Changes in colonic motility induced by sennosides in dogs: evidence of a prostaglandin mediation

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Changes in colonic motility induced by sennosides in

dogs: evidence of a prostaglandin mediation

G. Staumont, Jean Fioramonti, Jacques Frexinos, Lionel Bueno

To cite this version:

Changes

in

colonic motility induced by sennosides

in

dogs:

evidence of

a

prostaglandin mediation

G STAUMONT, J FIORAMONTI, J FREXINOS, AND L BUENO

From the Department of Pharmacology INRA and theDepartmentof Gastroenterology,

Rangueil

HQspital, Toulouse, France

SUMMARY

The effects of sennosides

on

colonic motility

were

investigated in eight conscious

dogs

chronically fitted with

two

strain

gauge

transducers in the proximal

colon, an

intracolonic silicone

catheter

and

a

polyethylene catheter implanted

in a

branch of

the

right colonic

artery.

Oral

sennosides (30

mg/kg)

inhibited colonic motility

for 12to18 h afterathreetosix hours delay, and

associated with

giant contractions and diarrhoea. The minimal oral dose of sennosidestoproduce

such

changes varied from

5to

15

mg/kg.

Intracolonicsennosides at the minimaleffectivedose

and

at 30

mg/kg reproduced the effects of oral sennosides, but with

a

shorter

latency

(0.5-45

h).

Intracolonic PGE2 (100 tg/kg) in

viscous gel medium orintra-arterial PGE2 (10

/tgfh)

inhibited

colonic

motility

and

induced

giant contractions often associated with defecation. The colonic

motor

changes induced by intracolonic sennosides

at the

minimal effective

dose, but not those

induced by

intracolonic PGE2,

wereblocked

by

intra-arterial indomethacin

(10

[&g/h)

or

piroxicam

(5

[tgfh).

These results suggest that

colonic

motor

actions of

sennosides are mediated through a

local

prostaglandins synthesis, asthey wereblocked by cyclooxygenase inhibitor and reproduced

by PGE2.

Sennosides, the main laxative components ofsenna

extracts, which chemically belong to the anthra-quinones,areknowntoinduce fluid secretionin the colon'2andtomodify colonic motility.-5Becauseof their dianthrone-13-glycoside structure a bacterial degradation of sennosides is necessary to obtain active laxative metabolites.6 For this reason senno-sidesarepharmacologicallyinert in the upper gastro-intestinal tract and have an action localised at the colonic level.

Theeffects of sennosides on colonic motility

re-maincontroversial: astimulationofperistaltic

pres-sure waveshas been reported in human after intra-luminal administrationthroughacolostomy3whereas

a reduction of the intracolonic pressure' and a

long lasting inhibition of the colonic myoelectrical activity4 have been described after oral administra-tion inmananddogsrespectively.These

discrepan-Address forcorrespondence: Dr J Fioramonti, Station dePharmacologie,

INRA, 180 chemin de Tournefeuille, 31300 Toulouse, France. Received forpublication11March1988.

ciesmaybeattributed to differences in methodology, the intraluminal application not being a classical routeand the electromyography technique not taking intoaccounttheamplitudeof contractions. The first aim of this study was, to describe the changes in colonic motility induced by oral administration of puresennosides in thedog,aspeciescharacterisedby

awelldefined colonic motorprofile.7

The secretory effects of sennosides have been shown to be mediated through a prostaglandin synthesis as they are blocked by indomethacin.28 Prostaglandins are also known to modify colonic motility. Prostaglandin E has been foundto induce

a persistaltic activity in isolated longitudinal strips of colon associated with a relaxation of circular muscles,9todecreasesigmoid intraluminal

pressure`

Colonic motility and sennosides

synthesis.Consequentlyattempts toblock the effects of sennosides by indomethacin and to reproduce thembyPGE2administrations were done. Because of the strong ulcerogenicaction ofindomethacin in dogs'3 and the complete inactivation of prosta-glandins by lungs,'4 indomethacin and PGE2 were locally infused through a catheter chronically in-serted inacolonic artery.

Methods

ANIMALS

Eightmongrel dogs,20-25kg inweight, were used in these experiments. Under halothane anaesthesia, a smallpolyethylene catheter(Biotrol Pharma, Paris, id 0.30 mm, od 0.70 mm) was inserted into a ramificationof the right colonic artery inthe opposite direction of the bloodstreamaccordingto atechnqiue previously described for a jejunal artery. 1' The catheter waspushed intotheartery overadistanceof about 2cmin suchawaythat thetip was located just

atthe siteofbifurcation of the artery. Itwasfixedto the artery and the mesentery with 2:0 polyester sutures (Fig. 1). The location and the size of the perfused segment was visualised by injecting metylene blue into the catheter. The location was

6-8cmfrom the ileocolonicjunctionandthe sizewas

3-5cm.

Two strain gauge transducers constructed in our

Fig.1 Representationofselective intra-arterialinfusion techniqueoncanine colon. The catheterwasintroduced

upstreamintoanarterialramificationuntil the vessel

bifurcation.

laboratory were sutured to the serosa of thecolon, oneontheperfused segment and one 10cmaborally. Eachtransducer had itsrecording axis paralleltothe transverse axis of thecolon in order to measure the contractile force of the circular musclelayer.

Asilicone catheter (Versilic ND, Verneret, Paris, id 1 mm, od 3 mm) was inserted into the colonic lumen at 3 cm from the ileocolonic junction. The free ends of the strain gauge wires, the intra-arterial and intracolonic catheters were directed subcutan-eously along the flank to emerge dorsally between the scapulas.Both catheters remained permeable for two tofourmonths.

RECORDINGS

Calibration of each strain gauge was carried out beforeimplantation. The colonicmechanical activity detected by the two transducers was recorded by connecting the strain gauges to a Wheatstone bridge amplifier(VT 2100, Vishay, France) connected to a potentiometric recorder (RK4 Rikadenki, Toshin, Japan) withapaperspeedof 1 mm/min. The motility index at each of the two colonic sites wasdetermihed by means of a quantitative computerised analysis using a microcomputer data processor (Epson HX 20)according to the technique of Hachet et al.'6 The motility index calculated by the processing system, which reported values at 60 min intervals, corres-ponded to the measurement of the area between the baseline and the contractile curve.

EXPERIMENTALPROCEDURE

The dogs were maintained in cages for recordings over 22 consecutive hours (from 830 to 630 am). Immediately after surgery the arterial catheterwas

continuously (22/24 h) perfused with a diluted heparin solution(1000 UI/ml,2ml/24 h) bymeansof

an insulin infusion pump (Syringe driver, Type MS16,PyeDynamics, Bushey,UK). Dogswerefed

once adayat900amwithamixtureof 250 g canned (Fido)and250 g dry(Royal Canine) food fordogs. The sennosides used in these experiments(a gift from Madaus &Co,Koln, WGermany)consisted of driedpurifiedsennacontaining 92% of sennosidesA

andB,5%of sennosides

A1,

C and D,3% of water. Sennosidesweregivenat astandard doseof 30mg/kg orallyorbyintracolonicroute.The minimal effective dose of sennosides was determined by 5 mg/kg successive increases froman initial dose of 5mg/kg untilaneffectoncolonic motilityappeared. Senno-side administrations were done three hours after the daily meal.

Louis, MO). Intracolonic administrations of PGE2 weregiven three hours after themeal and the

intra-arterial infusion began three hours after the mealand

lasted three hours.

Attemptstoblockthemotoreffects ofintracolonic

administration of sennosidesattheminimal effective dose or of PGE2 (100 itg/kg) were carried out by intra-arterial infusion of indomethacin (Sigma, St Louis, MO) at a rate of 10 ,ug/h, piroxicam (a gift

from Pfizer, Orsay, France) at a rate of 5 pg/h. The infusions startedtwohoursbefore intracolonic

administrations of sennosides or PGE2 and lasted sevenhours. Indomethacinandpiroxicamwerealso

intra-arterially infused alone at the same rate and during the same postprandial period in each dog. Sennosidesandpiroxicamweredissolved insaline, indomethacin in a 5% solution of NaHCO3. PGE2 was dissolved in absolute ethanol (10 mg/ml) and

storedat-20°C;further dilutionsweremadeweekly

andstored at4°C. The intra-arterial infusionrateof

drugswas0*2mV/handcontrolswereperformedwith infusionsofvehicleatthesamerate.Thecontrols for the effects of intracolonic administrations of senno-sidesor PGE2were intracolonic injection of saline

(5 ml) orexcipientofPGE2gel (5 ml) respectively.

Each experimentwas doneoncein eachdogwitha

minimal interval of48hours. The location and the

permeability of the arterial catheter was checked

dailybyarapid arterial bloodinflow in the tube when itwasdisconnectedfromthepump.

STAT1ISTICALANALYSIS

The motility indexes reported each hour after senno-side or PGE2 administration (expressed in g min/h

andgivenasmean(SD))were comparedwith those

observed during the sameperiod in control studies

with administration of the respective vehicle in the

same animals. Because of variable delay for the

inhibitoryaction ofsennosidesafteroral administra-tionaperiodof colonicmotorinhibitionwasdefined as the time including consecutive hourly motility

indexeswith valueslower than30% ofmeanmotility

index determined over 10 hours after vehicle

administration. The changesincolonic motility index during this period of inhibition were expressed as percentage of control values reported at the same

time after vehicle administration. In attempts to

block the action ofsennosidesorPGE2

intracolonic-allyadministered by intra-arterial infusions of indo-methacinor piroxicam, motility indexeswere

com-pared duringaperiod comprised between three and

five hours after the beginning of thd intra-arterial infusion-that is, betweenoneand three hours after

intracolonic administration of sennosides or PGE2.

The number ofpeculiar colonic contractions

some-times associated with defecation, previously de-scribedasgiantcontractions`7wasmeasuredby visual

inspection of the records and expressed as mean

(SD).Acontractionwasconsideredasgiantwhen its

amplitudewasatleasttwotimeshigher ofthemean

amplitude of contractions during the same hourly

period in control experiments. Comparisons were

performed using a T Wilcoxon's test for paired values.

Results

CONTROL

In absence ofanytreatment, eachdogexhibitedthe typicalpatternof colonic motility alreadydescribed.7 During a period comprised between three and 13

hoursaftermeal,itconsisted of contractions grouped

inphases lasting 8.9 (2.8)min, occurringatintervals

of18.4(5.1) min (mean (SD) foreight animals)and

correspondingtoameanmotilityindex of9.3(2.7)g

min/h. Administrations of vehicle of each drug used

in thisstudydidnotsignificantly(p<0-05) modify the motility index.

EFFECTSOF SENNOSIDE ADMINISTRATIONS Oraladministration of sennosidesatadoseof 30mg/

kginducedaninhibitionofcolonicmotility lasting12 to18hoursandappearingafteradelay varying from three to six hours (Fig. 2, Table 1). Abundant

Table1 Changesinmotility index andnumberofgiantcontractionsinducedbyadministrationof oral and intracolonic sennosides and intracolonic (IC) and intra-arterial (IA)PGE2.

SennosidesperOS Intracolonicsennosides

Minimal Minimal PGE2 IC PGE2IA

Control 30mglkg effectivedose 30mg/kg effectivedose 100ag/kg 10 sg/h Motilityindex 100 15(4.7) 22(7.3) 10-3(5.9) 17(7) 13(5.2) 20(8.5)

(% control)

Giantcontractions(n) 0 10-6 (4.4) 6-8(3.8) 11-5(3.9) 5.9(2.7) 3-3(1.8) 1-9(0.9)

Values aremean(SD) fromeight dogs.Changes in motilityindex wereexpressedas the percentageofcontrolmotility indexduringthe same

Colonic motility andsennosides Control

WPJLPJJ1LLIA

[69

Sennosides 30mg/kg peros Sennosides 10mg/kg peros l l l l 2 3 4 5 6 7 8 9 10

Hoursaftersennosidesadminstration

Fig.2 Changesinmechanicalactivityofthe proximal colon observedinthesamedog after oral administration ofsennosides

at30mglkg andat'the minimaleffectivedose'(10 mglkg forthisdog). They consisted ofamotorinhibitionassociated with

'giantmigratingcontractions' anddefecation.

diarrhoea always occurred four to 10 hours after sennosideadministration.Giantcontractions, lasting aboutoneminuteandwithanamplitudetwo tothree timeshigherthan thatofothercontractions appeared during this period of inhibition and were often associated with defecation. Each diarrhoeic defe-cationcorresponded to agiant contraction but each giant contractionwasnotassociated withdefecation. Theminimal effective doserequiredtoinduce these disturbances of colonic

motility

anddiarrhoeavaried between 5to 15mg/kg. The duration of the colonic inhibition after the minimal effective dose was

shorter than that induced by the dose of 30mg/kg and similarly the number ofgiant contractions was

lower(Table 1).Thereduction of themotilityindex observed after theminimaldose didnot

significantly

differ however

(p>005)

from that induced by the 30mg/kgdose

(Table 1).

Intracolonicinjection of sennosides induced diar-rhoea, giant contractions and an inhibition of the basalcolonicmotilitysimilar in duration and

ampli-tudetothatobserved after oraladministrationatthe same dosage. For each dog the minimal effective dose of sennosidesintracolonicallyadministeredwas

identical to that determined after oral administra-tion. The onlydifference observed between the two routes ofadministration was a shorter delay (0.5 to 1.5 h) in theappearance ofthecolonicinhibitionafter intracolonic administration.

EFFECTS OFPGE2 ADMINISTRATION

Intracolonicadministration of PGE2 (Dinoprostone gel TM) at a dose of 100rig/kg induced changes in colonicmotilityroughly similartothat observed after intracolonicadministration of sennosides(Fig. 3).A significant (p>OO1) decrease in colonic motility index (Table 1) occurred after less than one hour and lasted two to four hours. Giant contractions appeared in six of theeight dogs used, usually with diarrhoeic defecation(five ofeight dogs).

Infusion ofPGE2intoacolonic arteryatadose of 10 jig/h for three hours reproduced the effects of

PGE2 10pg/hIA

l l l l I I

-2 -1 0 1 2 3 4 5 6 7 8

Hours

Fig. 3 Effects of PGE2 on mechanical activity ofthe proximal colon using intracolonic administration and intra-arterial (IA)

infusioninthe samedog.A motorinhibitionappearedassociatedto'giantmigrating contractions' and sometimes defecation.

their intracolonic administration. An inhibition of

similaramplitude appeared within30 minutes after

the beginning of theinfusion and lasted for one to three hours after the end of theinfusion (Table 1).

Giant contractions and diarrhoeawere observed in six of theeightdogs.

ANTAGONISM OFCOLONIC MOTOREFFECTS OF SENNOSIDES

The inhibitory effect of sennosides on colonic

motilitywassuppressed (Figs. 4,5),whentheywere introduced into the colon at the minimal effective

dose during an intra-arterial infusion of indo-methacin (10 .tg/h). The number of giant contrac-tions was significantly (p<005) reduced (Table 2) and diarrhoeicdefecation occurred inonlyone dog.

Similarly piroxicam intra-arterially infused (5

Rg/h)

abolished theinhibitoryactionof intracolonic senno-sides andsignificantly (p<005)reduced the number ofgiant contractions (Fig. 5, Table 2). The motor colonic effects of intracolonic administration of

PGE2 (100

[sg/kg)

were not modified by the intra-arterial infusion of indomethacinorpiroxicam(Fig.

5, Table 2).

An intra-arterial infusion of indomethacin (10

Rg/h)

or piroxicam (5 rig/h) alone did not

produce any change of colonic motility (Fig. 5, Table2).

Discussion

Our results indicate that sennosides inhibit colonic motilityindogs and induce high amplitude contrac-tions associated with diarrhoeic defecations. They

suggest that these motor effects are mediated

throughaprostaglandin synthesisastheyareinpart

suppressed by indomethacin or piroxicam and are

reproduced by intracolonic andintra-arterial PGE2. Interpretation of the effects of intravenous administration of drugs is limited by the interaction

of severalsystemsaffecting thedrugandby unknown pharmacokinetic data of the drug at the level of

Table 2 Numberofgiant contractionsinducedbyintracolonic sennosides andPGE2 duringarterialinfusion of indomethacinorpiroxicamorof theirrespectivevehicle.

Intra-arterialinfusion (0.2 mllmin)

Vehicleof Indomethacin Vehicleof Piroxicam Intracolonic administration indomethacin (10 glh) piroxicam (5 iglh)

Sennosides(minimaleffectivedose) 53(1.8) 3.4(2.4)* 4.9(0.8) 2-9 (2.3)* PGE2(100

,ggkg)

2.0(0.8) 2.2(1.1) 1.6(0.7) 2.3(1.4)

Values are mean(SD)fromeight dogs. Giantcontractions were counted for 15 hours after thebeginningof theintra-arterialinfusion.

Colonic motilityand sennosides Sennosides intracolonic10mg/kg l Diarrhoea

1Uis,025ffi

L~~A

Indomethacin 120- 100- 80- 60-Sennosides intracolonic10mg/kg IndomethacinlOpg/kgIA -2 -1 0 1 2 3 4 5 Hours

Fig. 4 Effects ofanintra-arterial (IA)indomethacin infusiononthe colonic motor pattern inducedbyintracolonic sennosides at the'minimaleffective dose' (MED)inthe same

dog.The motorinhibition and diarrhoeicdefecationwere suppressed and the numberofthe 'giant migrating contractions'wasreducedduring indomethacin infusion.

the target organ. The interpretation of ourresults obtained withprostaglandinsismore accurate using

an intra-arterial infusion than an intravenous administration as prostaglandins are widely distri-buted in theorganism, haveavery shorthalf life

and

no storage,and arerapidly inactivated duringasingle passage through the pulmonary circulation.'4

More-overindomethacin is knowntobehighly ulcerogenic in dogs by comparison with other animal species.'` Intra-arterial infusion of indomethacin at a low dosage avoidedgastric ulcer formation.

The changes in colonic motility induced by oral administration of sennosides are partially in

agree-ment with a previous study carried out in dogs4 showinganinhibition of colonicmotility. This study4 did not describe the giant contractions seen in our

experiments, however probably because of theuseof

an electromyographic method instead of the mea-surementof the contractile force. Thegiant

contrac-tions have beenalways describedusingstrain gauge transducers7 18 and taking into account their short duration, their detection on a colonic electromyo-gram is probably not easy. Inhibition of colonic motilityand presenceofgiantcontractions associated with defecation seem to be common features of laxative induced changes in colonic motilityasthey

were previously observed with castor oil and mag-nesium citrate. 18

Thelatency of threetosix hours between the oral administration of sennosides and the appearance of

x E (0-4,

C~

Piroxicam

c120-

TI

o II 20 iicdeIA 2ml/h) Sennosides IC (med)

F/e

1

SennosidesIC (med)

£1

1185 PGE2 IC (lO0pg/kg) -I] mIndomethacin IA(lOpg/h) LJ or Piroxicam IA

(5

pg/h) PGE2 IC (100pg/kg)

Fig. 5 Comparative antagonism of intra-arterial (IA)

indomethacin andpiroxicam onchanges in colonicmotility

indexinduced by intracolonic (IC) sennosides given at the minimaleffective dose(MED) or PGE2 (100,.glkg). Values

weredetermined from one to three hours after intracolonic

administration ofsennosides or PGE2 and are mean ± SD

fromeight dogs. *Significantlydifferent(p<0-01) from values obtained with vehicle intra-arterial infusionof vehicle. Control(100%)corresponded to the motility index without any administration.

thecolonicmotordisturbancesprobably corresponds

to the orocolonic transit and was similar to that observed with otherlaxatives.'8Sennosidesareinert in the upper gastrointestinal tract,6 however, while other laxative compounds such as castor oil have been found to modify small intestinal contractile activity. ' Moreover the sennoside induced changes in colonic motility observed in dogs present some similarities with the decrease insigmoid intraluminal pressure' and the large amplitude contractions3 appearing after intraluminal application inman.

Severallaxatives20 andparticularlysennosides,2are

known to alter epithelial fluid transport resulting in netfluid accumulation. Thequestion arises whether the disturbances of colonic motility are caused by a direct action of sennosides or are aconsequenceof fluid secretion. In dogs it has been shown that infusion oflarge amounts of a hypertonic solution of mannitol did not reproduce the colonic inhibition induced by sennosides or other laxatives but onthe contrary, stimulated the basal colonic

motility.2'

On the otherhand, after oral administration of

senno-sides in rats, the acceleration of the colonic transit preceded the net fluid secretion.22 These two data indirectly favour direct action of sennosides on

_i

colonic motility and not a consequence of fluid secretion.

Senna extracts havebeenfound to increase prosta-glandin formation in the rat colon.28 On the other hand inhibition of prostaglandin synthesis by indo-methacin has been found to antagonise the secre-toryactionof sennosides in the rat colon.2 8 Our data indicatethat the colonic motoreffects of sennosides are also mediated through a local prostaglandin synthesis.

Indomethacin inhibits fatty acid cyclo-oxygenase butalsoinhibits calciumaccumulation by mitochon-dria and microsome.23 A blockade of the effects of sennosides by indomethacin may be attributed to an inhibition ofprostaglandin synthesis but also to an action onintracellular calcium movements and it has beenshown that the actionof sennosidesonintestinal electrolyte transport was calcium dependent.' The blockade of the colonic motor effects bypiroxicam which is a cyclo-oxygenase inhibitor without action on calcium uptake,23 indicates that the sennoside induced motor effects depend upon prostaglandin synthesis. Moreover these motor effects are repro-duced byintra-arterial orintraluminal administration of PGE2. These results are not in complete agree-ment with recent data showing that intracolonic administration of PGE2 did not modify colonic transit time and did not induce diarrhoea in rats.24 Suchdiscrepancymay beattributedtodifferences in the solvant use. In the first study24 PGE2 were

dissolved in saline whereas in ourstudyPGE2 were in aviscousgel medium,usedforendocervical applica-tion25whichprobablypermittedaslow releaseofthe compoundin the colonic lumen. ThePGE2-induced inhibition of colonicmotility described herein, how-ever may be related to the relaxation of colonic circular musclereportedusingin vitro preparations9 and confirmed by the decrease in sigmoid intra-luminalpressure observed after intravenous adminis-tration of PGE2 in man.'0 Moreover, an analogy could bepointedout betweenthegiantcontractions and the PGE2-induced stimulation of peristaltic activity of isolated longitudinal strips of colon.9 Furthermore, the inhibition ofbasalcyclic contrac-tions and giant contractions seem to be a common featureof laxativesinvolvingprostaglandinsasit also appeared after castor oil administration'8 which increased colonic prostaglandin production2627 but

notafterhypertonicmannitolinfusion2'which did not modifytheprostaglandinformation.2627

Finally, our results indicate that sennosides in-duced a colonic motorpattern which mayplay a role inprostaglandinmediateddiarrhoea.

The authors thank C Betoulieres, G Bories, M Caussette,and CSantamaria for their assistance.

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