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Der Einsatz des H2-Rezeptor-Antagonisten Cimetidin hat wesentliche Fortschritte in der Therapie von Erkankungen mit pathologish gesteigerter Sauresekretion gebracht,wie z.B. beim Ulks duodeni [2] und beim Zollinger-Ellision-Syndrom [3].Medikamentos bzw.toxisch verursachte Schlemhautlasionen des Magen-Darmtraktes lassen sich dagegen durch eine isolierte Blockierung der Sauresekretion nicht in ausreichendem Mase verhindern. Diese Tatsache hat das Interesse der Gastroenterologen an Pharmaka neu geweckt, deren Wirkung nicht allein auf einer Hemmung der Sauresekretion, sondern vielmehr auf einer Forderung bzw. Stabilisierung schleimhautschutzender Faktoren beruht.Zu diesen Substanzen zahlt einmal das Carbenoxolon, das seit langerer Zeit in der Ulkustherapie Anwendung findet. Dazu gehoren aber auch die Prostaglandine sowie nach neuesten Befunden auch das Prostacyclin.

It has been shown that human gastric mucosa contains a prostaglandin-sensitive adenylate cyclase system. Of the prostaglandins tested the E-type induced an about 3--3.5-fold increase of enzyme activity. The prostaglandin A2 by causing an about 2.5-fold enhancement of cAMP formation and the F-prostaglandins (1.4--2.0-fold stimulation) were less effective in activating the enzyme system. Maximally effective concentrations of histamine and prostaglandin E2 were additive with respect to enzyme activity indicating that both hormones act via individual adenylate cyclases.

After oral administration of 100 mg ranitidine a clear increase of intragastric pH values of just over 9 hours was observed in six patients. In four healthy probands inhibition of basal secretion was still demonstrable after 9 1/2 hours following ingestion of 150 mg ranitidine.

SH-Gruppen sind fur die katalytische Aktivitat einer Vielzahl von Enzymen von Bedeutung. Auch die katalytische Aktivitat der Adenylcyclase, die in Ratten fettzellen das gemeinsame Effektorsystem fur eine Anzahl lipolytisch wirksamer Hormone darstellt, ist ein SH-Enzym [1]. Daruber hinaus konnen Thiole [2] oder SH-Reagenzien [3] in isolierten Rattenfettzellen insulinahnliche Effekte auslosen, die als Hinweis fur die funktioneile Bedeutung von oberflachlichen Membran-SH Gruppen im Rahmen der Insulinbindung interpretiert wurden.

Die Rezeptorentheorie ist ein mechanistisches Konzept, das entwickelt wurde, um die Reaktionen des Gewebes und der Organe auf Arzneimittel und Hormone erklaren zu konnen. Das Rezeptorkonzept hat zu der Entwicklung vieler klinisch nutzlicher Medikamente gefuhrt, darunter der Betablocker, die hochspezifisch in pharmakologischem Sinne sind (Abb. 1).

Zahlreiche Prostaglandine haben antisekretorische und zytoprotektive Wirkungen am Magenschleimhautepithel von Tier und Mensch [2, 4, 8, 10]. Der Mechanismus der Zytoprotektion ist bisher nicht geklart [1, 5, 6].

In association with atypical pneumonia, a patient developed acute severe autoimmune hemolytic anemia. Hemoglobin temporarily was only 7.0 g/100 ml, so that the patient needed red blood cell (RBC) transfusion. Hemolysis was found to be caused by high titer cold agglutinins (CA), which occurred transiently during the acute period of the disease. CA of two different specificities, anti-I and anti-Fl, were demonstrated in the patient's serum. Antibodies of the two specificities were clearly separated by absorption/elution experiments using neuraminidase (RDE)-treated RBC. They were distinguished by serologic means: Both anti-I and anti-Fl react more strongly with adult RBC than with newborn and i adult RBC; in contrast to anti-I, anti-Fl does not agglutinate RDE-treated cells. Inhibition experiments showed that I-active substances prepared from papainized RBC exhibited both I and Fl antigenic activity. By RDE-treatment of I-active substances, Fl-activity was markedly reduced, while I-activity was increased.

The causal relationship of primary hyperparathyroidism and ulcer disease is reviewed. In contrast to earlier ideas careful clinical and clinico-chemical investigations have shown that in patients with manifest primary hyperparathyroidism neither is the incidence of ulcer disease raised nor are deviations from the normal behavior of acid secretion or the serum gastrin level to be observed in comparison with the average population.

Die medikamentose Behandlung der peptischen Ulkuserkrankung war in der Vergangenheit zum einen auf die Neutralisierung der gebildeten Magensaure (durch Antazida), zum anderen auf die Hemmung der Salzsaure- und Pepsinsekretion (durch Anticholinergika) gerichtet. Der Einsatz des Histamin-H2-Rezeptor-Antagonisten Cimetidin verstarkte noch zusatzlich diesen Trend.

Substituted benzimidazoles inhibit gastric acid secretion stimulated by histamine, pentagastrin and vagal innervation. In contrast to anticholinergic agents and H2-receptor antagonists these compounds also block secretion induced by exogenous cyclic AMP suggesting a more peripheral site of action. Recent data show that these substances inhibit a H+/K+-ATPase which is localized at the secretory surface of the parietal cells and is generally regarded as the proton pump within the gastric mucosa. Because of the unique distribution of H+/K+-ATPase the inhibitory action of substituted benzimidazoles may offer a new therapeutic approach in hypersecretory states.

Synonyma: Chondrocalcinosis articularis; Gelenkchondrokalzinose, Pseudogicht; Pyrophosphat-Arthropathie; englisch: calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, pseudogout syndrome, pyrophosphate arthropathy, pyrophosphate synovitis; franzosisch: chondrocalcinose articulaire, arthropathie lors de chondrocalcinose.

Antipyrine kinetics were determined in 6 healthy volunteers before and after the end of a 1 week treatment period of ranitidine 150 mg twice a day. The mean antipyrine half-life (h) was before 12.6 +/- 4.6 h and after ranitidine treatment 12.0 +/- 2.6 h. Antipyrine clearance (ml/min) and volume of distribution (1) were not altered following ranitidine administration. The results suggest that ranitidine has no influence on antipyrine-metabolism in healthy volunteers.

Multiple symmetric lipomatosis has been proposed to be associated with impaired catecholamine-responsiveness of hypertrophic adipose tissue at the level of beta-adrenergic receptors or adenylate cyclase respectively. We have studied the regulation of the adenylate cyclase by guanine nucleotides and adrenaline in 5 subjects suffering from multiple encapsulated lipomata. In the presence of GTP (0.1 mmol/l) basal adenylate cyclase activity averaged 0.5 +/- 0.3 nmol cAMP/mg protein/10 minutes in normal adipose tissue and 1.0 +/- 0.4 nmol cAMP/mg protein/10 minutes in hypertrophic adipose tissue respectively. The synthetic GTP-analogue GMP(PNP) (0.1 mmol/l) increased non-stimulated activity by about 100% in both tissues. Adrenaline (1 mumol/l-1 mmol/l) caused a dose-dependent increase of enzymic activity in both tissues which had a maximum of 130% above basal levels in the presence of GTP and of 300% in the presence of GMP(PNP) respectively. In one of the six subjects suffering from gluteal lipomata normal adipose tissue was obtained from the gluteal as well as the abdominal region on two occasions. Maximally effective concentrations of adrenaline (1 mmol/l) induced a 3-fold increase of enzymic activity in abdominal membranes compared with about a 1.7- and 1.75-fold increase in normal and lipomatous tissue from the gluteal region. The results show that encapsulated lipomata contain a normally reactive adenylate cyclase system.

Various prostaglandins posses antisecretory and cytoprotective actions on gastric mucosa. Cytoprotection by prostaglandins is unrelated to the inhibition of gastric acid secretion and can also be detected in small intestinal mucosa of the rat. Prostaglandins protect gastric mucosa against ulcerogenic compounds such as nonsteriod anti-inflammatory agents (NOSAC) as well as against the necrotizing affect produced by alcohol, 25% sodium chloride, 0.2 N solium hydroxide and 0.6 N hydrochloride acid. Prostaglandins protect in doses that are far too small to inhibit gastric acid secretion. At these doses no side-effects have been noted so far. This cytoprotective effect of prostaglandins might be beneficial in the treatment of a variety of diseases in which gastric mucosal injury in present.

Der Adenylzyklase wird eine grundlegende Bedeutung im Rahmen der basalen und hormonstimulierten Fettgewebslipolyse zugeschrieben.

The role of the number and size of adipocytes in the pathogenesis of obesity is reviewed. The observation that hyperplasia of adipose tissue is associated with child-onset obesity was over-interpreted. Nevertheless most recent studies suggest that fact cell size and number are regulated and can influence food intake. The discovery of preadipocytes has opened a new field or research offering the possibility of new concepts in the prevention and therapy of obesity.

Weight-maintaining fat-rich, "prudent," carbohydrate-rich, as well as energy-restricted diets (300 kcal/d) were fed in succession for 7 d to 12 healthy males of ideal body weight under metabolic ward conditions. At the end of each period isolated fat cells were prepared from subcutaneous abdominal adipose tissue and incubated in vitro in the absence or presence of adenosine deaminase, either alone or in combination with various lipolytic or antilipolytic hormones and agents. Variations in total energy intake and dietary composition had characteristic and specific effects on fat cell lipolysis in vitro. High carbohydrate and prudent diets resulted in low rates of nonstimulated glycerol release and impaired insulin action in the presence of adenosine deaminase (320 mU/ml). High-fat and energy restricted diets were characterized by high rates of nonstimulated glycerol release. Sensitivity of antilipolysis to insulin and prostaglandin E2 was 10 to 200 times lower respectively on energy-restricted than on fat-rich diets. The effects of alpha 2- and beta-adrenergic catecholamines and of N6-phenylisopropyladenosine were not affected by the preceding diets.

Synonyma: Zellulitis, Fibrositis, Pannikulitis, Rheumatismus des subkutanen Fett- und Bindegewebes, Zellulalgie.

The effects of hormones on human adipose tissue are reviewed with respect to the pathogenesis, prevention and therapy of obesity. Insulin. The insulin-resistance in the obese is associated with a decrease of the number of insulin receptor sites, which is likely to be secondary to increased insulin levels. Catecholamines. Human adipose tissue contains alpha- and beta-adrenergic receptors. Alterations in the relation of alpha- and beta-adrenergic responsiveness may be important in the pathogenesis of regional forms of obesity. Gastrointestinal hormones. As opposed to adipose tissue of other species lipolytic effects of gastrointestinal hormones were as yet not clearly demonstrated in human fat cells. Prostaglandins were implicated in the pathogenesis of metabolic obesity. However, the effects of these C-20 fatty acids on human adipose tissue remain to be elucidated. Parathyroid hormone has been shown to possess lipolytic activity in vitro. This property may be important under physiological conditions too. Triglyceride storage diseases and lipomatoses are discussed as models for studying impaired hormonal responsiveness in human adipose tissue.

The antilipolytic effects of N6-phenylisopropyladenosine and of prostaglandin E2 were studied with adipocytes of obese volunteers before and after 4 weeks of severe energy restriction [1250 kJ (300 cal)/day] in the presence and absence of adenosine deaminase (1.6 micrograms/ml, corresponding to 320 m-units/ml). The studies were undertaken to define more clearly the role that local modulators might play in adaptation of lipid mobilization to starvation in humans. Starvation was associated with an approx. 3-fold increase in non-stimulated lipolysis. Removal of endogenous adenosine resulted in a similar increase in basal glycerol release under both conditions, averaging 2 and 2.2 mumol/180 min per 10(6) cells respectively. The sensitivity of the cells to N6-phenylisopropyladenosine and to prostaglandin E2 was not changed by starvation in the presence of adenosine deaminase. These results are discussed in terms of the possible role that local regulators might play during dietary adaption in human fat-cells in vitro.

Es werden zwei hochempfindliche bioluminometrische Methoden zur Bestimmung von Gycerin und freien Fettsauren vorgestellt, die mit minimalen Serummengen auskommen (5–50 µl). Beide Methoden sind besonders fur sportphysiologische Untersuchungen geeignet. Daruber hinaus lassen sich zellphysiologische Untersuchungen mit geringen Zeltzahlen durchfuhren.

To elucidate the mechanisms of prostaglandin action in human adipose tissue the effects of prostaglandin E2 on isoproterenol-stimulated lipolysis in intact human fat cells and on adenylate cyclase activity of fat-cell ghosts were compared. In intact fat cells prostaglandin E2 caused a dose-dependent inhibition of isoproterenol -stimulated lipolysis which has a maximum of about 40 per cent; half maximal effects were observed at approximately 30 nmol/l prostaglandin E2. In broken cell preparation prostaglandin E2 displayed biphasic effects on adenylate cyclase activity with inhibition occurring in the nanomolar concentration range and stimulation at prostaglandin E2-concentrations above 1 mumol/l. The inhibitory component of prostaglandin E2-action was critically dependent on relatively high concentrations of GTP (greater than 1 mumol/l) and was augmented by sodium ions. The inhibitory component of prostaglandin E2-action on adenylate cyclase reflected the antilipolytic effects of this C-20 fatty acid in intact fat cells with respect to the effective concentration range and degree of inhibition suggesting that the antilipolytic effects of prostaglandins are in fact mediated via inhibition of human fat-cell adenylate cyclase.

The present knowledge about the differentiation of preadipocytes into adipocytes is reviewed. The adipose conversion is initiated by an as yet unknown serum factor and is enhanced by various hormones including insulin, prostaglandin F2 alpha, steroids, and prolactin; prostaglandin E1 and phorbol diesters are inhibitors of differentiation. Adipose conversion of fibroblasts (preadipocytes) is associated with the coordinate induction of key enzymes of the lipogenetic and lipolytic pathways and is accompanied by profound changes in hormone responsiveness. Pathophysiological studies with preadipocytes of genetically obese mice show differences between adipocyte precursors of obese animals and lean controls which may be casually related to obesity. Regional differences in the hormonal regulation of fibroblast conversion might be important for the sex differences of fat deposition in human beings.

The effects of meclofenamic acid on basal and hormone-stimulated adenylate cyclase in human colonic mucosa were tested. It is shown that meclofenamic acid is a relatively specific inhibitor of the stimulatory action of prostaglandins on the level of mucosal adenylate cyclase. This compound did not inhibit significantly the effects of vasoactive intestinal peptide (VIP) on the human enzyme system. VIP18-28 did not act as a partial agonist and did not inhibit the response to the intact VIP. Our studies suggest the existence of distinct receptor sites for both secretagogues (VIP and prostaglandins) in human colonic mucosa.

The sensitivity to hormones of the fat cell adenylate cyclase system was tested in uremic rats and in pair-fed control animals. Basal enzyme activities averaged 1.25 nmoles of cAMP formed per mg protein per 15 min in controls compared to 1.30 nmoles cAMP/mg protein/15 min in fat cell ghosts obtained from uremic rats. NaF caused an approximately 4-fold stimulation of enzyme activities in both systems. It was shown that parathyroid hormone should be included amongst the hormones which act as stimulators of the enzyme system. The responsiveness of the rat fat cell adenylate cyclase system towards saturating concentrations of ACTH, glucagon, epinephrine and parathyroid hormone was not altered in the presence of chronic renal failure.