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HISTORY AND CLINICAL FINDINGS A 23-year-old woman with deep (leg) vein thrombosis was hospitalised because the Quick value had not decreased despite administration of phenprocoumon. Two years previously she had sustained an anterior wall myocardial infarction and a scar on her right kidney had been an incidental sonographic finding. There was bluish, fine reticular discoloration over the toes of both legs. Physical examination was otherwise unremarkable except for obesity. INVESTIGATIONS The concentration of creatine kinase was raised to 250 U/l and that of lactate dehydrogenase to 300 U/l. The platelet count was decreased to 75/nl. The level of IgG anti-cardiolipin antibodies was raised (204 U/l) and the test for lupus anticoagulant positive. A biopsy of the skin from a toe revealing livedoid vasculitis, primary antiphospholipid syndrome (PAPS) was diagnosed. TREATMENT AND COURSE Noncompliance, excessive vitamin K ingestion, drug interaction and malabsorption were excluded as cause of the lacking action of phenprocoumon. Despite anti-coagulation with high-dosage low-molecular heparin and inhibition of platelet aggregation with ticlopidine and finally also immunosuppressive treatment with cyclophosphamide, skin necroses developed on the toes and she had recurrent pulmonary embolisms of which she died. CONCLUSION Standard treatment of PAPS is effective anti-coagulation with coumarin derivatives. Secondary resistance to coumarin is a rare occurrence: its cause remains unknown.

3T3 L1-cells, which undergo adipose conversion in vitro, possess a stimulus-sensitive H2O2-generating system in their plasma membrane, and its properties are virtually identical with those of the insulin-sensitive human fat-cell oxidase [Krieger-Brauer and Kather (1992) J. Clin. Invest. 89, 1006-1013]. Insulin and insulin-like growth factor I were found to be active stimulators of NADPH-dependent H2O2 generation. Surprisingly, the acidic (a) and basic (b) isoforms of fibroblast growth factor (FGF) as well as the AA and BB homodimers of platelet-derived growth factor (PDGF) had antagonistic effects on NADPH-dependent H2O2 generation in plasma membranes which were parallelled by corresponding changes in H2O2 accumulation in intact cells. bFGF and PDGF BB (which inhibit NADPH-dependent H2O2 generation) prevented the adipose conversion of 3T3 L1-preadipocytes, and this effect could be reversed by exogenously supplied H2O2. Conversely, aFGF and PDGF AA, which stimulated H2O2 generation, accelerated adipocyte conversion in the presence of insulin and were adipogenic in themselves. Consistently, expression of the adipocyte phenotype induced by insulin, dexamethasone and isobutylmethylxanthine was enhanced in the presence of exogenous hypoxanthine/xanthine oxidase, whereas antioxidants, such as N-acetylcysteine or ascorbate, suppressed the process of differentiation. It is concluded that the H2O2 produced in response to hormones and cytokines may contribute to the development and maintenance of the differentiated state.

Previous work demonstrated that human fat-cells possess a plasma-membrane-bound H2O2-generating system that is activated by insulin. Here we show that this system is under antagonistic control by various hormones and cytokines that typically act through several distinct receptor families. Similarly to insulin, oxytocin and tumour necrosis factor alpha acted as stimulators of NADPH-dependent H2O2 generation, whereas isoprenaline, a beta-adrenergic agonist, had inhibitory effects. Surprisingly, the acidic and basic isoforms of fibroblast growth factor as well as homodimeric platelet-derived growth factor AA and BB had antagonistic stimulatory and inhibitory effects on NADPH-dependent H2O2 generation. The agents tested acted at discrete ligand-specific receptors and their mechanisms of action were membrane-delimited and occurred in the absence of ATP. These findings implied that established pathways of signal transduction, including receptor kinases or second-messenger-dependent protein kinases A and C, were not involved and placed the stimulus-sensitive H2O2-generating system in a position comparable with adenylate cyclase. It was concluded that the stimulus-sensitive H2O2-generating system of human fat-cells meets all criteria of a universal signal-transducing system for hormones and cytokines that may link ligand binding to cell-surface receptors to changes in the intracellular redox equilibrium.

Recent findings indicate that platelet-derived growth factor (PDGF) plays a role in the generation of reactive oxygen species (ROS) as second messengers in smooth muscle cells (SMC). To identify the source and signal transduction pathway of ROS formation in SMC, we investigated PDGF-induced ROS formation. Stimulation of SMC with PDGF resulted in a rapid increase of ROS production. Using an inactivating antibody, we identified the increase to be dependent on p22phox, a NAD(P)H-oxidase subunit. ROS release was completely inhibited by the Gi protein inhibitor PTX as well as an antibody against Galphai1,2, however, not by antibodies against Galphai3/0, Gas, and Gbeta1beta2. The effect of PDGF on ROS production in SMC membranes could likewise be mimicked by the use of a recombinant Galphai2 subunit but not by Galphai3, Galphai0, Gas, and Gbetagamma subunits. Immunoaffinity chromatography demonstrated coupling of Galphai1,2 to the PDGF a-receptor, which, after preincubation of the SMC membranes with PDGF, was increased in the absence of GTPgammaS but decreased in the presence of GTPgammaS and prevented by PTX treatment. These data define a novel G protein-dependent mechanism by which PDGF signaling is transduced through direct coupling of the Gai1,2 subunit of the trimeric G proteins to the PDGF tyrosine kinase receptor.

Insulin caused a transient increase in H2O2 accumulation in human fat cell suspensions that was observed only in the presence of an inhibitor of catalase and heme-containing peroxidases, such as azide, and reached peak levels of 30 microM within 5 min. The cells contained a plasma membrane-bound NADPH oxidase, producing 1 mol H2O2/mol of NADPH oxidation, that was activated on exposure of intact cells to insulin at contrations that are physiologically relevant (0.1-10 nM). The hormone effect was rapid and was due to a selective increase in substrate affinity. The enzyme was magnesium dependent, required a flavine nucleotide for optimal activity, and was most active at pH 5.0-6.5. In contrast to all other hormone- or cytokine-sensitive NADPH oxidases that have been characterized in sufficient detail, the human fat cell oxidase retained its hormone responsiveness after cell disruption, and only Mn2+, but no ATP, was required for a ligand-induced activation in crude plasma membranes. The results demonstrate that insulin utilizes tyrosine kinase-independent pathways for receptor signaling and strongly support the view that H2O2 contributes to the intracellular propagation of the insulin signal.

The upcoming National Ignition Campaign (NIC) on the National Ignition Facility (NIF) will attempt to achieve fusion ignition and gain using a ≈1 MJ laser-driven hohlraum. In order to maintain the fuel on a low enough adiabat so it reaches adequate compressed areal density, the amount of ≫ 170 keV hot electrons generated, those that can penetrate to the DT fuel [1] has to be below 0.25 J for the first 7 ns of the drive pulse, and stay below 500 J during the peak of the pulse at 13 ns. On the NIF, hot electron spectra and yields are inferred from the ≪ 20 keV bremsstrahlung spectrum generated by the hot electrons depositing energy in the hohlraum walls using an absolutely calibrated Filter-Fluorescer (FFLEX) diagnostic [2]. An early version of FFLEX successfully characterized 20 – 120 keV brems-strahlung spectra generated by electrons having 30 keV temperature on vacuum hohlraum experiments using 4 NIF beams [3]. For the upcoming NIC experiments, however, the FFLEX must be capable of measuring x-ray spectra above 170 keV characteristic of electrons above that energy. We propose high energy (100 – 300 keV) channel upgrades that will allow us to estimate the generated hot electron populations with the required accuracy.

The effects of beta-adrenergic agonists on ATP utilization and adenine nucleotide breakdown in human adipocytes were examined. The catecholamine-induced increase in cAMP was associated with an enhancement of adenine nucleotide catabolism resulting in an increase in release of inosine and hypoxanthine which can not be reutilized for adenine nucleotide synthesis. Therefore, one-third of total cellular adenine nucleotides were irreversibly lost in the presence of 1 mumol/liter isoproterenol. The catecholamine-induced increase in purine release could be blocked by phosphodiesterase inhibitors, suggesting that cAMP is the main precursor of purines in the presence of beta-adrenergic agonists. However, epinephrine (in the simultaneous presence of the alpha 2-adrenergic blocking agent, yohimbine) and isoproterenol were 10 times more potent in stimulating purine release than in elevating cAMP. In addition, purine release ceased when cAMP was still markedly increased, suggesting a compartmentation of the cyclic nucleotide and/or involvement of the hormone-sensitive, low Km cAMP phosphodiesterase. The results document that white fat cells have an enormous potential for dissipating energy, and demonstrate that the pathway involving cAMP formation and hydrolysis constitutes the principle route of adenine nucleotide catabolism in the presence of beta-adrenergic agonists.

Basic fibroblast growth factor (bFGF), a ligand of receptor protein-tyrosine kinases, promoted the dissociation of G(s) and had antagonistic stimulatory and inhibitory effects on adenylyl cyclase and NADPH oxidase in human fat cell plasma membranes. The bFGF-induced activation of adenylyl cyclase was blocked by COOH-terminal anti-Galpha(s), indicating that it was mediated by Galpha(s). The inhibitory action of bFGF was mimicked by exogenously supplied Gbetagamma-subunits and was reversed by anti-Gbeta(1/2), or betaARK-CT, a COOH-terminal beta-adrenergic receptor kinase fragment that specifically binds free Gbetagamma, indicating that it was transduced by Gbetagamma complexes. The bFGF-induced inhibition of NADPH-dependent H(2)O(2) generation was also reversed by peptide 100-119, an inhibitor of G(s) activation by ligand-occupied beta-adrenergic receptors, indicating that the Gbetagamma complexes mediating the inhibitory action of the growth factor are derived from G(s). The findings suggest a direct, non-kinase-dependent, coupling of bFGF receptor(s) to G(s) and provide the first example of a ligand of receptor protein-tyrosine kinases that is capable of utilizing both types of component subunits of a single heterotrimeric G protein for dual signaling in a single cell type.

A 23-year-old woman with deep (leg) vein thrombosis was hospitalised because the Quick value had not decreased despite administration of phenprocoumon. Two years previously she had sustained an anterior wall myocardial infarction and a scar on her right kidney had been an incidental sonographic finding. There was bluish, fine reticular discoloration over the toes of both legs. Physical examination was otherwise unremarkable except for obesity.The concentration of creatine kinase was raised to 250 U/l and that of lactate dehydrogenase to 300 U/l. The platelet count was decreased to 75/nl. The level of IgG anti-cardiolipin antibodies was raised (204 U/l) and the test for lupus anticoagulant positive. A biopsy of the skin from a toe revealing livedoid vasculitis, primary antiphospholipid syndrome (PAPS) was diagnosed.Noncompliance, excessive vitamin K ingestion, drug interaction and malabsorption were excluded as cause of the lacking action of phenprocoumon. Despite anti-coagulation with high-dosage low-molecular heparin and inhibition of platelet aggregation with ticlopidine and finally also immunosuppressive treatment with cyclophosphamide, skin necroses developed on the toes and she had recurrent pulmonary embolisms of which she died.Standard treatment of PAPS is effective anti-coagulation with coumarin derivatives. Secondary resistance to coumarin is a rare occurrence: its cause remains unknown.

Previous results demonstrated that the adenosine that accumulates in human fat cell suspensions is derived from extracellular sources (Kather, H. (1988) J. Biol. Chem. 263, 8803-8809). To get insight into the mechanisms responsible for the lack of adenosine release, extracellular adenine nucleotide catabolism was minimized by 10 mmol/liter beta-glycerophosphate and 10 mumol/liter alpha,beta-methyleneadenosine 5'-diphosphate. Intracellular adenine nucleotide catabolism resulted in a release of inosine and hypoxanthine under these conditions that was increased markedly by isoproterenol. Experiments with inhibitors of adenosine deaminase and adenosine kinase indicated that the production of inosine and hypoxanthine proceeded via AMP deamination. Consistently, IMP levels were increased transiently in the presence of isoproterenol. In addition, the cells possessed a nucleotide phosphomonoesterase that was resistant to the inhibitory actions of ATP and alpha,beta-methyleneadenosine 5'-diphosphate and showed preference for IMP over AMP. Adenosine (approximately 1 nmol/10(6) cells/h) was also produced inside the cells. However, adenosine production was unrelated to ATP turnover via adenylate cyclase, and any adenosine formed was immediately reconverted to adenine nucleotides in the absence and presence of isoproterenol. It was concluded that adenosine is not released by intact human adipocytes, because the alternative routes of intracellular AMP catabolism are compartmentalized (at least in functional terms), and adenosine kinase is not saturated with substrate in the absence and presence of isoproterenol.

Many hormones exert their biological effects via increases in cyclic AMP. Hydrolysis of cyclic AMP yields AMP which is the first substrate of irreversible catabolic reactions. Any increase in its rate of synthesis can, therefore, lead to its further metabolism by dephosphorylation or deamination (Arch et al. 1978, Bidger et al. 1983). Among the products of AMP-catabolism, adenosine has a variety of biological effects, whereas inosine and hypoxanthine are relatively inert in biological terms (Arch et al. 1978). In adipose tissue adenosine influences glucose transport and acts as an inhibitor of cyclic AMP accumulation and lipolysis, both basal- and hormone-activated (Schwabe et al. 1973, Londos et al. 1980, Kather et al. 1985). It has therefore been proposed that adenosine is produced from cyclic AMP via the sequence cyclic AMP → AMP → adenosine and is utilized as an endogenous regulator of fat cell function.

Adenosine is known to modulate adenylate cyclase activity in a variety of tissues. We have tested the effects of adenosine on basal activity and the catecholamine- or prostaglandin E1-stimulated activity of the human fat cell adenylate cyclase. Adenosine caused a dose-dependent inhibition of basal enzyme activity as well as of adrenaline-and prostaglandin E1-stimulated rates of 3',5'-cyclic AMP accumulation. The adenosine-induced inhibition was specific since other nucleosides or their respective nitrogenous parent bases, with the exception of adenine, failed to mimic the action of adenosine. In addition, the adenosine-induced inhibition could be reversed by inclusion of adenosine deaminase. The results are compatible with the concept of adenosine acting as an inhibitor of lipolysis at the level of the membrane-bound adenylate cyclase. They show that this nucleoside can also inhibit the prostaglandin E1-induced stimulation of the human fat cell adenylate cyclase thereby suggesting that the effects of adenosine and prostaglandins might be antagonistic under conditions where prostaglandins act as stimulators of lipolysis.

Es wird ein Uberblick uber die molekularen Aspekte der Katecholaminwirkung und ihre klinischen Konsequenzen gegeben. Sowohl β- als auch (in einigen Geweben) α-Rezeptoren sind an das membrangebundene Adenylat-Cyclase System gekoppelt.

Human adipocytes are of limited viability (7 +/- 2% release of lactate dehydrogenase/h) and contain active ectophosphatases which are capable of sequentially degrading ATP to adenosine. At densities of 30,000-40,000 cells/ml, human fat cell suspensions accumulated adenosine, inosine, and hypoxanthine, and their concentrations were 38 +/- 8, 120 +/- 10, and 31 +/- 7 nmol/liter after 3 h of incubation. Dipyridamole (10 mumol/liter), an inhibitor of nucleoside transport, caused a 5-7-fold increase in adenosine accumulation which was reduced by 85% on inhibition of ectophosphatases by beta-glycerophosphate and antibodies against ecto-5'-nucleotidase or alpha, beta-methylene 5'-adenosine diphosphate (10 mumol/liter), respectively, indicating that most of the adenosine is produced in the extracellular compartment. Accordingly, the spontaneous accumulation of adenosine was reduced beyond 5 nmol/liter on inhibition of ectophosphatase activities or removal of extracellular AMP by AMP deaminase (4 units/ml). Added adenosine (30 nmol/liter) disappeared until its concentration approached 5 nmol/liter. Isoproterenol (1 mumol/liter) had no effect on adenosine accumulation regardless whether purine production from extracellular sources was minimized or not. In contrast to adenosine, the concentrations of inosine and hypoxanthine displayed only a modest decrease (30-50%) on inhibition of ectophosphatase activities. In addition, isoproterenol caused a 2-3-fold increase in inosine and hypoxanthine production which was concentration-dependent and could be inhibited by propranolol. It is concluded that the adenosine that accumulates in human adipocyte suspensions is almost exclusively derived from adenine nucleotides which are released by leaking cells. By contrast, inosine and hypoxanthine are produced inside the cells, and the release of these latter purines appears to be linked to ATP turnover via adenylate cyclase.

A semiautomatic determination of glycerol is described, in which luminescence produced by bacterial NADH-linked luciferase is measured by an automatic luminescence analyser (Berthold LB 950 T). The glycerol determination is based on the enzymatic conversion of glycerol to 3-phosphoglycerate, made irreversible by the presence of arsenate. NADH, formed in the glycerol-3-phosphate and glyceraldehyde-3-phosphate dehydrogenase reactions, is subsequently determined by the bacterial luciferase system. Stable kinetics of light emission were obtained by reducing the catalytic concentration of NAD(P)H: FMN oxidoreductase from 85 U/1 to 8.5 U/1. This method was applied to serum samples and validated by comparison with an enzymatic fluorimetric method. The new method is approximately 10 times more sensitive than the fluorimetric one. Moreover, it is simpler, more convenient, less time consuming and also less expensive than spectrophotometric, fluorimetric or radiochemical methods used for glycerol determination.

The effects of cytotoxic proteinaceous bacterial toxins on the adenylate cyclase cyclic adenosine monophosphate (cAMP) system of host cells are reviewed. Bacterial exotoxins affecting intracellular cAMP levels of host cells can be classified into two subgroups: (1) adenosine diphosphate (ADP)-ribosyl-transferases and, (2) invasive adenylate cyclases. Among the ADP-ribosylating toxins are the enterotoxins of Vibrio cholerae, of Escherichia coli and one of the pertussis toxins termed “islet-activating protein”. Toxins within this class share several structural and functional features. The three toxins consist of two functionally distinct parts: an A-component that is active enzymatically and a B-component that binds to surface receptors on cells or, if added in isolation blocks, the action of the complete toxin. The complete toxin shows little or no activity in broken cell preparations. When these toxins act on whole cells the contact is made initially through component B and then component A,but not B enters the cell and catalyzes the ADP-ribosylation of nucleotide regulatory components within the adenylate cyclase complex. The activities of the A-subunits of cholera toxin and heat-labile coli enterotoxin are directed against the stimulatory nucleotide-binding protein of adenylate cyclase whereas islet-activating protein probably alters the inhibitory coupling protein of host cells. Only recently two bacterial adenylate cyclases from Bacillus anthracis and Bordetella pertussis were described which are capable of invading mammalian cells. These invasive adenylate cyclases, like ADP-ribosylating toxins, require the presence of specific proteins for binding and are activated by calmodulin which is not present in bacteria. The role of this newly discovered class of bacterial exotoxins in infectious disease remains to be defined. Preliminary evidence, however, indicates that invasive bacterial cyclases may serve to suppress defense mechanisms in the host and thereby contribute to longer survival of parasitic bacteria.

Eine wichtige apparative Komponente in verfahrenstechnischen Anlagen ist die Pumpe. Spezielle Fordermedien verlangen spezielle Behandlung und somit auch spezielle Pumpen. Die Spaltrohrmotorpumpe ist konstruiert, um die Forderung nach Betriebssicherheit, Wartungsfreiheit, hohen Standzeiten und Umweltschutzanforderungen zu erfullen. Ihr Einsatzgebiet umfast auch das gesamte Spektrum der Fettsaureverarbeitung bezuglich Temperature, Druck, unterschiedlicher Viskositaten und Materialbestandigkeit. Besonders in unter Vakuum arbeitenden Anlagen ist eine absolute Abdichtung gegenuber der Atmosphare notwendig, was idealerweise von der Spaltrohrmotorpumpe verwirklicht wird und sich naturgemas zusatzlich in der vollkommenen Leckagefreiheit als Umweltschutzattribut auswirkt. Betriebssicherheit und Wartungsfreiheit werden durch serienmasige Komponenten zur auseren Uberwachung des Zustands von verschleisanfalligen Pumpenteilen erhoht. Die permanente Auswertung von Betriebserfahrungen zeigt, das diese Pumpenkonstruktion zur Fettsaureforderung als zuverlassige und problemfreie Anlagenkomponente gilt. Canned Motor Pumps for Fatty Acid Conveyance The pump is an important apparative component in process technological plants. Special conveyance media demand special treatment and with that special pumps. The canned motor pump is constructed to meet the requirements of reliability in service, exemption of service, long shelf life and environmental protection. It can be used in the whole range of fatty acid processing with respect to temperature pressure, different viscosities and material resistance. An absolute tightness to the atmosphere is especially necessary for plants working under vacuum conditions. This is realized in an ideal way by the canned motor pump and gets effects in addition in the complete exemption of leakage as attribute for environmental protection. Reliability in service and exemption of service are increased by standard components to outer control of the condition of pump elements which are susceptible to attrition. The permanent evaluation of processing experiences shows that this pump construction is a reliable and uncomplicated plant component for fatty acid conveyance.

Eine Pumpe, auch eine Spaltrohrmotorpumpe, mus fur die jeweiligen Betriebsverhaltnisse ausgelegt werden. Besonderer Schwerpunkt wird bei der Auslegung von Spaltrohrmotorpumpen fur den Einsatz in der Fettsaure-verarbeitung auf schonende Produktbehandlung gelegt. So ist das Eindringen von Luftsauerstoff in das unter Vakuum arbeitende System zu verhindern, eine partielle Uberhitzung des Produktes zu vermeiden, Vorkehrung gegen Unterschreitung des Stockpunktes zu treffen und die dampfdruckabhangige Haltedruckhohe besonders zu untersuchen. Diese Anforderungen gelten allgemein fur die Fettsaureverarbeitung, jedoch auch hier sind Produkte mit unterschiedlichen Eigenschaften im Einsatz, die jeweils eine speziell fur diesen Fall ausgelegte Pumpe erforderlich machen. Specific Criteria of Fatty Acids for the lay-Out of Canned Motor Pumps A pump must be layed out for the suitable working condition; this is valid, too, for a canned motor pump. Special importance in the lay-out of canned motor pumps for use in fatty acid processing is given to protecting product treatment. Thus entering of oxygen into the system, working under vacuum, is to prevent and a local overheating of the product is to avoid, measures against falling below the solidification point are to meet and the height of the maintained pressure, which depends on vapour pressure, is above all to investigate. These requirements are valid in general for the fatty acid processing. But products with different properties are applied in this area, too, which need each a pump which is layed-out especially for this case.

The effects of beta-adrenergic agonists such as isoproterenol, norepinephrine and epinephrine upon the adenylate cyclase activity of human fat cell ghosts were tested, each alone and in combination with the beta-blocking agent propranolol. Saturating concentrations of these agents showed a 2-6.5-fold increase of enzyme activity without addition of any artificial cofactors. Isoproterenol was more potent in stimulating the enzyme system than epinephrine and nor-epinephrine. Propranolol caused a dose-dependent rightward shift of the log-dose response curve of these beta-adrenergic agonists. The assay of human fat cell adenylate cyclase in vitro may provide a simple anc convenient assay system for the screening of beta-adrenergic drugs of potential therapeutic importance.

The effects of adenosine deaminase and of pertussis toxin on hormonal regulation of lipolysis were investigated in isolated human fat cells. Adenosine deaminase (1.6 micrograms/ml) caused a two-to threefold increase in cyclic AMP, which was associated with an increase in glycerol release averaging 150-200% above basal levels. Clonidine, N6-phenylisopropyladenosine, prostaglandin E2, and insulin caused a dose-dependent inhibition of glycerol release in the presence of adenosine deaminase. Pretreatment of adipocytes with pertussis toxin (5 micrograms/ml) for 180 min resulted in a five- to sevenfold increase in cyclic AMP. Glycerol release was almost maximal and isoproterenol caused either no further increase or only a marginal additional increase of lipolysis after pretreatment with pertussis toxin, whereas cyclic AMP levels were 500 times higher than in controls. The effects of antilipolytic agents known to affect lipolysis by inhibition of adenylate cyclase activity, i.e., clonidine, N6-phenylisopropyladenosine, and prostaglandin E2, were impaired. In contrast, the antilipolytic action of insulin was preserved in adipocytes pretreated with pertussis toxin. As in controls, the peptide hormone had no detectable effect on cyclic AMP after pertussis toxin treatment. The findings support the view that the antilipolytic effect of insulin does not require adenylate cyclase or phosphodiesterase action. In addition, the results demonstrate that, upon relief of endogenous inhibition, human fat cell lipolysis proceeds at considerable (adenosine deaminase) or almost maximal (pertussis toxin) rates. A certain degree of inhibition, therefore, appears to be necessary for human fat cell lipolysis to be susceptible for hormonal activation.

Prostaglandin E2 (PG E2) has biphasic effects on human fat cell adenylate cyclase with inhibition occurring in the nanomolar concentration range and stimulation at PG E2-concentrations above 1 mumol/l. Sodium ions stimulate the human fat cell adenylate cyclase in a hormone-like manner. The inhibitory component of PG E2-action is markedly augmented by sodium ions. In addition, the monovalent cation, by interfering with the stimulatory component of PG E2 discriminates between the opposing effects of PG E2 suggesting that the antagonistic effects of the E-type prostaglandins are mediated through distinct processes.

The effects of a single bout of exercise at 40% of maximum aerobic capacity with regard to alimentary lipemia and postprandial lipoproteins was studied in a cross-over design in 12 young healthy male volunteers. In addition to lipids and lipoproteins, lipoprotein lipase, free glycerol, free fatty acids, plasma insulin, and C-peptide concentrations were quantitated. Postprandial exercise reduced alimentary lipemia by 34% while lipoprotein lipase activity rose by 42%. The postprandial fall of high-density lipoprotein (HDL)3 was abolished and the rise of HDL2 accentuated. Free glycerol and free fatty acid concentrations were higher following the meal plus exercise regimen compared to the meal alone. It is concluded that at least part of the chronic effect of exercise may come from additive effects such as observed from individual bouts of muscular activity.

Alimentary lipemia was studied in 12 healthy young men with and without exercise. Three sets of experiments were performed. While continuous exercise of 90 min duration significantly reduced postprandial triglycerides by 26% (study I), this effect could not be observed when exercise was interrupted for 5 min after each 25 min (study II). Plasma free fatty acid concentrations, in the latter experiment, were significantly higher (by 311%) than during rest. When, in a third experiment continuous exercise was compared with intermittent physical activity, the latter condition significantly increased postprandial triglyceridemia, most probably due to precipitous rises of free fatty acids on each interruption of ergometry. It is concluded that in the third experiment the balance between triglyceride removal and triglyceride synthesis was shifted toward the latter. Whether exercise lowers, leaves unaltered, or raises plasma triglyceride levels may depend on subtle changes of experimental design.

The localization of the prostaglandin-sensitive adenylate cyclase in the upper gastrointestinal tract in human beings was studied. The prostaglandin-sensitive enzyme was almost evenly distributed throughout the fundic, antral and duodenal mucosa. The enhancement of enzyme activity in the presence of maximally effective prostaglandin concentrations exceeded basal levels by about 200%. The physiological role of the prostaglandin sensitive adenylate cyclase in gastric and duodenal function, however, remains to be established.

Fettzellen entstehen aus differenzierungsfahigen Vorlauferzellen (Praadipozyten). Praadipozyten entsprechen morphologisch und funktionell Fibroblasten. Der Differenzierungsvorgang ist gekennzeichnet durch die Ausbildung des typischen spharischen Erscheinungsbildes der reifen Fettzelle und durch die koordinierte Induktion von Schlusselenzymen der Lipolyse und der Lipogenese, sowie den Erwerb der charakteristischen Hormonempfindlichkeit der reifen Fettzelle. Der Differenzierungsvorgang wird durch einen bisher nicht charakterisierten Serumfaktor ausgelost und durch Insulin, Steroide, Prolactin, Prostaglandin F2α sowie Methylxanthine beschleunigt; er wird durch Cocarcinogene und Prostaglandin E1 gehemmt. Erste pathophysiologische Untersuchungen mit Praadipozyten von genetisch fettsuchtigen Mausen lassen vermuten, das sich eine genetische Pradisposition zur Obesitas schon auf Praadipozytenebene manifestiert. Regionale Differenzen in der hormonalen Regulation des Differenzierungsprozesses konnten zu den typischen, geschlechtspezifischen Unterschieden in der Verteilung der Korperfettmasse beitragen.

The influence of prolonged energy restriction (1250 kJ for 4 weeks) on insulin's antilipolytic action was investigated in abdominal adipocytes of obese subjects. An attempt was made to discriminate between dietary influences per se and indirect influences caused by changes in the concentration or action of adenosine. Prolonged energy restriction resulted in about a 3.5-fold increase in basal lipolytic rate which was associated with a corresponding increase in maximal response to insulin. Both these effects could be mimicked by adenosine deaminase (1.6 micrograms/ml) which increased glycerol release of adipocytes from fed donors to levels normally seen during starvation suggesting that the improvement of lipolytic responsiveness to insulin during energy restriction was an apparent one only, due to the fact that glycerol release was increased. To identify dietary influences that selectively affect insulin action the effects of insulin were compared with those of other antilipolytic agents in the presence of adenosine deaminase. Maximally effective concentrations of prostaglandin E2, clonidine and N6-phenylisopropyladenosine almost completely suppressed glycerol release before and during starvation. The extent of inhibition produced by these latter compounds was therefore related to basal activity by the same linear relationship in all experimental settings. By contrast insulin only partially depressed glycerol release and the relationships between basal activity and response to maximal concentrations of insulin were significantly different before and during starvation (P less than or equal to 0.01) in the presence of adenosine deaminase indicating that starvation selectively influences insulin action via mechanisms that are unrelated to the effects of other antilipolytic compounds. It is concluded that the main effect of energy restriction on insulin's antilipolytic action is an apparent one which is secondary increased lipolytic activity. Direct dietary effects on insulin action became apparent upon removal of endogenous adenosine. These tend to limit the maximal response to insulin and may be due to changes at the post-binding level but could also reflect an intrinsic property of insulin's antilipolytic action.

Some of the effects of GTP on human fat cell adenylate cyclase activity were studied. This nucleotide caused a dose-dependent inhibition of basal activity without affecting the hormone-activated rate of cAMP formation. Maximal effects were observed at GTP-concentrations of about 1 x 10(-4) M. The relative extent of hormonal stimulation was about 1.5-fold increased in the presence of 0.1 mM GTP.

Prazosin sinks the pathologically increased blood pressure, reduces pre- and afterload in myovascular insufficiency and has an interesting influence on plasma lipid fractions with regard to the coronary risk. Prazosin thus intervenes in the three cardiovascular disease processes, which often exist simultaneously, which are mutually caused. Studies which have taken place in the meantime demonstrate the possibilities of Prazosin as a treatment for Raynaud's disease and gangrene. The relatively long bio-availability of the preparation led constantly to the discovery of additional ranges of application, but did not deliver any new findings which would have made restrictions of the original application necessary. On the contrary, Prazosin proved to be especially favourable and capable of being universally applied in the illnesses which frequently accompany hypertension and cardiac insufficiency.

Das Pankreasgewebe des Saugetieres besitzt eine endokrine und exokrine Funktion, die beide morphologisch-anatomisch voneinander getrennt sind. Uber 90 % der Druse ist exokriner Funktion, wobei Azinuszellen verantwortlich fur die Sekretion von Enzymen sind, die zentroazinaren bzw. intercalaren Gangepithelien Sitz der Wasser- und Elektrolytsekretion (d. h. Na+, Cl- und HCO 3 - ) sind [1]. Elektrophysiologische Untersuchungen machen einen aktiven Transportmechanis mus fur HCO 3 - -Ionen im Pankreasgangsystem wahrscheinlich [2].

The effect of different doses of the newly developed histamine H2 receptor antagonist ranitidine on the sodium taurocholate-induced decrease of the potential difference across the human gastric mucosa was investigated in 18 healthy persons. It was shown that ranitidine protects the human mucosal epithelium against this agent both in acid-inhibitory and non-acid-inhibitory dosages. The results suggest that besides the prostaglandins histamine H2 receptor antagonists possess cytoprotective properties at least against bile acids.

Human gastric mucosal adenylate cyclase has been shown to be sensitive to histamine and catecholamines. Stimulation of enzyme activity by histamine and catecholamines were selectively blocked by cimetidine and propranolol, respectively. Combination of both hormones at maximally effective concentrations were additive, indicating that human gastric mucosa contains at least two separate hormone-sensitive adenylate cyclases.

Prostacyclin and its stable catabolite 6-keto-prostaglandin F1 alpha were tested on the human colonic mucosal adenylate cyclase which represents the key enzyme in the secretory process in this organ. Prostacyclin was able to activate dose-dependently the human cyclase system. Saturating concentrations of prostacyclin and 6-keto-prostaglandin F1 alpha (each 0.28 mM) increased the enzyme activity 2.5-fold and only 1.4-fold, respectively. The presence of prostacyclin receptor sites in human colonic mucosa suggests a physiological role of this novel prostaglandin in human colonic function.

The effects of adrenaline, noradrenaline, and of the alpha 2- and beta-selective agonists clonidine and isoproterenol were studied in fifteen obese subjects before and after 4 weeks of caloric restriction (300 cal day-1). Basal glycerol release averaged 1.4 mumol (10(6) cells)-1 (180 min)-1 before starvation and 2.8 mumol (10(6) cells)-1 (180 min)-1 during starvation (P less than or equal to 0.1). Before starvation adrenaline and noradrenaline caused a 2-3-fold increase of glycerol release. This lipolytic effect disappeared during starvation. An inhibitory effect of adrenaline was observed instead which was maximal at an adrenaline concentration of 1 mumol 1(-1) (P less than or equal to 0.05). The dose-response relationships of the alpha 2- and beta-selective agents clonidine and isoproterenol were not appreciably changed by caloric restriction. The increase of basal lipolytic rate and the reversal of adrenaline action seen during caloric restriction could be mimicked by removal of endogenous adenosine using adenosine deaminase (1.6 microgram ml-1). In addition, inclusion of N6-phenylisopropyladenosine (1 mumol 1(-1)) into the medium reverted the adrenaline-induced inhibition seen during caloric restriction. The results suggest that local modulators such as adenosine are of primary importance for the apparent change of responsiveness to adrenaline and noradrenaline seen during starvation of human fat cells in vitro.