

motility

of that organ.

Nejmark (1977)

studying

sheep

recently

described the

_{relationships}

_{between these pressure}

_changes,

the

mechanical

_activity

of the Oddi’s

_sphincter

and the movements of bile

_through

the

biliary

tract. _{That author also noted the presence of}

slow,

periodic

pressure

fluctua-tions due to

_changes

in the tonus of the

_gallbladder.

Furthermore,

comparative

et

_{al., 1956).}

However, Ludwick and Bass

_{(1967) studying monkeys}

and

_dogs

did not

record any evidence of electrical or mechanical

_gallbladder

_{activity, except}

for a

slight

rise in _pressure

_just

after

_feeding

in

_dogs.

Similar results were obtained in

_pigs,

for which

_only

an antral-like

_activity,

considered to be an

artefact,

was recorded

(Laplace, 1976).

It has been

_recently

shown in anaesthetized

_sheep

that both

_vagal

stimulation and the administration of CCK or

_pentagastrin

in vivo can induce an increase in

intraluminal

_gallbladder

pressure due to the contractile

_activity

_{of that organ ;} this

would

_represent

the mechanism involved in the

_post-feeding

_response

_(Pass

and

Heath,

_1977).

It was

previously

proposed

that the mechanism of bile excretion involved

the _pressure

_gradient

between the

_biliary

tract and the duodenum. This has been attributed to the coordinated motor

_activity

of

fhe

_cystic

and common bile ducts with that of the

_sphincter

of Oddi

_(Mallet-Guy

et

al., 1933 ;

_Wyatt,

1967 ;

Sarles et

al.,

1975 ;

Nejmark, 1977).

No

_{morphological}

differences in the

_biliary

tract of ruminant

and

_{monogastric species}

have been detected

_(Boyden,

_1965).

However, the continuous

gastric

emptying

of ruminants indicates that their

_biliary

excretion and

_gallbladder

emptying

may not be limited to the

post-feeding period (Harrisson, 1962).

This is confirmed

_by

the fact that

_feeding

does not induce

_changes

in the duodenal

_motility

in

_{sheep (Bueno}

et

al.,

1975)

and

_by

the observation of

_{cyclic gallbladder}

_pressure

changes (Caple

and

Heath,

1971).

The aims of this work were

_(i)

to demonstrate that the

_gallbladder

has electrical

activity

and to determine its mechanical

_significance

and

_nycthemeral

_{organization ;}

(ii)

to ascertain how this

_activity

is related to that of the rest of the

_biliary

tract, and

(iii)

to

_investigate

the nature of the extrinsic nervous and

_{gastro-intestinal}

hormones

influencing

gallbladder

electrical

_activity.

Material and methods.

’

Animal

_preparation.

- Six Lacaune

ewes

_weighing

35-50

_kg,

housed in metabo-lism cages, and

receiving

hay

and water ad libitum were used for these

_experiments.

Surgery

was

_{performed aseptically}

in the fasted animal under

_thiopental

ana-esthesia

₍₂₀

_{mg/kg IV).}

Access to the

_gallbladder

and the

_biliary

tract was achieved

by

a 20-25 cm incision

_along

the

_{right hypochondrium.}

_{Ten groups of}

nickel-chro-mium electrodes were

_{chronically implanted}

_using

a

_{technique previously}

described for the small intestine

_{(Ruckebusch, 1973)}

at the

_following

sites : two _groups on the

gallbladder

(apical

pole

and

_neck),

one on the

_cystic

duct and two others on the com-mon bile duct at 1 and 4 cm,

_{respectively,}

from the

_junction

of the ducts. Six additional groups were

_implanted

on the abomasal antrum and the duodenal bulb at 5 and

0.5 cm,

respectively,

from the

_pylorus,

on the duodenum

_(at

5 cm on either side of Oddi’s

sphincter),

and on the

_proximal

_jejunum

at 3 and 4 m from the

_ligament

of Treitz. In 2 of the

_sheep,

two strain _gauges were

_attached,

one on the

_gallbladder

at an

equal

distance from its

_poles

and on the

_antihepatic

_border,

and the other on the

greater

curvature of the abomasum at 5 cm from the

_pylorus,

the sensitive elements

being placed transversally

to the

_longer

axis _{of the organ.} A silastic catheter

₍₃

mm

Recordings.

- The electrical

activity

was recorded from the free end of the elec-trodes connected to an EEG machine

_(Reega

_{XII, Alvar,}

93

_Montreuil).

The electro-myograms were

_registered

_daily

_(time

constant : 0.1

_sec.)

_{during periods}

of 8

_hrs,

with a _paper

_speed

of 4.5 and 7.2

_cm/min.

or recorded

_continuously

after summation

of the

_spike

bursts at 20 sec. intervals on a multichannel

_{potentiometric}

recorder,

at a low paper

speed (9

cm/hr) (Latour, 1973).

Simultaneous

_recording

of strain _gauge tensions

_(mecanogram)

and

_{corresponding}

_{electromyograms}

were made

_continuously

on a rectilinear pen

_{polygraph (Physio}

_IV,

Narco

_Bio-Systems,

_Texas).

Experimental procedure.

-

Starting

48 hrs after surgery, electrical

activity

was

recorded

_during

30 to 40

_days.

After an 8 to

_10-day

control

_period,

the animals were fasted for 72 hrs to

_analyze

the effect of the

_digesta

flow on the

_gallbladder

_activity.

Five

_days

after

_feeding

_they

received CCK-PZ

_{(GIH, Stockholm)}

and CCK-OP

(Kine-vac N.

_D.)

_{intravenously}

at doses of 0.5-1-4

_{Ivy Dog Units/kg}

and 0.1-0.2

_mcg/kg,

respectively.

The effects of these administrations were

_compared

to those of duodenal acidification

_by

a

_hydrochloric

acid

_(0.1

_N,

2

_ml/min.).

Nervous

_{orthosympathetic}

sensitivity

of the

_gallbladder

was tested

_by

intravenous administration of the

_following

substances

adrenaline,

_isoprenaline

_{phenylephrine}

at

_3,5

and 150

_{mcg/kg, respectively.}

The effects of

_neostigmin

_(Prostigmine

N.

D.,

40

_mcg/kg

_IV)

and

_{of atropine sulfate}

(0.1

and 0.5

_mg/kg

_IV)

were also

_{investigated.}

Results.

Gallbladder

_{electromyogram.}

- The electrical

activity

of the

_gallbladder

_apex showed

_rapid

isolated

_{potentials (200-250}

_!tV),

each

_lasting

0.5 to 1.5 sec.

_They

appea-red in

_cyclic

_{periods (type A)}

or

_dispersed

_(type

_B)

at a

_frequency

of 5 and

_13/min.,

without direct

_propagation

on the vesicular

body (fig.

1,

table

_{1) ;}

these

_rhythmic

phases

of the

_{apical pole}

had a mean duration of 6.2 _± 1.9 min. and

_appeared

at a

Electrical

_activity

of the neck of the

_gallbladder

_presented

the same basic isolated

spikes

as at _{the apex, and} was

_grouped

in short

_{phases lasting}

1 to 2 min. The

elec-tromyogram

also

_presented

_rhythmical

series of 15 to 20 bursts of

_spikes

_(6-10

_Hz),

occurring

after the end of a

_period

of

_apical

_activity

and in association with the

beginning

of a

_myoelectric

_complex.

Biliary

tract and duodenal coordination. - The

biliary

tract

_(cystic

and common bile

ducts)

presented

bursts of

_high

_{amplitude potentials (200-300}

_yV)

which were either

isolated and localized in the common bile duct with a

_high

_percentage

₍₄₂

_p.

₁₀₀₎

of

retrograde

propagations

(fig. 2),

or

_{cyclically propagated}

from the

_cystic

duct to

the

_sphincter

of Oddi. Each of these

_propagated

bursts started on the

_cystic

duct 0.81 ! 0.22 sec. before the occurrence of an isolated burst on the duodenal

_bulb,

which was

_propagated

in the duodenum to

_beyond

the

_ligament

of Treitz. This burst arrived at the choledoco-duodenal

_{junction 0.43 !}

0.11 sec. after that

_propagated

from the

_cystic

duct to the common bile duct had reached the last

_biliary

electrode

site, i.e. at about 4 cm from the

_sphincter.

This was the main

_{propagation pattern}

observed for this

_activity

since more _{than 87 p. 100 of the bursts} in the

_biliary

tract

were associated with the

_propagation

of duodenal bulb

_activity.

The

_cyclical

_periods

of

quiescence

of the duodenal bulb and the antrum

_following

the occurrence of bursts

in series on the duodenal bulb associated with the duodenal

_development

of RSA . were concurrent with the lowest

_spiking

_activity

level of the

_biliary

tract

_{(fig. 3).}

Electro-mechanical

_{relationship.}

- Simultaneous

recording

of the electrical and mechanical activities of the

_{gallbladder corpus}

showed that the

_phases

of electrical

activity

were associated with a slow increase in the muscular tone

_reaching

a tension

of

_{approximately}

_{2 g between the} two

_fixing

_points

of the strain _{gauge. These} oscilla-tions of the basal tension were observed

_{predominantly}

in the case of

_cyclic

_activity

(type A)

of the

_gallbladder.

Rapid

low

_amplitude

oscillations,

not

_individually

correlated with bursts of

variations of tension on the

_gallbladder

was not linked with that of the

_potentials

or

their

_frequency.

Basal tension was maximal when antral

_activity

was reduced and its

slow variations were attenuated

_{(fig. 4). During}

a

_{prolonged fasting period}

₍₇₂

_hrs)

the

cyclic

activity

disappeared

with a

_progressive

reduction of the number of

_rapid

potentials

in the

_gallbladder

_apex

_during

the first 24 hrs of

_{fasting. Refeeding}

was followed

_by

a restoration of the

_cyclic

_pattern

in 36 to 48 hrs.

Effect

of

CCK-PZ and CCK-OP. - The administration of CCK-PZ

(0.5 IU/kg

IV)

In fed animals induced an immediate series of

_spike

bursts in the

_gallbladder

_lasting

1.5 min. which was followed

_by

an

_{high frequency of potentials during}

4 to 6 min. after the

_injection

_(fig.

_5).

Increasing

the dose from 0.5 to 4

_IU/kg

did not

_present

a dose-effect

_{relationship.}

On the

_contrary,

at 4

_IU/kg

a reduction in the

_gallbladder

motor response was observed

_(table

_2).

_During

a slow intravenous infusion of CCK-PZ

_{(1 IU/kg)}

the

cyclic

organization

of the

_gallbladder

_activity

was abolished and

_{replaced by}

a

conti-nuous

_disorganized

_high

level

_activity

with

_potentials

_occuring

at a

_frequency

of

24.5 !

2.1 min., the normal

_cyclic

pattern

being

restored at the end of the infusion

(fig.

6). During

CCK-PZ

infusion,

the electrical

_activity

of the common bile duct was

reinforced

_by

an increase in the

_frequency

of

_propagated

bursts.

_{Concurrently,}

the

duodeno-jejunal electromyogram

showed a continuous

_irregular

_activity

_phase.

Such effects did not

_persist

_beyond

the

_period

of infusion

_{(fig. 6).}

The intravenous bolus

_injection

of CCK-OP induced both a

_primary

series of

continuous

_potentials

followed

_by

an increase in the

_spike

occurrence similar to that observed for CCK-PZ

_(table

2,

_fig.

_5).

The maximal

_primary

_response was obtained

at a dose of 0.1

_ygjkg

and was

_{approximately}

half of that observed for CCK-PZ at

Acidification of the duodenum

_by

slow

_perfusion

of HCI

_{(0.1 N)}

did not

_reproduce

the effects of CCK. The

_cycles

of

_gallbladder

_activity

were not

_disrupted

_but,

on the

contrary,

were reinforced from 30 min. to 2 hrs after the end of the infusion

_period

(fig. 6).

The common bile duct and the duodenum

_presented

an

hyperkinesia during

the 20-30 first minutes of

_{perfusion ;}

this

_excitatory

effect was followed

_by

a reduction

in the total

_activity

associated with an increase in the duodenal

_apparition

of the

regular

spiking

activity

at

_only

40-50 min. intervals in

_place

_{of 97 !}

13 min.

Sympathomimetic drugs.

- At 3

mcg/kg

IV,

adrenaline

_{suppressed gallbladder}

spiking

activity

for

3,

to 4 min. as well as that of the antrum and duodenum

_{(fig. 7).}

This response was

_particularly

marked for the apex as

_compared

to the neck but the

spiking

activity

reappeared

earlier at _{the apex, and} a normal

_{frequency of spikes}

was

obtained within 10 min. after

_injection

_(table

_3).

Similar but

_{prolonged (6-7 min.)}

effects were obtained with

_isoprenaline

_{(5 mcg/kg) (table}

3,

fig. 7).

On the

_contrary,

phenylephrine

(150

mcg/kg)

induced

_{gallbladder hyperactivity corresponding}

to a 3-4 min. increase _{of about 400 p. 100} in the occurrence

_frequency

_{of gallbladder rapid}

potentials.

Effects

of neostigmine

and

_atropine.

- The

of 3.2 from 30 to 60 sec.,

_following

administration of

_neostigmin

(30

_{mcg/kg) (table 3).}

On the

_{contrary, atropine}

_suppressed

this

_spiking

_activity

for 1.5-2 hrs at a dose of

0.5

_{mg/kg (fig.}

7,

table

_3).

These effects were limited to 40-50 min. with a dose of 0.1

_mg/kg.

Discussion.

This work demonstrates the existence of electrical

_activity

in the wall of the

gall-bladder in

_sheep,

associated with slow variations of its wall tension in accordance with the

_{cyclic changes}

in _{intraluminal pressure}

_previously

described

_{by Caple}

and Heath

₍₁₉₇₁₎

for this

_species.

These

_findings

differ from those of Ludwick and Bass

(1967)

who did not _{detect any electrical}

_activity

in

_dogs

or the

_{monkeys, observing}

only

pressure

changes

after

_feeding.

However,

neither the

_frequency

_patterns

of the

potentials

recorded at the

_{apical pole}

nor those of the

_body

and the neck of the

gall-bladder can be attributed to a duodenal

_(Klimov

and

Kotelnikovci,

1973)

or an antral

rhythm,

as

proposed by Laplace (1976)

for

_pigs.

No fundamental anatomical

diffe-rence has been determined in the

_gallbladder

structure of

_{sheep (Schreiber,}

₁₉₄₁₎

which would

_explain

_{the selective presence of electrical}

_activity

in _{the organ of that}

species

as

_compared

to other

_species.

A

_striking

feature is _{the presence of} an _apex

_cyclic

_activity

which cannot be cor-related with that of the other

_parts

of the

_biliary

and duodenal tracts. It is

_commonly

accepted

that bile formation is due to a combination of continuous

_(basal)

secretion

and

_{cyclic-adaptive changes}

in relation to other

_{digestive glands.}

In ruminants the

delivery

of bile into the duodenum increases the volume of the bile secreted, while

emptying

the reticulo-rumen reduces the

_secretory

rate

_(Harrison,

_1962).

In ad

libi-tum-fed

animals,

a

cyclic

contraction wave of the apex can be considered as a motor

adaptation

to

_changes

in bile volume as a _{consequence of}

_secretory

waves. This

hypo-thesis is reinforced

_by

the

_{disappearance}

of this _{response under} starvation.

The presence of a

_specific

electrical

_activity

of the

_cystic

and common bile ducts

in

_sheep

_{agrees with the}

_rhythmic,

_spontaneous,

mechanical activities recorded for the

_{extrahepatic biliary}

tract of other

_species

in vitro

_(Tooli

and

Watts,

₁₉₇₀₎

as well as

in vivo in anaesthetized

_(Tansy

et al.,

₁₉₇₁₎

or conscious

_{dogs (Doyle}

and

_{Farrar, 1965).}

The

_propagation

of

_spike

bursts

_along

the common bile duct was coordinated with that of the

_{corresponding}

duodenal bulb

_activity.

_Taking

into account the earlier arrival of the former at the

_sphincter

of

Oddi,

it seems

_likely

that bile is delivered to

the intestine

_just

before each

_digesta

bolus.

The continuous

_spike

_activity

of the

_neck,

associated with that

_{propagated by}

the

_cystic

duct after a

_spiking

_activity

_period

of the apex, may serve as a backflow

preventing

reflex.

The

_stimulatory

motor action of CCK observed in humans

_(Park

et

_{al., 1970)}

and

the on-off response.

According

to Robison et al.

_(1971),

_{CCK may} act at the level of smooth muscle cells

_by

_{way of cAMP.}

Duodenal acidification acts as a

_{CCK-releasing}

_{factor ; however,}

the different characteristics of the

_gallbladder

motor _{responses observed for acid and CCK}

sugges-ted that other _{factors may modulate this response} in

_sheep.

In vivo _assays on

_dogs

to measure the relative

_potency

of CCK-OP on induced

gallbladder

contractions, as

_compared

to

_purified

extracts of

_CCK,

have shown that 1 mg of CCK-OP is

_equivalent

to 27

_{Ivy Dog}

Units of CCK. In this

_{investigation,}

an

equivalent gallbladder spiking

response was _{obtained for 0.5 IDU of CCK and 0.2 fL9}

of CCK-OP per

kg

of

_{body weight, corresponding}

to a 92-fold

_{greater potency}

for CCK-OP

₍₁

mg of CCK-OP is

_equivalent

to 2 500 IDU

_{of CCK).}

Nervous control of

_gallbladder

_activity

in

_sheep

does not differ from that of cats

with

_respect

to the effects of

_adrenergic

and

_cholinergic

_drugs.

A distinction could be made between the effects of

_excitory

« mimetics and

inhibitory

p mimetics

when

phenylephrine

and

_isoprenaline

were administered

_(Crema

et

al.,

_1969).

The net

inhibitory

response obtained with adrenaline may be attributed to the low

proportion

of

_receptors

in the

_gallbladder

_{(Persson, 1972),}

as well as to the

_sensitivity

level of the two kinds of

_receptors.

The

_excitatory

action of

_neostigmin

on electrical

spiking

activity

concurs with the pressure

_changes

observed in

_sheep

after

acetyl-choline administration

_{(Hallenbeck, 1967)}

and

_{during vagal}

stimulation

_(Pass

and

Heath, 1977).

Re 5

u en d6cembre 1978. Accept6 en mars 1979.

Résumé. L’activité

_électrique

de la _vésicule, du tractus _biliaire, de la zone

antro-duodé-nale a été _enregistrée

_pendant

4 à 6 semaines chez 6 brebis adultes à _partir d’électrodes

intrapariétales

fixées à demeure. Chez trois sujets, les

_{électromyogrammes}

de la vésicule

et de l’antre ont été comparés aux

_{mécanogrammes}

obtenus à _partir de _jauges de contrainte

placées

au même niveau.

L’électromyogramme

de la _pointe de la vésicule biliaire est constitué de

potentiels

rapides (0,5-1,5 s)

isolés dont le

_{développement}

en série de 40 à 50

_{pendant 6,2 _!}

_1,9 mn

a lieu 4 à 5 fois _par heure et correspond pour chacun des

cycles

à des élévations lentes de

la tension

_pariétale.

Au niveau du col de la vésicule, ce _type de _potentiels est moins

_fréquent

mais _persiste associé à une activité

_phasique

de

_{potentiels groupés}

en 10 à 12 salves inter-venant à la fin d’une période d’activité

cyclique

de la zone

apicale.

L’électromyogramme cysto-cholédocien présente,

toutes les 80-120 s, 1 ou 2 salves de

potentiels

propagées

(7 cm/s)

et associées aux activités

_cycliques

du bulbe et du duodénum.

La formation de chacune de ces salves au niveau du canal _cystique par rapport au bulbe

duodénal assure un

_décalage

de 0,4 s entre l’arrivée de ces salves à proximité du

sphincter

d’Oddi, d’où un déversement intra-duodénal de bile

_précédant

l’arrivée du contenu duodé-nal.

L’administration intraveineuse de CCK-PZ

(0,5

à 4

_IDU/kg)

au même titre que celle de CCK-OP

_(0,1

et 0,2

mcg/kg)

procure une _riposte motrice de la vésicule avec une

_phase

primaire de

_{potentiels groupés}

durant 60-80 s suivie d’une

_{période d’augmentation}

(5-10

mn)

de la

fréquence

des

poten#iels,

1 _{j.g de CCK-OP ayant des effets

_équivalents

à ceux

de _2,5 IDU de CCK-PZ

_(GIH).

La

_perfusion

intraveineuse lente de CCK-PZ

_{(1 IDU/kg/h)}

ne procure que la réponse secondaire avec une _augmentation de 42 p. 100 de la _fréquence

Enfin, l’administration de sulfate

_{d’atropine (0,1 mg/kg)}

au _{même titre que} celle d’adré-naline

_{(3 mcg/kg)}

ou

_{d’isoprénaline (5}

_mcg/kg)

abolit l’activité

_rapide

vésiculaire alors

que l’administration de

phényléphrine

la renforce. Ces résultats

_suggèrent

un effet

stimu-lant des substances

_{cholinergiques}

et a

adrénergiques

alors que la stimulation des

récep-teurs

adrénergiques

est inhibitrice de la motricité vésiculaire.

En définitive, ce travail _permet de conclure que la vésicule biliaire

possède

une

acti-vité

_électrique

_organisée

_{correspondant}

à des contractions _toniques de la paroi non liées

à la motricité

cysto-cholédocienne

et duodénale, à

l’exception

d’une zone réduite au niveau du col.

Contrôlée sur le

_plan

hormonal par la CCK-PZ, cette fonction motrice est néanmoins

dépendante

d’une innervation

_{cholinergique}

et _x-mimétique excitomotrice et 3-mimétique

inhibitrice.

’

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