Regulation of hepatic metabolism by extracellular nucleotides and eicosanoids

259

____._

Review

Regulation of hepatic metabolism by extracellular nucleotides and eicosanoids The role of cell heterogeneity

Extracellular

Inmduaiun

nucleotides: sources, recep(ws and ef-

feels in the liver Purine and pyrimidine millimolar

nucleotidrs are present in

concentrations inside the liver cells; their

function in energy tronsfcr PI renaions

is well-established.

space. however.

I diverse In

these nwleotides

biosyntoeric

the extmcellular are short-lived

ATP is released into ibe exirxe!!uiar

space from

synaptic vesicles as cotransmitter of the sympathetic nervous system and from purinergic nerves in the autonomous

nervous system (for

l,Z).

only. In recent years it became clear that extracellu-

and Ap,A

Iar nucleotides in micromolar

during degranulation of blood plate!ets upon stimula-

and submicromolar

concentrations exert horowne-like

actions on various

ATP,

ADP,

the diadenine

reviews see Refs.

molecules and are detectable by refined techniques

nucleotides AplA

and also other nucleotides are liberated

tion with thrombin, and the in vitroestimated

Plasma

cell types, including liver cells, after binding to spe-

concentrarion of ATP following platelet activation is

cific receptors on the ccl1 surface. Recent studies

about 12 PM 13.41. Other sources include ATP re-

have shown that the hepatic response to extracellular

lease by exocytosis from the adrenai medulla and

nucleotides and also othe; stimuli is composed of

there is some evidence that ATP can also be spaifi-

complex network interactions between different hep-

tally released by an as yet unidentified,

atocyte populations involving eicosanoids 8s signals

totic mechanism from the cytoplasma of a variety of

non-exocy-

in the communication betweerl hepatic p;ueochymal

cell types, including vascular endothelia and smooth

and non-parenehymal cells and also an acinar hetero-

muscle cells (for review see Ref. 2). Extracellular

geneity regarding effector and inactivation sites for

cleotides are short-lived molecules in viva and are

some of these compounds (so-called ‘perivenous SEBV-

rapidly hydrolyzed to the corresponding nucleosides

eager cell hypothesis’). This article briefly describes

by different nucleotidases found in the plasma and on

nu-

some aspects of nucleotide and eicosanoid action in

the surface of cel!~. In whole blood, the balf-iife of

liver and the role of hepatocyte heterogeneity in me-

extracellular ATP is about 2 min, .%hereas it is more

diating the hepatic response to a variety of stimuli.

than 6 min for Ap.,A,

o16&8Z7WWSo3So~ 1989ElscvierScicnce PublishersB.V. (BiomedicalDivision,

and it was concluded that di-

D. HAUSSINGER

260 accnine nucleotides

may rl~t as signal molecules even

at sites far away from However,

the plate!et

the actual half-life

aggregate

[S].

in viva may be consid-

erably shor:cr in view of the high activities of ectonucleotidases found on the surface of many cell types. This suggests that extracellular

nucleotides

exert their effects predominantly their site of liberation. iophosphatase responsible

plasmrr

py-

membrane

has

[6] and may, at least partially,

be

for the fact that in isolated perfused

rat

liver extracellular NM

ac.zr

A highly active nucleotide

in rat liver

been characterized

probably

on structures

ATP in concentrations

is comp:e:elg hydrolyzed

up to 100

during a single liver

passage without ADP being released into the effluent

guished:

receptors can be distin-

P,- and P, purinoceptars.

Pt putinoceptors

are stimulated by the nu-leoside adenosine, but oat by the nucleotides ATP or ADP, linked

and are positively

to adenylate cyclase activation;

description

their role and

is beyond the scope of this paper. On the

other band. extracellular purinergic

ATP and ADP interact with

P, receptors, whose subtypes have phar-

macologically Burnstock

been characterized

(for r-view

ran!: order ot potency

and classified

with other Ca’+-mobilizing adrenergic

hepatocytes

leads to the mobilisation

P,-recep

of purinergic

cells

Caz’ with an

increase of the cytosolic free CaZt concentration lowing

the formation

of myo-inositol

fol-

t ,4,5-trisphos-

The response of isolated perfused rat liver to extraATP or ADP in micromolar

complex.

concentrations

is

There is an increase of the portal pressure,

a stimulation

of hepatic glucose output,

take, glutamate [7,10,14],

movements

oxidation

oxygen up

and citric acid cycle flux

a decrease of bile flow 1151, a rapid,

tran-

and other Ca2’-mobilizing (i) An activation stimulushtduced

of

chamtels

following

uptake

across the liver plasma

[IO] (Fig. 1) consisting of an initial

and a subsequent

and K+ movements

net K+

net K+ release. The Ca’+

are similar

to those observed

[18,19]. The complex of extraceUular

hormones

K+ ATP

are likely

due

event?..

face of the plasma membrane of the pump

apamin-sensitive

[2@], (ii) An

Cazc-activated

the rise of cytosolic

K+

free Cc?+

[21]. This increase in potassium

conductance

may in

turn

membrane,

as was

hyperpolarize

shown

the plasma

in micropuncture studies on MDCK cells [22],

transport

membrane

such as alpha-

of the K+/Na+-ATPase following a removal of an inhibitory Ca*+ pool

opmhrg

2-3 min of ATP addition

quence of net K+ movements

AP,A.

nerve stimulation

of at least hvo different

in the microenvironment

increasing

se-

5,

under the influence

to a superimposition

sient net release of Ca’+ from the liver during the first [iO.16] and a complex

hormones,

perivascular

located at the internal

pbate (IP3) [ll-131. cellular

agonists.

[16,17] or prostaglandin

P2 re-

or bepatoma

of intracellular

““cteotides

by

of some ATP analogues sug

gest that the liver contains the purinergic in isolated

ertracenutar diadenine

Ap,A and ATP on the effluent K+ and Ca” concentrationin perfusedrat liver. The influent K* and Ca2’ concentrations were 5.9 and 0.3 mM, rerpectivety.The nucteoriderinduce a rapid net releaseof C& from the liver beingcompteredwithin 3 min and there is a stowCa” reaptake following withdrawal of the nuckotides.This ion responsepattern is alsofoundwith alpha-adrenergicagoonists. perivaxutar nerve stimulatian and pmrtaglandins.but is characteristicallydifferent from that obtained with extracell~hr UtTp, peptide tcuk~trienesor the syntheticthrombxane A, annlogueU-46619. Compare with Fig. 2. From Ref. 23.

see Ref. 8). Studies on the

tor subclass [9,10]. Stimulation ceptors

of the

Fig. 1. Effect

171. Two classes of purinegic

the

driving

force

systems, as reflected

extracellular

Na+-dependent

concentration

ratio

presence of extracellular

ATP (Kaiser,

S. and HPus-

singer,

observation).

In perfused

D.,

glutamine

for

by an increased intra/

unpublished

liver, the haemodynamic,

metabolic

in the

and ion flux re-

REGULATION

261

OF HEPATlC METABOLISM

spoases 8s obse:ved with ATP cannot be mimicked by AMP

or adenosine in equimolar concentrations.

indicating th.lt the ATP and ADP responses are not mediated by a stimulation of P, purinoceptors by the hydrolysis product adenosine [IO]. 41~0 other extracellular purine nucleotides are potent regulators of metabolism and haemodynamics in perfused rat iiver in the following

rough O&I’

Ap,A

= y-S-ATP > ATP = ADP >>jQ.

>j3-S-ATP

inethylene

of potency: Ap,A

=-

ATP = GTP 110,231. The effects of the

diadenine nucleotides and ATP on glucose release aad ion fluxes are half-maximal trations of I-8,uM lS,U],

at influent concen-

in the intact perfused liver [7,10,

whereas in isolated hepatocytes a halkmaxi-

ma1 stimulation

of glycogen phosphorylase by ATP

OECUISalready at OSpM interestingly,

[24].

not only purine nucleotides, but also

the pyrimidine nucleotides UTP and UDP exert powerful effects on hepatic metabolism and hemodynamits, whereas CTP, IX’

and UMP are nearly ineffec-

tive [lo]. In perfused liver, extracellular UTP is more potent than ATP on a molar basis and the hepatic responses to both nucleotides are different [lo].

This

holds for the time-courses of net Ca2+ release, K+ movements (compare Figs. 1 and 2) and glucose outpat and for the much higher vasoconstrictive potency of extracellular

UTP

compared to ATP: UTP

infu-

sion at a concentration of 1 PM to isolated perfused rat liver leads already to a doubling of the portal piessure. In addition to these differences in hepatic response to both nucleotides. several additional lines of evidence suggest that extracellular

UTP

acts on re-

ceptors distinct from the known purinergic P2 receptors. i.e. on the hypothesized ‘pyrimidinergic tors’ [IO]. fi) The effects of extracellular

-

20 nun -

Fta. 1. Effect of the ertmcettutarUTP on the effluent I‘+ and Cal’ concentrationin perfusedrat liver. The inauent K+ and Ca’* mncentrarionswere 5.9 and0.3 mM. respectively.Extracellular UTP inducesa slow and pmtongednet refeazeof Ca” fmm the liver lastingfor more than 8 min and there is a slow Ca” m-uptake following withdrawal of the nucteotide.This inn responsepattcm IS different from that in Fig. 1 and is also found after infusionof leukotrieneD, and C, and the thmmboxaneA, analogueU-46619. From Ref. 10.

recep-

ATP and

Involvement of hepptie pareaehymxd and non-paren-

UTP on hepatic glucose output are additive. (ii) De-

chymal cells in the mpon5e to extreeellutar

sensitization of the purinergic

tides: role of eicosanaids in eetl-eell ccnnmenieptioo

methylene

P2 recepi lr by a./%

no&o-

ATP in rabbit ear artery a+olishes the

ATP- but not the UTP-induced The ‘pyrimidinergic to a Ca2+-mobilizing

vasoconstriction 1251.

receptor’ seems also to be linked mechanism as suggested by a

In the liver. cxtracellular

oucleotides act on both

parenchymal and non-parenchymal cells. A direct effect on hepatic parenchymal cells is demonstrated in

prolonged net Ca’+ release from the liver following

isolated hepatocyte suspensions, where extracellular

UTP addition (Fig. 2) and the finding that the UTP-

ATP, AhA.

induced hyperpolarization

phorylase a activity [9,23,24,26]

in Ca*+-free media [22].

of MDCK

cells i3 blunted

Ap4A and UTP increase glycogen phos-

free Ca*+ concentration

[11,12].

and the cytosolic Because hepatic

262 non-parenchymal

cells,

bc:

not

parenchymal

the

from the liver and a complex

sequence

of K+ move-

cells, have repeatedly been shown to be engaged in

ments across the plasma membrane [34.35]. Howev-

eicosanoid synthesis [28-301. a response of hepatic

er, the time-courses of these ion movements are

non-parenchymal

cells to these nucleotides

is re-

characteristically

different

flected by an about IO-fold stimulation

of prostaglan-

prostaglandins

din E*, D, [23,27]

B, [23,26]

117,191, nerve stimulation

and thromboxane

rat liver. It is at present unclear

lease from perfused whether

re-

besides prostaglandins and thlomboxanes

also lipoxygenase products are formed in the intact

[l&19],

rine nucleotides

to those observed with alpha-adrenergic

agonists

[17] and extracellular

[l&16,23];

but resemble

those

puob-

UTP [lo] (compare Fig. 2).

tained with extracellular

The responses of perfused liver to the thromboxaue

liver under the influence of extracellular ATP, UTP,

Al analogue U-46619,

Ap,A

trienes, were comp!etrly aboiishea m the presence of

and ApqA. This, howwer,

seems likely in view

of a 40% inhibition of the MP-stimulated

glucose re-

but not to the peptids leuko-

the thromboxane A, receptor antagonist BM 13.117,

lease by the lipoxygtnase inhibitor nordihydroguaia-

whereas

retie acid (NDGA)

[31]. In line with the pxvious sug-

171883 blocked the effects of peptide leukotrienes

the leukotriene

receptor

antago&

LY

gestion raised by Oecker [29,30] on an important role

[26,34,35]. These studies showed that peptide leako-

of arach:donate products in signal exchange between

tricnes in nanomolar concentrations may not only act

different iiver cell populations, eicosanoids released

as mediators of inflammation,

from hepatic non-parenchymal

ulators of hepatic metabolism via a probably recep-

cells under the intlu-

ewe of extracellular nucleotides interact directly and

to:-mediated

indirectly

antagonist stcdier the possibility exists that the leu-.

with hepatic parencbymal cells. Evidence

mobilization

but also as potent reg

of IX’.

From receptor

for this comes from studies on the effects of eicosa-

kotriene responses are mediated by leukotriene

noid infusion to perfused rat liver and on the effects

not by leukotriene C, 1261, and the effects of leuko-

of cycle- and lipoxygenase inhibitor:

triene C, in perfused liver arc explained by its rapid

and eicosanoid

receptor antagonists on the nucleotide responses. Additwn

of prostag!dndin D,, i$ and 5.

to isol*

conversion to leukotriene

D4,

D., oy gamma-ghttamyl-

t:onsferase. The mechanism lunderlylng the stimula-

ted perfused rat liver stimulates glycogenolysis and

tion of glywgenolysis

ghttama’e oxidation

anes, as observed in the intact liver, is not yet under-

and increases the portal vein

These effects are xcompa-

pressure [18.19,32-341.

nied by Ca*+ and K+ transients [I8,19],

mimicking

those observed with other Ca”+-mobilizing

agents

by leukctwtes

and thrombox-

stood. In contrast to prostaglattdins, the thromhoxane A, analogue U-46619 and leukotrienes C, and D4 are without effect on glycogen phosphorylase II activ-

such as phenylephrine or extracellular ATP, and sug

ity in isolated hcpatocytes (261, indicating that these

gest a receptor-mediated

eicosanoids may not act directly on hepatic parenchy-

hepatic patenchymal

mobilization

of Ca*’

from

cells. In line with this is the

marked increase of glycogen phosphorylase a activity in isolated rat hepatocytes following

prostaglandin

mal cells to stimulaie glycogenolysis. Also the possibility that the vasoconstriction accompanying thromhoxane and leukotriette infusion could stimulate glp

addition 1261. These findings suggest that prostaglan-

cogenolysis as a consequence of hypoxic liver areas

dins liberated by extracellular nucleotides from hep-

may not serve as an exclusively satisfxtory

atic non-parenchymal cells may act as signals for par-

tion.

enchymal cells, triggering there the glymgenolytic

trienes exert only small effects on the portal vein

Compared

to thromboxanes,

explana-

peptide

buko-

response, at least in part. A vasoconstriction and a

pressure [35]. whereas their effect on glucose output

stimulation of glucose output is also ohserved in iso-

is similar. Further, a 40% inhibition

lated perfused rat liver upon infusion of stable throm-

namic response to leukotriene

boxane A, analogues Il9.34.35)

prusside did oat affect glucose output 13,1]. Accord-

and of the peptide

leukotrienes C, and D1 134-361. Thew action also in-

ingly, other not yet identified

volves a slow and prolonged mobi!i?ntiou

the glycogenolyiir

of Ca*+

of the hemody

C, by sudium nitrosignals may mediate

response to thromboxanes

and

REGULATION

OF HEPATIC METABOLISM

peptide kukotrienes

263

in the liver. The situation re-

sembles that with platelet activating factor (PAF):

observation [26]. It should be emphasized that eimsanoids are not exclusively mediating the effects of

PAF stimulates glycogenolysis in the intact perfused

extracellular

liver, but not in isolated rat hepatocytes [38].

act as signals between non-parenchymal

Further support for a role of eicosanoids in mediating the response of the liver to extracellular

nucIe~-

nucleotides in the liver, however, they and paren-

chymal cells modifying the response of the liver to extracellular

nucleotides.

Differences

in eicwanoid

tides comes from studies with inhibitors of eicosanoid

production cannot at present explain the different re-

synthesis and eicosanoid receptor antagonists. Ir. the

sponses of perfused liver to extracellular

presence of the thromboxane A2 receptor antagonist

UTP,

BM 13.177 (at concentrations sufficient to

block the

ATP and

respectively. Even in the presence of in&me-

thacin or the thromhoxane receptor antagonist BM

A2 attalogue U-46619 in

13.177 the about 7-fold higher vasoconstrictive po-

perfused liver), the initially overshooting po, ta! pres-

tency of UTP compared to ATP is preserved [26]. In

sure increase normally

addition there were no significact qaaatitative differ-

effects of the titmtttboxane

observed during the first 3

min after addition of extracellular ATP, UTP, Ap,A

ences in the stimulation

or Ap4A is completely abolished [23.26], whereas the

thromboxane

steady-state pressure increase observed thereafter is

ATP, respectively [26,27].

not affected. This initially

overshooting pressure in-

crease coincides with the peak thromboxane release

of prostaglandio

B, release by extracellular

0,

and

UTP

and

It is of interest to mention that in the last years a role of eicosanoids as signals between non-parenchy-

from the liver and the data show that thromhoxanes

mal and parenchymal hepatic cells and in mediatiq

liberated under the influence of extracellular nucleo-

the (glycogenolytic)

tides partially mediate the nucleotide-induced

been in&red

hemo-

response of the intact liver has

not only for the actlo? nf extrzreltlular

dynamic changes. The glycogenolytic response of the

nucleotides, but also for a variety of other stimuli,

liver to extracellular

such as phorbol ester [33], perivascular nerve stimu-

ATP,

UTP

and the diadenine

nucleotides i!: not affected in the presence of the

lation 127,311, endotoxin

thrtimbousrc

munoglobulin

receptor antagonist during the first 3

min of nucleotide addition; however, thereafter it is significantly decreased [23,26]. Accordingty. hoxanes liberated

by extracellular

[37], heat-aggregated im-

1381. zymosan and aracbidonic

acid

1391.

throm-

nucleotides

are

also involved in mediating the glucose response after

&ml

a 3 min delay and one might speculate that this time

vation uf extracellular

period is required for the formation

the perivenous scavenger cell hypothesis

of as yet un-

bepalocyte heterogeneity regarding the inactlnucleotides and eicowoids:

known signals mediating the glycogenotytic effect of thromboxanes.

Similar effects on the nucleotide re-

Recent studies with the isolated perfused rat liver

sponses are observed after cyclooxygenase inhibition

have shown that in addition to non-parenchymal

by indomethacin

parenchymal

pressure

response

[26,31]. A decreased glucose and to extraceliular

ATP is also ob-

served in the presence of nordihydroguaiaretic an inhibitor

acid,

of lipoxygenase [31], suggesting an in-

ceW

cell interactions also another type of

liver cell heterogeneity must be considered, i.e. a Mnal subacinar heterogeneity

regarding

eicosauoid

and nucleotide effector sites on the one hand and the

volvement of leukotrienes as mediators. In line with

biological

this would be the finding that the leukotrlene

other hand. It is well-established that the liver has a

l&/E4

inactivation

of these compounds on the

receptor antagonist LY 171883 significantly inhibited

high capacity for inactivation,

the glycogenolytic and pressure response to extracel-

tion and excretion, of a variety of signal molecules,

lular UTP;

including extracellular

however, LY

thromboxane

receptor

171883 exhibits also some

antagonistic

concentrations employed,

activity at the

which could explain this

i.e. uptake, degrada-

nucleotides and eicosanoids.

Whereas hepatic non-parenchymal

cells can roughly

be seen as the production site of eicosancids, paren-

D. H&JSSlNGER

264 rhyotal cells appear to be the major site of their de-

only to scavenge ammonium ions which escaped pefi-

gradation ]2P]. In view of the high hepatic activties

portal detoxication by urea synthesis (for review see

for hxzctivadon of prcstaglandins, trienes,

thromhoxane

[10,34,42].

of

leuko-

analogues and extracellular

nucleotides [7,10,23,28,34,40-421 extraction

peptide

these

with a single-pass

compounds

of

70-100%

steep eicosanoid and nucleotide concen-

Ref. 43), but also to prevent the escape of a variety of biologically

highly potent signal molecules into the

systemic circulation,

thereby restricting their action

to the sinusoidal space. Such a hypothesis of a perivenous scavenger cell population

134). which elimi.

tration gradients exis! aiong the liver acinus. Studies

nates a variety of potentially toxic compounds before

with the perfused rat liver [10,34,~42] showed that the

the sinusoidal blood reaches the systemic circulation,

hemodynamic, ion flux and glycogenolytic effects in-

should have considerable impact on our understand-

duced by extrxellular

ing of liver function in health and disease because

ATP, prostaglandin 5,.

leu-

kotriene C, and the stable thmmtwane

A2 analague

many types of iiver disease are associated with a pre-

U-46619, as observed in physiologically

anterograde

dominantly perivenous liver cell necrosis. Such a le-

(from portal to hepatic vein) perfusion, are largely

sion should impair

abolished in retrograde perfusions (from hepatic to

been demonstrated recently with respect to ammonia

this scavenger function

as has

portal vein). These studies showed a zonal heteroge-

detoxication 1431, thereby allowing the escape of po-

neity regarding

tentially harmful metabolites or signal molecules into

effector

and degradation

sites of

these signal moiecolcs. In the case of extracellular nucleotides and prostaglandin

the systemic circulation.

Fz. the hepatic re-

sponses could be restored in retrograde perfusions; however,

far higher influent concentrations of thr

stimuli were required.

These experiments

Csncluding remark

suggest

the perivenous compartment of the liver acirrus as the

With respect to the short-term regulation of hep-

predwminant site of degradation of extracellular ATP

atic metabolism

ano of prostaglandins.

knowledge

Accordingly,

these stimuli

and hemodynamics,

our present

suggests complex network

interactions

were already degraded during retrograde perfusions

between various cell types in the liver, i.e. not only

before they reached their respective receptors lo-

between the different types of resident ‘hepatoeytes’

cated further downstream and these effector

inside the liver sinusoids

sites were only reached when

but also circulating blood cells. For example, stimulation of blood platelets by thrombin may liberate a va-

either exceedingly high doses of the signal molecubs

ri+)r

were infused or when the perfusion direction was in

which in turn not only mediate platelet aggregation,

the physiological anterograde direction.

hUi also induce a vasocorMiction

Interesting

of nucleotides,

such as ADP,

Ap,A.

Ap,A,

partly directly,

ly, the perfusion direction had no effect on the stimu-

partly by triggering thromboxane and prostaglandin

lation of “CO:

formation

production from added [I-%J]gluta-

and release from

sinusoidal liver cells.

mate by these compounds. a parameter reflecting the

These and other eicosanoids, as well as the nucleo-

metabolism of the small perivenous parenchymal cell

tides themselves. also trigger the metabolic response

population

of parenchymal

containing

glutamine

synthetase.

shows that this small perivenous compartment

This was

Ca’+-mobilizing

liver cells via remptor-mediated mechanisms. It is likely that the sig

acrivated by extracellular ATP and prostaglandin F20

nal molecules involved in this communication include

regardless of the perfusion direction and makes it

further, as yet unrecognized compounds besides ex-

likely that this compartment simultaneously was the

tracellular

major site of inactivation of these signal molecules.

the available experimental

Thus, one major function of the perivenous hepato-

direct conclusions as to what is really happening in-

cytes near the outflow of the sinusoidal bed is not

side a liver acinus.

nucleotides and eicosanoids. At present techniques only allow in-

REGULATION

OF HEPATIC

MEiABOLISM

(Freiburg)

during

the course

fully acknowledged. Fruitful (Freiburg), D.

Keppler

discussions

with

Prof.

Prof. Dr. W. Gerok (Heidelberg)

and

Dr.

K.

Decker

was supported

by Deutsche

(F&burg),

Prof. Dr.

Sonderforschungsbereich

Cr.

Tran-Tbi

pr0gr8llllIl.

T.-A.

of our studies

are grate-

Our own work reported

herein

Forschungsgemeinschaft 154 and

the

Heisenberg-

admintsrration of glocagon and Ca” nmbilizing a&?vts to the perfused rat liver could involve at 1eu1 two separate I Burnstock G. Present stems of puti”crg*c neurotranrmw sion - implications for vascular ccmrol. II: Nobin A. Owma”” C. Ameklo-Nobin B. eds. Neuronal Messengers in Vascular Function Amsterdam: Elrevier Science Publishers. 1987: 327-210. 2 Gordon JL. Extracelbdar ATP: effects. sources and fare. Bi.xbem J ,986; 233: 309-319. 3 Fladgaard H. Klenow H. Abundant ~m”““t~ of diadenosine J’.S”-P’.~.tetraphorph~tr are present and rclcasable. but metabolically inactive. in human platc1e.s. Biocheml 1982~208: 737-742. 4 Ldthje J. Ogitvie A. The prnrnce of diadenosine 5’S”‘P’.P’aipbosphate (Ap,A) in human ptatelets. Uioshem Biophys RaCommun 1983: 115: 253-260. 5 Ltttbje A. Ogilvie A. Catabolism of Ap,A and Ap,A in whole blood. EurJ Biocbem 1988: 173: 241-245. 6 Bischoff E. Tran-Thi T-A. Decker KFA. Nucteotidc pymphosphatascof rat CtirJ Biachrm 1975:51.353-361. 7 Hlttcsbtger D. Stehle T. Gerok W. Tran.Tbi T-A. Decker K. He~atocyte beter”Sc”eity I” respoiu; to ertraee,,“,sr hTP. EorJ Bioxbem 1987: 169: 645-650. 8 Burnstock G. Kennedy C. Is there a oasis for distingoisbing two types of P,.purincrgic receptors? Gen Pharmacol 1985: 16: 433-440. 9 Keppens S. De Wulf H. Characterization of the liver P1-purinoceptar involved in the activation of gtycogen phasphorylare. BiochemJ 1986: 240: 367-371. IO H~urringer D. Stehle T. Gerok W. Actions of extracellular UTP and ATP in perfored rat hvcr. Eur J Biocbem 1987; 167: 65-71. I Charert R, Blackmore PF. Extort JH. Cbarsnaizatio” of responses of isolated rat hepatocytes to ATP and ADP. J BiolCbem 1985; 260: 15789-15794. 12 Smddan JM. McGivan JD. Effects of ATP and adenosine addition on activity of “xoglutarate dehydrogenase and the coocemration of cytoplasmic free Cn’+ in rat bepatocyter. EorJ Biacbem ,985; 151: 567-572. 13 Horstman DA, Tenoes KA, Putoey JW Jr. ATP-induced Ca** mobilisa:i”n and inoritol 1.4.5.trisphosphate formation in H-35 hepatoma cells. FEBS Lert 1986: 204: 189-192. 14 Bon”” DR. Roberts”” SM. Olson MS. Stimulation of glycogenotyris by adenine nucleotides in fix perfused rat liver. Biocbem J 1986: 237: 773-780. I5 Krell H. Jaexhke H. PrsffE. Regulation ofcanalicular bile formmi”” by alphe ddrcnergic action and by external ATP in the isolated prfoaed rat liver. Biocbem Biopbys Res COrnrn”” 1985; 131: 139-145. lb Altin JG, Bygrave FL. The influx of Cs++ induced by the

liver.

1

pathways. B;ochem J 1987: 242: 43-M. 17 H&singer D. Stehle T, Gerok W. S% H. krk~ular nerve stimulation sttd pbenylephrine rcsfa?ses in rat liver. Metabolic effects, Ca” and K’ flues. Fur J Biochem 1987: lb% 197-203. 18 Hlursm~er D, Steble T. Tran.Tbi ?:A, Decker K, Gerok W. Prostaglandin responm in isolated perfwed rat liver: Cat+ and K* fluxes. hemodynamic and metabolic effects. Biol Chem Hoppe-Seyler ,981; 368: 1509-1513. 19 Altin IG. Bygrave FL. Prostaglandin Fl., and the thmmboxane A, analogue ONO-lll:3stimulate Cat+ fluxesand other physiological responses in rat liver. B&hem J 1988; 249: 677-68% 20 Capiod T. Berth”” B, Poggiati 1, Burges~ GM. Claret M.

21

22

23

24 25

26

27

Tbe effect of Ca+‘-mobilizing hormones on the KC/Nat pump in isolated rat liver hepawytes. FEBS Len 198% 141: 49-52. Burgers GM. Ctaret M, Jenkinson DH. Zffects of @nine and apad” “o the calcium-dependent potassium prmeability of mammalian hepatoqtes and red cells. J Physiol ,981:317:67-W. Lang F. Plockioger B, Hnussinger D. Paolmicbt M. Effects of extracellular nxleotides on electrical properties of sobconfluent Madin-Darhy cattine kidney cells. B&him Bio,,hys Acta ,988: 943; 471-476. Bosshard, E, Gemk W. Wursinger D. Regulation of parencbymat and no”-pareochymal cell function by the disdenine mckotides Ap,A and Ap,A. Biochim Biophys Aaa 1989; 1010: 151-159. Keppcns S, De Wulf H. P1-purioergic controi of livergtycoeuolvsis. Bi”chemJ198.%231: 797-799. ion i(iigelgen I, Hhssinger D. Starke K. Evideoce for z vasoco~triction-mediating receptor for UTP. distinct fmm the Pz purinoceptor, in rabbit ear anety. NaunynSchm.iedcberg’s Arch Pharmacot 1987; 226 556-560. Hausrineer D, Busrhardt E. Stehle T, Stall B, Wettstcbt M. Gerok W. Stimulation of thmmboxane release by extraeellular UTP and ATP from o&used rat liver: role of eicosanoids in mediating the nucieotide responses. EorJ Biocbem 1988; 178: 249-256 Tran-Thi T-A, HPussinger D. Gyofko K, Decker K. Stimulation of orostaalandin rele.xe bv Ca**-mobilizine seems from the &used rat liver. Biol ?hem Hoppe-Seyir 79sS; 369: 65-68.

28 Tran-Tbi T-A. Gyufko K, Henningcr H, Bosse R, Decker K. Studies on synthesis and degradation of eicasanoida by rat hepatocytes in primary ctdtote. I. Hepatol 1987; 5: 322-331. 29 tiecker K. Eicosaooids. signal molecules of liver cells.

266

D.

Semin Liver Dir 1985:5: 175190. 30 Decker K. Biochemistry 2nd functions

31

32

33

34

35

36

37

of eicoranoids. I”: Kim A. Knwk DL, Wisse E, eds. Cells of the Hepatic Sinusoid. Vol. 1. Rijswijk: The Kupifer Cell Foundation. 1086;53-58. lwai M. Jongerman” K. Possible involvrms”, of eicow “oids in Ihe action of symparhmic “ewes a” carbohydrme metabolism and hemodynamics in perfused ,a, liver. FEBS Le,, ,987;22,: 15%16L1 Buxton DB, Fisher RA, Briseno DL. Hanah”” DJ. Olson MS. Glycogenolvtic a”d henmdynamic responses 10 heata@,ega,ed immunoglobulin G and prostagiandin E, in the perfused rat liver. Biochem J 1987; 243: 493-498. Tran-Thi T-A, Gyuflto K, Hawringer D, Decker K. Net prosieglandi” ,elease by perfused ,a, liver aflcr stimulado” with phorboi 12.myrislale 13.acetate. J Hepmo, 1988: 6: 151-1.57. Hkussinger D, Steble ?. Hepatocyte beterogeueily in respunse 10 eicosanoidr. The p&venous scavenger cell hypothesis. EurJ Biochem 1988; 175: 39%403. HS”ssi”ger D, Stehle T, Gerok W. Effects !r”kotrie”es and the ,hmmboxa”e Al analogue U-46619 is isoiatcd perfused rat liver. Biol Chem Hoppe-Zzyler 1988; 369: 97-107. Jwai M, Jungcrman” K. Leukouicncs increase glucose and lacfme ourput and dccmase fiow I” perfused m, liver. Bia chemBiophysResCommun 1988: 151: 283-290. Casteleijn E. Kuiper 3. Van Rooi] HCJ. Knmps JAAM.

of

HAUSSINGER

Koster JF. Van Bake, TJC. Endotoxi” stimulared glycoge“@sir in the liver by means of intercelfular comm”“icatie”. J Biol Chem 1988,263: 6953-6955. 38 Buxton DB, Hanaha” DJ. Okm” MS. Slimulatio” of glycogenulysis and pla,e:e:-acrivariog factor production by heataggregated immunoglobuli” G in perfused ,a, liver. J Biol Chem 1984:259: 13758-13761. 39 Dieter P, Alli” JG. Decker K. Bygmve FL. Possible i”volvrtnr”, of cicoranoids i” ,he rymosa” and arachidonir acid-induced oxygen uprake. glycogenolyrir and Cat+ mo-

40

41

42

43

bilization in rhe perfused rat liver. Em I Biochem 1987: 165: 455-460. Ormstad K, Uehara N, Orrenius 8, Oming L. Hammarstriim S. Uptake and metabolism of Leoko,rie”e C, by isolaled m, organs and cells. B&hem Biophys Res Commu” 1982; ,“4: ,434-,440. Keppler D, I:uber M, Weckbecker G. Hegmsn” W, Denrlinger C, Guhlma”” A. Leokotriene C, metabolirm by bepatoma cells and liver. Adv Enzyme Regul 1987, 26: 211-224. Weltstein M. Gerok W. Htiussinger D. Metabol~m of ewwiny1 leukorrienes in “on-recirculating ,a, liver perfusion: hepatacyle bemrogeneity in uptake and hiliary excretion. Eur J Biochem (in press). H;iussi”ge, D, Sies H. Gerck W. Functional hepmocyte heterogeneity in ammonia me,abo,ism. The inorcelkdar glutamine cycle. J Hepatol 19&i; 1: 3-14.