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K Jungermann

Publications and source records attributed to K Jungermann.

At least 19 recordsLinked to original sources
PubMed1992

Modulation of the glucagon-dependent activation of the phosphoenolpyruvate carboxykinase gene by oxygen in rat hepatocyte cultures. Evidence for a heme protein as oxygen sensor.

The glucagon-dependent activation of the phosphoenolpyruvate carboxykinase (PCK) gene is modulated by oxygen. It was proposed that heme proteins might function as O2 sensors; their actions are impaired after replacement of the central Fe2+ ion by Co2+ and inhibition of heme synthesis by succinylacetone (SA). Therefore, the effects of CoCl2 and SA, alone and in combination, on the glucagon-dependent induction of PCK activity and PCK mRNA were investigated at different physiological oxygen tensions in primary rat hepatocyte cultures. The cells were exposed to 50 microM CoCl2 and/or 2 mM SA from 4-24 h. After addition of fresh media without CoCl2 or SA, PCK was induced with 1 nM glucagon. PCK activity and PCK mRNA were elevated to 100% at 16% O2 and to about 65% at 8% O2. CoCl2 reduced these increases to about 45% at 16% O2 and to about 35% at 8% O2. SA lowered the inductions to about 50% and 40% each at 16% and 8% O2. CoCl2 plus SA diminished the elevations to about 5% at both oxygen tensions. In the presence of CoCl2 and/or SA, ornithine decarboxylase induction by insulin was not impaired; lactate dehydrogenase did not leak from the cells, which in electron microscopical inspections had normal cell structures. These findings support the hypothesis that a heme protein is involved in the activation of the PCK gene and that it acts as an O2 sensor.

Animals↗
PubMed1992

Increases in intestinal glucose absorption and hepatic glucose uptake elicited by luminal but not vascular glutamine in the jointly perfused small intestine and liver of the rat.

1. Previous studies have shown that an arterial-to-portal glucose concentration gradient may be an important signal for insulin-dependent net hepatic glucose uptake. It is not known whether intestinal factors also contribute to the regulation of hepatic glucose utilization. This problem was studied in a newly developed model which allows luminal perfusion of the small intestine via the pyloric sphincter and a combined vascular perfusion of the small intestine via the gastroduodenal artery and superior mesenteric artery, and of the liver via the hepatic artery and portal vein. 2. In both the presence and the absence of 1 mM-glutamine in the vascular perfusate, only about 7% of a luminal bolus of 5500 mumol (1 g) of glucose was absorbed by the small intestine, and nothing was taken up by the liver. 3. With small doses of 75-380 mumol (11-55 mg) of luminal glutamine, but not with 300 mumol of alanine, the intestinal absorption of the luminal glucose bolus was increased almost linearly from 7% to a maximum of 40% and the hepatic uptake from 0% to a maximum of 22%. 4. The increase of hepatic glucose uptake caused by luminal glutamine was only observed when the glucose load was applied into the intestinal lumen, rather than into the superior mesenteric artery. 5. The relative hepatic glucose uptake (uptake/portal supply) was enhanced from 0% to 55% with an increase in portal supply by luminal glutamine, whereas with a similar range of portal glucose supply the relative hepatic uptake by the isolated liver, perfused simultaneously via the hepatic artery and portal vein, was slightly decreased, from 20% to 15%. 6. Addition of various amounts of portal glutamine and/or alterations in the Na+ content of the portal perfusate failed to mimic the luminal glutamine-dependent activation of hepatic glucose uptake. Therefore the luminal-glutamine-elicited activation of hepatic glucose uptake was apparently not caused by a simple increase in the portal-arterial glucose gradient, by glutamine itself or by Na(+)-dependent alterations in hepatic cell volume. The results suggest that luminal glutamine caused not only an increase in intestinal glucose absorption by unknown mechanisms but also the generation of one or more humoral or nervous 'hepatotropic' signals in the small intestine which enhanced the hepatic uptake of absorbed glucose.

Absorption↗
PubMed1992

Signal propagation via gap junctions, a key step in the regulation of liver metabolism by the sympathetic hepatic nerves.

Cell-to-cell communication via gap junctions has been proposed to be involved in the metabolic actions of sympathetic liver nerves in the rat. The effects of hepatic nerve stimulation and noradrenaline-, PGF2 alpha- and glucagon infusion on glucose metabolism and perfusion flow were studied in perfused rat liver in the absence and presence of the gap junctional inhibitors, heptanol, carbenoxolone and (4 beta)phorbol 12-myristate 13-acetate (4 beta PMA). (i) Stimulation of the hepatic nerve plexus increased glucose output, decreased flow and caused an overflow of noradrenaline into the hepatic vein. (ii) Heptanol completely inhibited not only the nerve stimulation-dependent metabolic and hemodynamic alterations but also the noradrenaline overflow. Thus the heptanol-dependent inhibitions were caused primarily by a strong impairment of transmitter release. (iii) Carbenoxolone inhibited the effects of neurostimulation on glucose metabolism partially by about 50%, whereas it left perfusion flow and noradrenaline overflow essentially unaltered. (iv) 4 beta PMA reduced the nerve stimulation-dependent enhancement of glucose release by about 80% but the noradrenaline-dependent increase in glucose output only by about 30%; the increase in glucose release by PGF2 alpha and by glucagon remained essentially unaltered. 4 beta PMA reduced the nerve stimulation-dependent decrease in portal flow by about 35% but did not affect the noradrenaline-and PGF2 alpha-elicited alterations, nor did it alter noradrenaline overflow. The results allow the conclusion that gap junctional communication plays a major role in the regulation of hepatic carbohydrate metabolism by sympathetic liver nerves, but not by circulating noradrenaline, PGF2 alpha or glucagon.

Alcohols↗
PubMed1992

Metabolic and hemodynamic responses of bivascularly perfused rat liver to nerve stimulation, noradrenaline, acetylcholine and glucagon in thioacetamide-induced micronodular cirrhosis.

Thioacetamide-induced rat cirrhosis was characterized by single-cell necroses, fibrosis, nodular parenchyma, decrease in parenchymal volume density and an increase in liver weight per body weight so that the total amount of parenchyma was not altered. The glycogen content was normal, and signs of decompensation were not found. Isolated livers were single-pass perfused by way of both the hepatic artery and the portal vein. In the normal livers stimulation of the nerve plexuses around the hepatic artery or portal vein (7.5 Hz; 2 msec) and infusions of noradrenaline (1 mumol/L) by way of either vessel and of acetylcholine (10 mumol/L) by way of the artery only increased glucose output, reduced both portal and arterial flow and increased the intravascular pressures. Glucagon (0.5 nmol/L) augmented glucose release and had no hemodynamic effects. In chronically thioacetamide-injured livers all stimuli caused smaller metabolic alterations per gram of liver weight and decreased portal flow more and arterial flow less with stronger enhancements of intravascular pressures than in the controls. The lowered metabolic responsiveness per gram of cirrhotic liver was largely compensated by the increase in liver weight. Thus despite massive histological alterations and pronounced increases in stimulation-dependent resistances - predominantly in the portal system - cirrhotic rat livers responded in their glucose metabolism to nervous and hormonal stimuli in almost the same manner as normal livers.

Acetylcholine↗
PubMed1992

Inhibition by noradrenaline and adrenaline of the increase in glucose and lactate output and decrease in flow after sympathetic nerve stimulation in perfused rat liver: possible involvement of protein kinase C.

In perfused rat liver stimulation of the hepatic nerve plexuses increased via alpha 1-receptors glucose and lactate output decreased flow and caused an overflow of noradrenaline into the hepatic vein. Infusion of noradrenaline and adrenaline also elicited similar metabolic and hemodynamic alterations via alpha 1-receptors, whereas infusion of isoproterenol via beta 2-receptors enhanced glucose output and slightly reduced lactate release without affecting flow. The influence of circulating catecholamines on the nerve stimulation-dependent changes was investigated. Noradrenaline (100 nmol/L) or adrenaline (40 nmol/L) but not isoproterenol (1 mumol/L), which themselves caused about half-maximal alterations, strongly inhibited the nerve stimulation-induced increase in glucose and lactate output and decrease in flow but had no effect on noradrenaline overflow. The protein kinase C activator (4 beta)phorbol 12-myristate, 13-acetate (100 nmol/L) but not its analog (4 alpha)phorbol 12,13-didecanoate (100 nmol/L) strongly inhibited the metabolic and hemodynamic changes caused by nerve stimulation or noradrenaline infusion. The protein kinase C inhibitor H7 (20 mumol/L) partially prevented the inhibition of the nerve actions by noradrenaline. The results lead us to conclude that noradrenaline and adrenaline inhibited the metabolic and hemodynamic nerve actions by means of a mechanism involving protein kinase C rather than presynaptic alpha-receptors or beta-receptors. The catecholamines apparently increased via alpha 1-receptors inositol 1,4,5-trisphosphate, which in turn enhanced cytosolic Ca2+ and thus altered metabolism and in part hemodynamics, and diacylglycerol, which in turn activated protein kinase C and thus feedback inhibited the signal chain from alpha 1-receptors via G proteins to phospholipase C.

Animals↗
PubMed1992

Hepatocyte heterogeneity in the metabolism of carbohydrates.

Periportal and perivenous hepatocytes possess different amounts and activities of the rate-generating enzymes of carbohydrate and oxidative energy metabolism and thus different metabolic capacities. This is the basis of the model of metabolic zonation, according to which periportal cells catalyze predominantly the oxidative catabolism of fatty and amino acids as well as glucose release and glycogen formation via gluconeogenesis, and perivenous cells carry out preferentially glucose uptake for glycogen synthesis and glycolysis coupled to liponeogenesis. The input of humoral and nervous signals into the periportal and perivenous zones is different; gradients of oxygen, substrates and products, hormones and mediators and nerve densities exist which are important not only for the short-term regulation of carbohydrate metabolism but also for the long-term regulation of zonal gene expression. The specialization of periportal and perivenous hepatocytes in carbohydrate metabolism has been well characterized. In vivo evidence is provided by the complex metabolic situation termed the 'glucose paradox' and by zonal flux differences calculated on the basis of the distribution of enzymes and metabolites. In vitro evidence is given by the different flux rates determined with classical invasive techniques, e.g. in periportal-like and perivenous-like hepatocytes in cell culture, in periportal- and perivenous-enriched hepatocyte populations and in perfused livers during orthograde and retrograde flow, as well as with noninvasive techniques using miniature oxygen electrodes, e.g. in livers perfused in either direction. Differences of opinion in the interpretation of studies with invasive and noninvasive techniques by the authors are discussed. The declining gradient in oxygen concentrations, the decreasing glucagon/insulin ratio and the different innervation could be important factors in the zonal expression of the genes of carbohydrate-metabolizing enzymes. While it is clear that the hepatocytes sense the glucagon/insulin gradients via the respective hormone receptors, it is not known how they sense different oxygen tensions; the O2 sensor may be an oxygen-binding heme protein. The zonal separation of glucose release and uptake appears to be important for the liver to operate as a 'glucostat'. Thus, zonation of carbohydrate metabolism develops gradually during the first weeks of life, in part before and in part with weaning, when (in rat and mouse) the fat- and protein-rich but carbohydrate-poor nutrition via milk is replaced by carbohydrate-rich food. Similarly, zonation of carbohydrate metabolism adapts to longer lasting alterations in the need of a 'glucostat', such as starvation, diabetes, portocaval anastomoses or partial hepatectomy.

Animals↗
PubMed1992

Daily variations of the involvement of beta-receptors in the sympathetic nerve action on glycogenolysis in perfused rat liver.

In perfused rat liver perivascular nerve stimulation (7.5 Hz, 20 V, 2 ms, 5 min) at the liver hilus caused an increase in glucose release, a shift of lactate uptake to output and a decrease in arterial, portal and total flow. The influence of the alpha 1-receptor blocker prazosin and the beta-antagonist propranolol on these nerve effects were studied in the isolated rat liver perfused via both the hepatic artery and the portal vein in three experimental series at 9 a.m., at 2 p.m. and at 8 p.m. 1) The nerve stimulation-dependent increase in glucose output was maximal at 9 a.m. (100%), halfmaximal at 2 p.m. (50%) and very low at 8 p.m. (15%). The alterations in arterial, portal and total flow were similar in all three series. 2) At 9 a.m., at 2 p.m. and at 8 p.m. 5 microM arterial plus portal prazosin nearly completely inhibited the metabolic alterations and blocked the reduction of arterial, portal and total flow by 80%. 3) At 9 a.m. 10 microM arterial, portal and arterial plus portal propranolol inhibited the increase in glucose release to less than 25% and the shift of lactate uptake to output to about 50%. At 2 p.m. this inhibitory effect was not observed, neither by selective arterial or portal, nor by simultaneous arterial plus portal addition of 10 microM propranolol. At 8 p.m. the influence of propranolol could not be studied because of the too small control values. The nerve stimulation-dependent reduction of arterial, portal and total flow was not influenced by propranolol, neither at 9 a.m. nor at 2 p.m.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Role of intralobular compartmentation in hepatic metabolism.

The model of metabolic zonation is based on the finding that periportal and perivenous hepatocytes possess different activities and amounts of enzymes and thus different metabolic capacities. Periportal cells catalyze predominantly oxidative energy metabolism of fatty and amino acids, ureagenesis, glucose release and glycogen formation via gluconeogenesis, bile formation and protective metabolism. Perivenous hepatocytes carry out preferentially glucose uptake for glycogen synthesis, glycolysis coupled to liponeogenesis, glutamine formation and xenobiotic metabolism. The input of humoral and nervous signals into the periportal and perivenous zones is different; gradients of oxygen, substrates and products, hormones and mediators and nerve densities exist which are important not only for the short-term regulation of metabolism but also for the long-term regulation of zonal gene expression. The specialization of periportal and perivenous hepatocytes has been characterized well for the metabolism of carbohydrates, amino acids, ammonia and xenobiotics as well as for the formation of bile. Zonal flux differences have been calculated based on the distributions of enzymes and metabolites, they have been observed in periportal-like and perivenous-like hepatocytes in cell culture and in periportal- and perivenous-enriched hepatocyte populations as well as in perfused livers during orthograde and retrograde flow. Oxygen and insulin/glucagon gradients could have a prominent role in the induction of zonation of carbohydrate- and cell-to-biomatrix interactions in that of ammonia-metabolizing enzymes.

Amino Acids↗
PubMed1991

Interactions of nuclear protein from cultured rat hepatocytes with the cyclic AMP responsive elements and the NF1-CTF site in the promoter of the rat phosphoenolpyruvate carboxykinase gene.

Nuclear extracts from cultured rat hepatocytes were analyzed by gel mobility shift assay for protein binding to the cyclic AMP responsive elements CRE1 (-96/-77) and CRE2 (-152/-132) and the NF1-CTF binding site (-121/-99) of the phosphoenolpyruvate carboxykinase (PCK) promotor. Binding was very weak to the CRE2 and CRE1. The NF1-CTF site formed two complexes with nuclear protein. Protein binding was increased, when the NF1-CTF site was coupled to the CRE1, and further, when it was coupled to both the CRE1 and the CRE2. Complex formation was not altered by treatment of the hepatocytes with glucagon or with glucagon and insulin. Thus, protein binding was most efficient when all three elements were in context, which might be necessary for full transcriptional activation of the PCK gene.

Animals↗
PubMed1991

Binding of cytosolic protein from cultured rat hepatocytes to the 3'-end of phosphoenolpyruvate carboxykinase mRNA--significance for protein-mediated mRNA stabilization.

In vitro transcripts of the 3'-non-translated region of the phosphoenolpyruvate carboxykinase (PCK) gene both in "sense" and "antisense" orientation bound cytosolic protein from cultured rat hepatocytes as demonstrated by electrophoretic mobility shift assay. Binding of cytosolic protein was increased 3-fold and PCK mRNA was enhanced 10-fold by treatment of the hepatocytes with 10 nM glucagon. The similar time course of the glucagon-induced increase in protein binding to PCK mRNA 3'-end and in PCK mRNA suggests that protein binding might be involved in the stabilization of PCK mRNA.

Animals↗
PubMed1991

Modulation by oxygen of the glucagon-dependent activation of the phosphoenolpyruvate carboxykinase gene in rat hepatocyte cultures.

In liver phosphoenolpyruvate carboxykinase (PCK) activity, protein and mRNA are localized predominantly in the periportal zone. The activation of the PCK gene by glucagon was studied in primary rat hepatocyte cultures under physiological arterial and venous oxygen tensions [16% and 8% (by vol.)]. PCK gene expression was monitored on the level of transcription, mRNA abundance and enzyme activity as well as enzyme synthesis and degradation. 1. Transcription of the PCK gene was increased by 10 nM glucagon maximally after 0.5 h; it reached nearly basal levels again after 2 h. The increase in transcription was 45% lower under 8% oxygen than under 16% oxygen. 2. PCK mRNA was maximally increased after 2 h under 16% oxygen and after 4 h under 8% oxygen; it subsequently declined to twice the basal values after 8 h. The maximal increase after 2 h was 50% lower under 8% oxygen than under 16% oxygen. 3. PCK enzyme activity was maximally increased after 4-6 h. The maximal enhancement after 4 h was 50% lower under 8% oxygen than under 16% oxygen. 4. The increase in PCK enzyme activity was due to an enhanced synthesis rate of PCK protein. The rate increased after 3 h was 35% lower under 8% oxygen than under 16% oxygen. 5. The degradation of PCK protein was equal under both oxygen tensions. The results show that in cultured rat hepatocytes the induction of PCK gene expression is modulated by physiological concentrations of oxygen. The modulation occurred at the level of gene transcription, mRNA abundance, enzyme protein synthesis and enzyme activity. The periportal to perivenous oxygen gradient could be the major factor responsible for the predominant expression of the PCK gene in the periportal zone.

Animals↗
PubMed1991

Mechanism of the permissive action of dexamethasone on the glucagon-dependent activation of the phosphoenolpyruvate carboxykinase gene in cultured rat hepatocytes.

Rat hepatocytes were cultured for 24 h in the presence or absence of 100 nM dexamethasone (DX). After a medium change, phosphoenolpyruvate carboxykinase (PCK) was induced by addition of glucagon at different concentrations, from physiological 0.1 nM to hyperphysiological 10 nM, again in the presence or absence of 100 nM dexamethasone. 1. With dexamethasone addition during the culture and induction phase (DX+/+), 10 nM glucagon increased PCK mRNA abundance (Northern blot analysis) and activity (in vitro translation) synchronously to the same extent with maxima after 2 h and PCK enzyme activity after a time lag with a maximum after 6 h. The total detectable PCK mRNA amount was apparently also translationally active. 10 microM N6,2'-O-dibutyryladenosine 3',5'-(cyclic)phosphate (Bt2cAMP) as the second messenger had essentially the same effect as 10 nM glucagon. 2. In the absence of dexamethasone during the preculture and the induction phase (DX-/-), 10 nM glucagon and 10 microM Bt2cAMP could enhance PCK mRNA only about half-maximally. Glucagon or dexamethasone added alone in physiological concentrations of 0.1 nM and 100 nM, respectively, were unable to increase PCK mRNA. However, treatment of the cells with dexamethasone also enabled 0.1 nM glucagon to enhance PCK mRNA to a maximum after 2 h, independent of the presence of dexamethasone during the induction period (DX+/+ and DX+/- cells). Thus, dexamethasone was a permissive agent in that it shifted the sensitivity of the cells towards glucagon into the physiological concentration range. 3. In the presence of dexamethasone during the culture and induction phase (DX+/+) 0.1 nM glucagon maximally enhanced the transcription of the PCK gene (nuclear run on) fourfold after 30 min; in the absence of dexamethasone during both phases (DX-/-) glucagon was without any effect. The overall transcriptional rate was not significantly different in cells with and without dexamethasone during the culture and induction phase (DX+/+ vs. DX-/-). Thus, dexamethasone acted permissively mainly on the transcription of the PCK gene. 4. With culture in the presence of dexamethasone over decreasing periods of time, 1 nM glucagon could induce submaximal PCK mRNA amounts already after 1-3 h steroid culture. This restitution by dexamethasone of the PCK mRNA inducibility by glucagon was inhibited by cycloheximide. This suggested that ongoing protein synthesis was required for the permissive action of dexamethasone on the expression of the PCK gene. The results allow the following conclusions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Differential effects of human anaphylatoxin C3a on glucose output and flow in rat liver during orthograde and retrograde perfusion: the periportal scavenger cell hypothesis.

1) During orthograde perfusion of rat liver human anaphylatoxin C3a caused an increase in glucose and lactate output and reduction of flow. These effects could be enhanced nearly twofold by co-infusion of the carboxypeptidase inhibitor MERGETPA, which reduced inactivation of C3a to C3adesArg. 2) During retrograde perfusion C3a caused a two- to threefold larger increase in glucose and lactate output and reduction of flow than in orthograde perfusions. These actions tended to be slightly enhanced by MERGETPA. 3) The elimination of C3a plus C3adesArg immunoreactivity during a single liver passage was around 67%, irrespective of the perfusion direction and the presence of the carboxypeptidase inhibitor MERGETPA; however, less C3adesArg and more intact C3a appeared in the perfusate in the presence of MERGETPA in orthograde and retrogade perfusions. It is concluded that rat liver inactivated human anaphylatoxin C3a by conversion to C3adesArg and moreover eliminated it by an additional process. The inactivation to C3adesArg seemed to be located predominantly in the proximal periportal region of the liver sinusoid, since C3a was less effective in orthograde perfusions, when C3a first passed the proximal periportal region before reaching the predominant mass of parenchyma as its site of action, than in retrograde perfusions, when it first passed the perivenous area. These data may be evidence for a periportal scavenger mechanism, by which the liver protects itself from systemically released mediators of inflammation that interfere with the local regulation of liver metabolism and hemodynamics.

3-Mercaptopropionic Acid↗
PubMed1991

Control of glycogenolysis and blood flow by arterial and portal adrenaline in perfused liver.

In isolated liver from fed rats, simultaneously single-pass-perfused via both the hepatic artery (80 mmHg, 30-35% flow) and the portal vein (10 mmHg, 70-65% flow), adrenaline was infused either singly or jointly via the hepatic artery or the portal vein in the absence or presence of the alpha 1-blocker prazosin and the beta 2-blocker butoxamine. It was found that: (1) arterial adrenaline caused increases in glucose and lactate output which were slower in onset, smaller in peak height but longer in duration than did portal adrenaline; (2) arterial adrenaline elicited a much more pronounced decrease in flow and increase in pressure in the ipsilateral vessel than did portal adrenaline, and arterial, but not portal, adrenaline elicited qualitatively similar alterations also in the contralateral vessel; (3) arterial adrenaline caused metabolic changes mainly via alpha 1-receptors, with beta 2-receptors playing a permissive role via haemodynamic alterations, whereas portal adrenaline acted only via alpha 1-receptors; (4) arterial adrenaline decreased arterial flow via alpha 1-receptors counteracted via beta 2-receptors and operated on portal flow as portal adrenaline only via alpha 1-receptors; and (5) arterial adrenaline was extracted to a far greater extent than portal adrenaline. The results indicate that the hepatic artery and the portal vein can function as independent sites of hormonal signal input, which interact by complex, still undefined, mechanisms.

Animals↗
PubMed1991

Eicosanoid-mediated increase in glucose and lactate output as well as decrease and redistribution of flow by complement-activated rat serum in perfused rat liver.

Rat serum, in which the complement system had been activated by incubation with zymosan, increased the glucose and lactate output, and reduced and redistributed the flow in isolated perfused rat liver clearly more than the control serum. Heat inactivation of the rat serum prior to zymosan incubation abolished this difference. Metabolic and hemodynamic alterations caused by the activated serum were dose dependent. They were almost completely inhibited by the cyclooxygenase inhibitor indomethacin and by the thromboxane antagonist 4-[2-(4-chlorobenzesulfonamide)-ethyl]-benzene-acetic acid (BM 13505), but clearly less efficiently by the 5'-lipoxygenase inhibitor nordihydroguaiaretic acid and the leukotriene antagonist N-(3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-propoxy]-4-chlorine-6-meth yl- phenyl)-1H-tetrazole-5-carboxamide sodium salt (CGP 35949 B). Control serum and to a much larger extent complement-activated serum, caused an overflow of thromboxane B2 and prostaglandin F2 alpha into the hepatic vein. It is concluded that the activated complement system of rat serum can influence liver metabolism and hemodynamics via release from nonparenchymal liver cells of thromboxane and prostaglandins, the latter of which can in turn act on the parenchymal cells.

Animals↗
PubMed1991

Distribution of cyclic AMP phosphodiesterase in microdissected periportal and perivenous rat liver tissue with different dietary states.

Cyclic AMP phosphodiesterase was measured in liver homogenates and microdissected periportal and perivenous liver tissue from rats in different dietary states under different conditions of substrate saturation and effector stimulation. A radiochemical microtest, more sensitive by 2-3 orders of magnitude than the usual assay, was established for the determination of the activity in liver samples corresponding to 200-800 ng dry weight. At saturating cyclic AMP concentrations (46 microM) phosphodiesterase was homogeneously distributed within the liver acinus of fed rats. Starvation for 48 h led to a decrease in the overall activity and to a heterogenous distribution with slightly higher activities in the perivenous zone. At physiological cyclic AMP concentrations (1.8 microM) phosphodiesterase showed a flat zonal gradient in livers of fed rats with higher levels in the periportal zone; after 48 h starvation it was homogeneously distributed. In the presence of cyclic GMP (2 microM) the basal activity at physiological substrate concentrations was stimulated to a greater extent in the perivenous zone. This led to a homogeneous activity distribution in the fed state and to a heterogenous pattern with a slight perivenous maximum in the fasted state. Thus there was no or only a small zonal heterogeneity of signal transmitting enzymes such as cyclic AMP phosphodiesterase and glucagon-stimulated adenylate cyclase (Zierz and Jungermann 1984). This similar signal transducing capacity in the periportal and the perivenous area will contribute to maintain the zonation of signal input due to the hormone concentration gradients across the liver acinus.

1-Methyl-3-isobutylxanthine↗