Effects of glucagon on systemic and splanchnic circulation in conscious rats with biliary cirrhosis

69

Effects of glucagon on systemic and spianchnic circul&ion in conscious rats with biliary cirrhosis

Raimondo Cerini, Abraham Koshy, Antoine Hadengue, Samuel S. Lee, Philippe Gamier and Didier Lebrec L’t:,lir6dc Rmh.~rche~ L Phyiopurhologie H@miqvr (INSERM md Fondrtmn de Recherche m Hormonologie, (Recwed 21 Sepember (Accepted L4January

U-24). H@iml Benujm Frmn~ (France)

Clichy.

19R8, ,989,

To elucidate the relationship between the haemodynamic changes and glucagon in cirrhosis, we infused physiologic and supraphysiologic doses of this hormone in conscious rats with portal hypertension due to biliary cirrhosis. Cardiac output and splanchnic organ blood flows were measwed by the radioactive microsphere method before and 30 min after glucagon infusion at doses of 2.5 and 10 oglmio. Serum glucagon increased from a basal level of 92 k 17 pgiml (mean f S.E.) to 399 f 89,llSl ?k 136 snd 2064 C 328 pg/ml, respectively, in sham-op erated rats, and from 743 + 75 pg/ml to 14”7 * 197, 1583 + 356 and 2957 f 649 pg/ml, respectively, in cirrhotic anituals at 2.5 and 10 nglmin doses. In both groups, cardiac output did not change after glucagoo infusion at 2 and 5 nglmin doses, suggesting that factors other than glucagoo are primarily respunsible for the systemic hyperdynamic circulation in cirrhosis. Portal tributary blood tiow increased significantly after glucagon infusion in sham-operated rats by 34 and 65% at doses 0:‘5 ngiml and 10 @ml, respectively, and in cirrhotic rats by 29% at a dose of 10 q/ml. However, par, 31tributary blood flow did not change after glucagon infusion at the physiologic dose of2 @min. This study shows that gluccgoo infused at a physiologic dose does not increase splanchnic blood fknv, although it increases portal tributary blood flov .at supraphysiologic doses. Tbe discrepancy between blood glucagon levels and splanchnic haemodynamic responses suggests that glucagon plays only a minor role and that other factors are primarily responsible for the hyperdynamic state of the splanchnic circulation in rats with biliary cirrhosis.

-. WE s~pparted in part by a grant from ths C&w Narronakd’A\sourancc Maladiedes TravailteursSatariCrand the Instirut et de la RechercheMedicale. Dr. A. K&y hcid a feliowshipfrom the Fondwion pour la RechercheMddicate,and Dr. S.S. Lee from the Medicai ResearchCouncil ofCanada. This studywas xesenredin part al the 23rd Meeting 01the Eur0peanAssociationfor the Studyof the Liver, Leuven,Bet8ium.25-27 August. 1988, Id hasbeenpublishedin abstracrform (J. Hepato!. 1988:7 (suppI.1): Sl9). Cormpondenc. D. Lebrec,INSERM U-24, Hdpithl Beaujon, 92118Clichy. France.

‘Ibis work

Nationalde IBSant6

I : Dr.

0.68.8278189~193.50@ 1989Ekevier SciencePublishersB.V. (BiomedicalCivinon)

70

It has been demonstrated that both byperglucyo~aemia and b:iperkinetic circulation are present in p.1’ tients with cirrhosis [l-3]. Glucagoo p:oduces vasedilatation [4] and causes splanchnic and systemic hyperapmia [5-71. It has therefore been suggested that glucaguunmay be responsibie for the hyperkinetic circulation observed in portal hypertension. This association bss also been demonstrated in anaesthetized portal hypertensive Tats [8,9]. Further, the use Of specific glucagon antibodies reduce, portal tributaty b:osd flo-wby about 30% in portal vi in stenosed rats [a]. However, in rats with porta! vein stenosis perfanned 6 months earlier, the !lyperdynamic circulation decreases while hyperglocagonaemia persists [9]. It also appears that patients with portal hypertension due to portal vein obstruction ha’ e a hyperkinetic circulation with normal plasma glucagon levels [lo]. Therefore, the relationships between serum glucagon levels, cardiac output and portal tributary blood flow are not clear. This study was undertaken to assess the systemrc and splanchnic haemodynamic effects of glucagon infusion of physiologic and supxiphysiologic doses in Lwscious rats with portal b,;‘pertension due to cirrhosis.

MaterisIs and Nkthods Animals

Sixty four male Sprague-Hawley rats (Charles River. Saint-Aubin-I&-Elbeuf, France) were divided in two groups. It the first group, a secondary biliary cirrhosis with portal hypertension was produced by bile dwt ligation, while the other was composed of sham-c?erated rats. These &~rl procedures were performed under ether anaesthesia 3-4 weeks before the haemodynamic studies as previously described [lo]. Rats were allowed free access LOfood and water until 14-16 h before the study, when to ad was withdrawn. At the time of the haemodywnic investigation, the mean weight for each group was similar.

R. CERINI et a,.

Glucagon base, (Novo Industrie Pharmaccutique, Paris, France) dissolved in distilled water, was perfused into a venom catheter. Each dose of glucagon was dissolved in 0.6 ml of 0.9% N&I. Isotonic saline was perfused as ;!^CPbo. Mzan arterial pressure, cardmc outpur alit x&t. al blood flows were measured before and at the 30th nin of continucus infusions of either isotonic saline (0.02 ml/mitt) or glucagon (2.5 or 10 ng/min). Placebo and the ‘hree glucagon doses consisted of eight rats each. Blood samples for rjucagon determination, were drawn fir&mthe carotid artery, centrifuged at 4 “C and sto-ed at -20 “C until the time of assay. Glucagon levels were determined by a double antibody radioimmunoassay using antibodies from IRE-Meugenix (Belgium) in blood samples pretreated with aprotinin.

Cardiac output and regional blood flows were measured by the radioactive muosphere method as previously described [lOj. in brief, the left ventricle (catherized via the right carotid artery), the left jugular vein and a femoral artery were cannulated under rther anaesthesia. After catheter insertions, the animals were securely p!aced in a restrtining apparatu, and allowed to reawaken. A precounted aliquot of 15 pm diameter ‘“‘Ce-labelled microspheres (New England Nuclear, Boston, MA, U.S.A.) suspended in 5% Ficoll 70 (Pharmacia Fine Chemicals AB, Uppsala, Sweden) and ultrasonically agitated was injected into the ~~entricularcatheter and flushed with 0.7 ml of isotonic saline over 45 s. Starting 5 s before the microsphere injection, the reference blood sample was withdrawn from the femoral arterial catheter at 0.8 mllmin for 1 min. Thirty min after saline or glucagon infusion, a second injection of “‘Sn-labelled microspheres was perforixeJ. The animals were then killed with an overdose of pentobarbital sodium. Individual organs were dissected and placed in individual tubes for counting using a gamma counter (camp tour gamma G 4Go0, Kontron, Montigny-Le dretoneaux, France) at energy settings of 70-120 and

280-loo0 kav fo: ‘“‘Ce and “‘S”, error

due to the spillover

nel was corrected Adequate ference

wing

microsphere of
Three

of “‘S”

animals

rejected calculated

The chan-

and

mixing

between

no,

from

‘%I

respectiveiy. into the ‘%e “‘Ce

was analyzed

standards.

was assumed

by Student’s

data by one way analysis “i correction

by a dif-

considered

paired

t-test and unpaired

of variance

for m&iple

with a Bonferro-

comparisons.

P < 0.05 was

significant.

the left and right kidney.

meeting

the study.

this reqnirement, Cardiac

by the followixp

output

formula:

were

(CO)

was

ReSUlls

(ml/min) =

CO

(radioactivity injected (cpm)/reference blood sample radioactivity pressed

@pm))

Y 0.8 (ml/min).

per 100 g body W. (cardiac

cular resistance

(TVR)

was calculated

ing formula:

TVR

tial pressure

(nun Hg) x 8WCO

blood tivity

(dyws~cnt‘“)

flows were calculated

la: organ

blood flow = (organ

injected

tary blood

(cm))

This

index).

= (mean

(mlhnin).

intestine,

colon and mesentery

Sfatistical

analysis

formutribu-

as the sum of stomach, with pancreas

of 2.5 and 10 ng/min

TABLE

and

Glucagcm

are expressed

as mean

+ S.E.

were

significantly and cirrhotic

glucago”,

respectively.

flows. Systemic

Results

levels

sham (‘.u -L 17 pg/ml)

In both groups of animals, the infusion of glucagon caused dosedependent increases in glucagon activity. The plasma glucagon levels were 399 + 89, 1151 f. 13’1and 2064 + 328 pgml in sham; and 1497 + 558.15~3 5 1007 and 2957 +_ 1837 @ml in cirrhotic animals, after the infusion

(cpm)/radioacFortal

g!t;cz&~

between

rats (743 ? 75 pe/ml).

ane-

Regional

by the following

x CO (mUmin).

flow was calculated

different

by the follow-

x id

activity

Bias?plasmi

was exTsJtal vas-

Paired

data

mean

extracplanchnic infusions

arterial

pressure

had

haemodynavrics no significant

or heart

effect

rate (Tables

o”

I and 2).

1 GLUCAGONINSHAKOPER~TEDRATS

SYSTEMICANDEXTRASPLANCHNICH4EMODYNAMICEFFEC7CSOF Values are means * S.E.

--~ __

_

Pkebo

GlUC‘3g.D”

O.O2ml’m;.-

2 nghnin

5 n* i.in

basal values 30 min aitx

basal values Mmin zltvr -___

basal values

Cardiac output (ml~min+l’X) g bodywt.“) 36.520.5 Rear1 rate (beatslmin) 409229 Mean:.rterial pressure 114t4 (mm Hg) TOW! vasculu resistance :dynescm-s x W) 84.1t2.7 Heart (mbmin-‘. gtissuew-‘) 5.05*0.54 Kidneys Wml”g tissue wt. .I) 7.49kO.40 L”“gS (ml.mi”-‘.g tissue wt.-‘) 3.67kO.54 ___ -_Signitienntly different [rum basal

~______ 30 mi” after

III “ghni” basal values 30 r&u after _~

36.6&O 2

37.0r1.4

36.6*l.Ll

34.9kl.l

35.7t1.1

34.7kl.O

4042?8

40822,

409*22

397*2*

39w26

397f35

38.9fl’ 4GQ+31

1?8f4

113F3

114%3

11553

11753

115+3

llBf3

85.7+3.9

83.2*3.5

85.6+4.7

86.5k3.2

a3.5+4.0

83.5+3.l?

77.3k3.6’

5.92~0.58

6.36r1.02

7.99&1.1,5

7.49+0.9!;

9.81+0.42*’

5.8&“.65

9.47rO.W

80210.70

9 17+0.82

1 11.26+1.13

14.61~1.07’*

9.58+0.75

,3.47+1.63*

2.54:CO.55

2.6X0.58

2.34f0.47

3.59t0.54 values ‘P-C

10.73fl.l

4.32~0.65 4.42?0.8:1 _____-_ 0.01. *’ P <. 0.05

2.46eO.24

72 1” addition,

glucago”

extraspianchnic change

at 2 “g/mitt

effect.

cardiac

index.

However,

or

n&tin,

portal

did not

cxased

by 64% in sham-operated

bad ncr systemic

At 5 nglmin,

glucagon

in cirrhotic

this dose significant-

ly increased renal blood flow in sham-operated but not in cirrhotic rats. Infusion of glucdgo? at IO nglmi”

crezwnts

sig”ifica”:ly

cantly

increased

cardiac

Ac-

cordingly, total vascular resistance decreased

by

and 7% ir bile duct

10% and 6%, respectively. ly increased

renal

vein.

increxed

blood

flow in both

sham

haemndynamic

(Tables cantly @tin

infusion effect

3 and 4). increased

on

depemkd

arterial

glucagon

on in-

in the territory blood

of

flow signifi-

infusion

at 10 “timin

systemic

effect

The

in either

pre><“ce

at 2 nglmin

and saline

splanchnic

haemodynamics

Portal tributary

blood

by 34% after glucagon

in sham-operated

of hypergiucagonaemia

has been wel! documented correlates

in human

Hydegree of hep-

[l-3,10,!2].

with the

atocellular dysfunction [IOJZ] and appears

Splanchnic haemodynamics na

increase

in-

ano by 29%

and cir-

had no significant

cirrhosis

had

Hepatic aft-r

perglucagonaemia

tkw

rats.

in the two groups.

group.

The glucago”

This

itow sigmficantly

This dose also significant-

rhotic rats. Saline infusion or extrasplacchnic

ligated

animals.

blood

m blood FWJ of all organs

the portal

index by 10% in shamanimals.

operated

tributary

solu-

to pancreatic munoreactive be higher

at 5

rats, but did not change

in

bile duct ligated rats. After glucagon infusion at IO

SYSTEI 1IC AND EXTRASPLANCHNIC

HAEMODYN4MIC

glucagon

to be dw

“t the hormone

values

have been

[2j Im-

reported

to

hypertenwe by portal vein SenDsis than in sham animals [8,9]. However, the clinical significance of this experimental finding constrasts that found in patients

flow signifiinfusio”

hypersecretim in anaesthetized

EFFECTS OFGLUCAGON

portal

rats rendered

IN CIRRHOTIC

R+.i S

“afuel are “lPd”S + SE.

.._

basal vnlus

3Omin pier

basal values

30mm after

647kl.O

62.9kt.S

62.6+1.4

61.6+2.2

61.8+1.9

63.8kl.2

68.2+1.4*

IOS~IS

406k2S

4c6i26

40243

396+40

401+30

4Oz+z3

1cw4

102k2

,04+3

103*3

1@4+3

msc3

x.S+3

45.:*1.5

4: li0.S

43.9’0.7

43.7FI.S

44.2i1.7

43.a+1.3

41.0*1.1*

8.16+0.4

Q&+0.83

6.93ZO.54

8.65+0.7S

lC.12kO.71

12.84~3.48

9.07ko.77

11.23kt.14**

17.84k1.42

17.34f1.32

16.92f1.41

17.41*1.12

18.87+1.25

23.92k3.37

3.00+0.25

2.91f0.29

4.02kO.44

3.SLk0.52

3.20C0.38

3.6420.48

basal values

-.___-_ _~~ ~.___ Cardiac out at (ml.min. P WI gbodywt:‘) 64.3*1.1 Heart rate (katslmin) 397f14 Mean arterial pre%“re umf4 (mm Hg) Total vascular

!. min

__-

after

u-.

basal value< 31111””afwr -

resistance (dym~wn~

44,,fl Heart (mUmin-‘.g dsue WC’) Kidnevs (ml&in-‘.g tissw uV1) 1 ungs (mt~min-‘,g tissue wt.-‘)

4

Significantly different from basal Va!xs *P < 0.01, *‘Pi

0 05.

18.97_C1.S2 25.36~1.78”’

3.Wk0.33

S.3Sf1.24

HAEMODYNAMICEFFECI

2 OF GLUCAGON

IN ClRRHOSiS

73

with portal vein obstruction who have normal gluca-

and the other found increase.; blood levels in fasted

gw !evels [lo]. Father,

rats [U]. The present study performed in fasted rats

reports of glucagonaemia in

experimental cirrhosis are scanty. There is a report of

with cirrhosis due to bile duct ligation, showed high

increased immunoreactive

basal glucagon levels and thus offers the possibility of

thykitrosamine

glucagon levels in dime-

induced cirrhosis in dogs [13] and

investigating the role of hyperglucagonaemia

two apparendy contradictory reports in carbon tetra-

hyperdynamic

chlorita induced cirrhosis in rats [14,15]. One group

sive animals.

fourd normal serum glucagon levels in fed rats (141

TABLE

in the

circulation of these portal hypertzn-

In this study, when glucagon was infused at 5

3

SPLANSHNIC Values are mVmio per flow. Liver and hepatic

HAEMODYNAWC

EFFECTS .,F GLUCAGON

2 nglmin

au2 rn”rnm

RATS

Gastric Intestinal Cotonic Spknic kferentericpancreatic Portal tributary Hepatic sptnncnnx

5 ng’min

0.78kO.12 1.24f0.12 O.StkO.07 2 25+n 31

0.63f0.05 1.39f0.08 0.83~0.&3 * 44t0.33

basal values 30 min aR :r basal valuer ______ 0.85SW9 O.BlfO.09 0.78?0 39 1.54*0.20 1.64+0.74 ,.79ro.,3 1.08+_0.14 1.05+0.16 1.0~3+0.07 1.74to.x 2.3t+n 3R z.27co.52

0.98kO.06 4.66+0.24 0.56+o.tl5 6.5WO.3L

t.O4j;O.t3 4.96+0.31 0.67+0.10 7.08kO.57

0.86~0.10 4.27kO.37 0.7OiO.07 6.13f0.40

ba;:

Sigllilieanrtydiffcrent

SPLANCI

1N SHAM-OPERATED

means f S.E.. erprersed in mtimin per g lirsue wt.. cxcepl for portal !ributary and planchnic btoad flows exprersed in tMI g body wt. Portal tributary blwd flow is the sum of gastric. inteadnal, colonic, sptenic and mewmeric-pancrearic blczd blood flow is equal to hepatic arterial blood flow. Splanchnic blood flaw is equal IO the sum of portal tributary blood flow arterial blood flow.

vaks

30 min after

from basal values *PcO.O5,

INK rlAEkiODYNAM!C

*‘Pi

1.08~0.12 4.41?0.46 0 73+0.05 643~0.48

1.OSfO.LS 4.4lkO.3: 0.75*0.M 6 52i0.33

10 ngimin 30 min after

basal values 30 III,” after

0.93kO.W 2.56f0.29” t.24+o.tcl 2.51+0.%3

0.80+0.W~7r 1.53+0.15 2.77f0.20** 0.90~cl.00 t.32+0.12* 2.45f0.22 2.50+0.48

t.51t0.17* 5.93+0.48” 0.999fO.W 8.7O+O.66”’

0.85fO.03 4.2650.22 0.69k0.M 6.36+0.2!

0.37+0.05” 7.02+_“.41**** 0.89WtC’ 9.75i;3.84”

0 01, **‘P
EFFECTS OF GLUCAGON

IN CfRRHOTtC

RATS

Valller are means + SE., expressed in mUmin per g tissue wt., ercrpt for portal tributary and sptznchnic bled flows expressed in mllmin per jr) g Lody wt. Portal tribmary blood flow is the sum of gastric. kestmal, coboic. splenic and mesenteric-parrrea!rc bload flows. Hepric blood flow is equal to hepafic arrcrial blood now. Splanchnic blood flow is equal to the sxm of penal venous tibutary blood flow at d hepatic arterial blood Bow. Organ blood Aow

(nlmin-’

perg

dssue VI,.)

Gesrric Intestinal Cotonic SplCIlk Mesenteric-pancreatic Ponaltributwy “eCl.%tic ---r--S+mchnic

&nificz~ntly different

Gt”cag0”

Placebo -.0.02 m!Jmin -basal values 30 min alter

2 ngimin 5 ngonin -basal values 30 min after basal values M mi? after

t.52iu.12 ,.93+0.24 1.2liO.12 l.S33+0.14 1.41+0.10 8.17+0.42, ir.8izO.09 15.13kO.75

1.66~022 2.?3+0.26 1.4lkO.14 1.0210.12 1.25i0.14 8.17f0.51 0.78+L’.O7 13.70+0.69

..51+0.21 1.93f0.26 1.4OkO.16 t.t9+O.W 1.42+0.08 8.42f0.43 0.89fO.W/ 15.39+0.46

from basalvalues

1.4o+o.t5 2.65f0.23 1.3OkO.12 0.87k.O.12 1.47+0.15 7.97f0.43 0.77f0.07 13.44-cO.78

1.67+.d.12 2.53+“.34 1.69k0.22 1.29+0.28 1.32f0.12 8.36f0.79 0.78f0.07 13.81+0.@5

*P
*.W+O.lt 2.99+0.36 1.7t7+0.25 1.2OiO.23 1.52+0.16 8.81+0X4 0.87i1.01 15.10cu.91***

lo&T bzat vzher

30 min after

1.6u+0.13 l.Ss+u.26 3.58f0.19’ 2X+10.17 !.3&kU.O!J l.PfO.16 1.42k0.35 t.Oz*5.17 l.llCO.13 1.58~0.15’ 8.47+0.40 to.WTku.67** 0.79+o.O9 1.10~0.08”’ 13.76+0.85 18.54?0.99* -__

R. CERINI

74

et al.

ng/min (17 “g/kg per min), in sham-operated rats, sr-

cncc of 57% (34.92 and 61.59 ml/min per 100 g body

terial plasma glucsgon *ox to a levei rbar was some-

wt.)

what higher than the concentration measured in cir-

this dose increased portal tributary

rhotic rsts. This result is similar to that found in the

34% (4.41-5.93

between sham and cirrhotic rats. In addition, blood flow by

mllmin per 100 g body wt.), but this

only comparable study, where a dose of 18 “g/kg per

increase explains only 38% of the difference between

min, wss found to raise arterial plasma glucagon lev-

sham and cirrhotic rats (4.41 and 8.36 ml/min per 100

els to 952 pg/ml in normal dogs [16]. To implicate glu-

g body wt.). Further, at s glucsgon infusion rate of 10

eagon as the sole mediator of the hyperkinetic circu-

ng/min in shan rats, blood glucagon levels increased

laion

to more than two times the level in cirrhotic rats but

in cirrhosis, arterial blood concentrations of to those occurring in cirrhosis,

portal tributary blood flow did not reach the values

should be capable of increasing cs~diac output and

found in cirrhotic rats. Thus, glucagon per se cannot

glucsgon,

similar

portal tributary blood flow to the same level as ob-

account for the hyperdynamic

sawd

and explains only part of the byperdynamic splsnch-

in cirrhosis. When glucagon was infused at

ng/min, a dose sufficient to raise the blood glucagon

systemic circulation

nit circulation of biliary cirrhotic rats. This implies

leveis above those found in cirrhosis, cardiac output

that glursgon

db: not change, which is in contrast with t>e differ-

sham and cirrhotic rats.

ReferelleeS

and short-termportal hypertenwe rats:the relation to sys*emit ghxagonlevels.Hepatology 1986:6: 414-418. 10 Smith.LaingG, OrskovH, Gore MBR, Sherlxk S. Hyperglucagoosemiain cirrhosis.Relationshipto hepataeellular damage.Diaberologia1980;19: 103-108. 11 Lee SS, Gi,cd C. Brailla” A. Hallcogue A, LchrecD. Ho. madynamic characteriaationof chronic bile duct-ligated rats: effectsof pentobarbitalsodium. Am J Phyaiol 1% 251:0176-G1&a 12 Kabadi UM. RisensteinAB, Tucci J. Pellicone J. Hypexnlucogonemia in hepatic&hair: its relation to hepatccelMar dysluncfion &d normalization on recovcry~Am J Gastroentorol1984;79: 143-149. 13 Radziuk I. Durn6 J. McDonald TJ. l.evv M. We&r M. Decreasedse&ity of glucorewr~over~13&cagon and its hypenecretion in hepatic cirrhosisin dogs. Clin Res ,977: 25: 397A. 14 Ahvmark A, Mamlok V, Greeley GH, Samor A, Thompson JC. Insulin and glwagon production in experimental cirrhosis.AnnSure 1987:205:Q-12. 15 lkeda T, TakeuchyT, h&rakami I, Mokuda 0. Tominaga M, Msshiha H. Secrelinn aad degradationof rnsulinsnd glucagonin carbon tetlachloride-inducedliver ijury rats. AmJ Physic41986:251: E&O-E@& 16 PremenAJ, Hall JE, Smith MJ. Postprandialregulationof renal hemodpamin: role of pancreaticglucagw. Am J Phyriol1985: 248: F656-F642.

1 Marco J. Diego J, Villanueva Ml.. Diaz-Fierros M, Valverdc I, SegoviaJM. Elevated plasma glucagonIweIr, in cirrhnsisoftheliver. NEngl J Med 1973:2: 1107-1111. 2 Sherwin RS, FisherM, Bcsrofff. et nl. Hyperglucagonemia in cirrhosis: altered secretionand sensilivy to glucagon. Gastrcenterology1978:74: 1224-1228. 3 ShankarTP, Fredi JL, HimmelsteinS, SolomonSS, Duckrortll WC. Elcvatcdgrowth, ormonelevelsand insulin resistancein pana.:~ wirh cirrlxris of the liver. Am J Med Sci 1986:29: 248-254. 4 Fa&AE. Glucagonand the circulation. Pharmaml Rev 1983:35: 181-217. 5 Tihblin S, Xock NG, SchenkWG. Splanchnichamodynamic respanscs to glucagon.Arch Surg1970;IW: 84-89. 6 Kock NG, Tibblin S. SchcnkWC Hemadynamicrcspxws 10 glueagon:an experimentalstu.ly of central, viscera,and peripheraleffects.Ann Surgery1Y70;171:373-379. 7 KravetaD, Arderiu M, BoschJ, FusterJ, Visa J, Casamitjana R, Rod&J. Hyperglucagonemiaand hyperkiwlic cir. cullion after portocavalshunt in the rat. Am J Physiol 19*7;*52: GZ57-Gx.1. 8 Benoh JN, Barrowann JA, Harper SL, KvietysPR, Granger DN. Role of humoralfactorsin the intestinalhyperemia asseciawdsirh chronicportal hypertension.Am J Physiol 1984;247: G486-G493. 9 Sikuler E. GmszmannRJ. Hcmodynamicrtudies in long-

~.~

sensitivity

is not different

between