THE MODIFICATION OF FUNCTIONAL COMPONENTS OF BILE FORMATION BY THE TERPENIC COMPOUND EPOMEDIOL(EPD) IN THE RAT.

Giuliana Zanninell~) A. Tavanti) Maria E. Munoz S. Del Vecchio*and G.L. Ricci! Dept of Gastroenterology, Clinica Medica I I , Policlinico Umberto I 00161 ROME - I ta ly.

The present study'investigates the mechanism of action of the terpenic compound EPD on bile formation, being the molecule excreted into bile as an osmotically active ether of glucuronic acid. Experiments started at the 2nd h after surgical preparation of rats. After 20 min basal bile collection (NaCl 0.16 M through the right jugular vein) a Na+Taurocholate (TC) infusion was started at one of the following rates: O, 120, 240 nmol/min/100g b.wt. At steady state bile was sampled at 40-60 min. While the TC was s t i l l ongoing, EPD was infused (0, 20, 50 mg/kg/h) during each administration of TC; bile was sampled at steady state (40-60 min). Results: The i .v . administration of EPD is able to increase bile flow (BF) by 15-40%, the effect is dose dependent. At low BA secretory rate the effect is greater: BA independent bile flow (intercept of the regression line) is increased (p<O.01) while the slope is less steeped (p<O.01). The choleretic action was much greater in rats depleted of BA for 8 h. The output of Na+ K+ and Cl- after TC administration was increased to a different extent (p<O.01) and in a dose dependent fashion. The mean anionic gap of bile was 0.39 * 10 -3~Eq/min/lO0 g in basal condition, 0.59 * 10-3~Eq/min/100 g under TC, 0.70 *10-3~Eq/min/100 g under EPD. No significant changes were observed in UDP-glucurony] transferase assayed in the l iver at the end of the experiments both with bil irubin (BR) and p-nitrophenol as acceptor substrates. 15-20% increase of BR- glucuronidation was recorded when EPD 10-3M was added in vi tro to homogenates. This phenomenon was not observed after digitonin activation of the enzyme. Conclusion: EPD was able to increase bile flow (BF) and electrolite output by a mechanism which is dose- dependent and apparently additive to that exerted by BA. The increase of the anionic gap may be accounted for to the excretion of EPD-glucuronide as an anionic species. The increase in Na+ excretion suggests a Na+

coupled symport.

CAN EXCITATORY NEUROTOXIC AMINO ACIDS BE REGARDED AS PATHOGENETIC AGENTS OF HEPA-

TIC ENCEPHALOPATHY ?

M.L. Zeneroli, C. Vezzelli, A.M. Russo and M. Baraldi* III Dep. of Medicine and

Chair of Pharmacology and Pharmacognosy*, Modena University, Modena, Italy.

The generalized depression of the central nervous system (CNS) which characterizes hepatic en

cephalopathy (HE) due to fulmJnant hepatic failure galactosamJne-induced in rats was attributed

to an imbalance between inhibitory and excitatory neurotrasmitter systems leading to a prevalen

ce of the first one. Loss of neurons and loss of brain zinc support the hypothesis that the su-

persensitivity of ~-amJnobutyrJc acid-benzodJazepJne receptors in HE results from disuse and/or

denervation phenomena. It has been suggested by others that HE could result from a down-regula-

tion of gluatamatergic receptors eventually due to an increased presence of neurotoxic excitato

ry amino acids in the brain such as glutamate or the tryptophan derivative, ehinolinic acid. To

test this hypothesis the antagonist of excitatory amino acids, 2-amino-7-phosphonoheptanoic a-

cid (APH) was continuously infused Jntraventricularly by Alzet osmotic pumps (27 ug/day) to ga-

lactosamJne-Jnjected rats (N. 40). The presence of APH in the brain did not counteract the deve

lopment of HE but, by the contrary, precipitated all the galactosamine-injected rats in a seve-

re stage of HE. Glutamate receptors studied in these brains showed a decreased affinity paral-

felled by an increased number of binding sites. An effect which can be attributed to the presen

ce of the antagonist APH on excitatory glutamate receptors. These data seem to confirm that HE

Js a result of a functional imbalance between inhibitory and excitatory systems in the brain,

but seem to negate a pathologenetic role of excitatory amino acid accumulation in the brain du-

ring HE.

$199