Search

Summary Chronic adrenalin administration (4 mg/18 hrs) by means of a subcutaneous depot capsule leads to hypoglycaemia and adrenalin depletion of the suprarenal gland within 18 hrs. Simultaneous application of glucose prevents hypoglycemia as well as adrenalin depletion. By injection of 3 H-labelled tyrosine 10, 20 or 30 min before killing and subsequent detection of the quantity of labelled tyrosine and adrenalin in the sera by mixing them with a standard solution containing considerable amounts of unlabelled tyrosine and adrenalin, and by passing them through a Sephadex G-10 column and finally detecting the radioactivity of the fractions in a liquid scintillation-counter, we could prove that during the stage of hypoglycaemia an enhanced adrenalin synthesis and secretion did take place regardless of a high extraglandular level. In animals treated with adrenalin and glucose, NaCl solution or alpha-methyl-tyrosine methylester-HCI no increased resp. no turnover at all could be seen. Therefore, we conclude that there is not only a lack of a direct negative feedback system between adrenalin synthesis, secretion and extraglandular level but also that the enhanced synthesis of adrenalin that can take place in spite of a high serum level can initiate a fatal circulus vitiosus.

Summary In a frequently cited paper Sokal, Sarcione and Henderson (1964) doubted the physiological glycogenolytic role of adrenaline (A). By using isolated perfused rat livers, they found adrenaline to be effective at doses higher than 140 ng/ml while a mere tenfold increase in glucagon leads to expressed glycogenolysis. Our in vivo experiments carried out with controlled release systems for adrenaline show that marked glycogenolysis takes place at an adrenaline serum level of not more than 20 ng/ml while endogenous glucagon levels do not differ from controls. We think, that the reason for those controversial results lies (1) in the fact that Sokal, Sarcione and Henderson (1964) diminished the glycogenolytic action of adrenaline by blocking its α-component for the reason of an easier perfusion, and (2) they further diminished its glycogenolytic action by omitting corticosterone, which is well known for its permissive role in adrenaline induced glycogenolysis in vivo.

Question: It was to be investigated whether a constant relatively low enhancement of thecatecholamine level can produce myocardial lesions. This experimental study deals with the influences of permanent low concentrations of isoproterenol (ISO) on the heart.

Low doses of isoproterenol, given permanently by a new application-method, show the same effects on salivary-gland enlargement of rats throughout approx. 6 days than 10fold higher concentrations given by previous workers as single daily injections.

Summary Two further cases of human pheochromocytomas were kept in tissue culture for three months. The cultures were parted into two groups: one group was treated with nerve growth factor (NGF), the other group served as the control. The catecholamines in the medium were determined radioenzymatically (Da Prada). NGF-treatment led to lower contents of adrenaline, noradrenaline and dopamine. Cultures without NGF had higher levels. Electron micrographs showed catecholamine granula during the whole culture period. NGF treated cultures contained more catecholamine granula than the untreated cultures. Though the number of catecholamine granula was increased by the NGF-treatment, the medium contained less catecholamines than in untreated cultures. It may be concluded that NGF influences the liberation of adrenaline, noradrenaline and dopamine in tissue culture: though NGF treated cells contained more catecholamine granula, the catecholamines were retained in the pheochromocytoma cells.

Implantable coated Eudragit matrix tablets containing adrenaline in various concentrations should overcome the problem of additional handling stress during long term infusions. The efficiency of those tablets was tested in vitro, as well as in vivo using labeled adrenaline. Both in vitro and in vivo testing yielded satisfactorily output rates up to 20 h whereby the liver and serum content of 14C-fragments served as an additional prove for the postulated mode of action. Good correlation has been found between the mentioned out-put rates and adrenaline serum levels (measured according to Da Prada).

Les auteurs ont etudie l'influence de l'administration continue a long terme d'adrenaline par un systeme de liberation controlee sur les taux d'adrenaline plasmatique et les activites des enzymes metabolisant la noradrenaline dans le foie de rat. Les resultats indiquent: 1) la demi-vie de l'adrenaline depend de l'augmentation du taux plasmatique d'adrenaline et de sa duree et; 2) l'activite monoamine oxydase du foie est un des facteurs responsable de la regulation de la demi-vie de l'adrenaline

Rats were exposed to electrostatic fields of different intensities and exposure times, after which the osmolality of the serum and the concentration of neutral fat and cholesterol in the serum were measured. The triglyceride and cholesterol concentrations of the sera were independent of the strength of the electrostatic field and independent of the length of exposure of the animals in the constant field or Faraday cages. They always lay within normal limits, but moved according to the conditions of the constant field: the neurtal fat concentrations to the upper, and the cholesterol concentrations to the lower limit. The differences compared to the controls could be confirmed statistically.

The effects of adrenaline (A) on liver T3 and rT3 neogenesis from T4 were studied in Wistar rats. The animals were implanted subcutaneously either with A or placebo (P) especially coated tablets which linearly released the hormone. The serum A values 6 hrs after implantation of 7.5, 15.0 and 45.0 mg tablets were 6.5 +/- 1.31, 6.8 +/- 1.8 and 16.4 +/- 1.9 ng/ml, respectively vs 4.4 +/- 2.5 ng/ml seen in P pretreated group. The output rates of A were 0.11 (7.5 mg), 0.18 (15 mg) and 0.52 microgram/ml (45 mg). The pretreatment with A led to hyperglycemia and the "low T3 syndrome". Neogenesis of T3 from T4 in medium containing liver microsomes of P pretreated rats was 5.49 +/- 0.25 pmol of T3/mg protein/min and decreased in A pretreated rats to 3.82 +/- 0.17, 3.12 +/- 0.27 and 3.06 +/- 0.11 pmol of T3/mg of protein/min. Neogenesis of rT3 from T4 in microsomes from P group was 1.52 +/- 0.09 pmol rT3/mg protein/min and increased after A to 2.71 +/- 0.11, 2.60 +/- 0.21 and 2.21 +/- 0.34 pmol of rT3/mg protein/min thus showing no dose dependency. Enrichment of microsomes medium with cytosol either from P or A pretreated rats had no effect on T3 generation thus excluding effect of A on cytosolic cofactor. Although cytosol further increased rT3 neogenesis this was seen regardless of whether cytosol was obtained from A or P implanted rats. It is concluded that A decreases the activity of T4-5'-deiodinase in liver, and possibly increases the activity of T4-5-deiodinase.

As a further step in the development of implantable retard systems for simultaneous delivery of inulin and PAH, a system based on Eudragit® matrix retard tablet has been deviced. It should be able to release a sufficient amount of both substances to maintain constant and well measurable serum and urine concentration in the 36 hours interval between 12–48 hours p.o. The feasibility of the technique was checked by monitoring the behaviour of renal function after administration of a permanent adrenaline application, which we used as a well defined noxa.

Under the conditions of pair feeding, water-deprived rats predominantly use fat as a metabolic fuel, whereas total energy turnover as measured by oxygen consumption is not altered. Plasma free fatty acids are elevated in dehydrated rats, indicating enhanced lipolysis. Reduced hepatic fatty acid synthesis and reduced triacylglycerol secretion into the blood seem to be the main factors for the decrease of plasma triacylglycerol, observed 48 hours after the onset of water deprivation. Enhanced plasma levels of corticosterone (about 100%) and glucagon (about 50%) may contribute to the metabolic situation observed in water deprivation.

An intraperitoneal depot capsule was developed to improve the hitherto used in vivo test methods for chronic action of water soluble substances (repeated injections or permanent infusion which immobilizes the experimental animals). The capsule allows free movement of the animal and guarantees long-term continuous output of the substance. The effectiveness of the capsule was examined using adrenaline as test substance. In these experiments the maximum period of effectiveness and the consequences of permanent occupation of the receptors due to continued supply of adrenaline were studied.

Chronic treatment of rats by subcutaneously implanted A-depot capsules lead through a ca. 12 h hyperglycaemia to hypoglycaemia at 18 h p.o. SDH and G-6-Phase activities in the liver were compared during hyper- and hypoglycaemia using both histochemical and biochemical methods. The results show high triglyceride-contents, lack of glycogen and high G-6-Pase activities in the livers of animals during both hyper- and hypoglycaemia. Striking differences were found concerning SDH-activities: While biochemical measurements show enhanced activities during hyperglycaemia, hypoglycaemic values remain in the "normal" range. Nevertheless histochemical investigations show an amazing re-distribution of SDH-activities from the periportal areas towards the lobule centre. Therefore we think, that biochemical and histochemical methods should be combined to unveil such pseudonormalities. Further, this re-distribution shows the ability of the liver to cope with damage by shifting important processes away from fat-infiltrated areas.

The nephrotoxic actions of high single oral doses of fumaric acid monoethylester (FA ME) have been investigated in the rat. Fifty mg of this substance produced morphologic lesions of the glomeruli without reducing GFR. Following 100 mg, the lesions were more pronounced and GFR was diminished by about 40%. Despite of hemorrhages in kidney cortex the urines did not contain erythrocytes. Urinary protein was augmented in single cases only. Fifty to 100 mg FA ME induced a marked concentration defect after water deprivation. In parallel FA ME reduced lactate production from glucose by kidney inner medulla in vitro. After in vivo application, however, no morphologic lesions were found in this zone of the kidney. FA ME had no effect on oxygen consumption of kidney slices despite of proximal tubular lesions observed histologically after 100 mg orally. Thus, 100 mg of FA ME have distinct nephrotoxic effects in the rat.

Summary Adrenaline applied in the form of a retard tablet was implanted subcutaneously under short ether anesthesia under the neck skin of rats. Animals in the V 15 group received one 15 mg adrenaline tablet and those in the V 30 group two 15 mg tablets. The tablets were removed after 24 h. Twenty-two h later plasma catecholamines with the exception of dopamine are elevated in accordance with the amount of adrenaline applied. Histological examination reveals hyalinisation of the vasa afferentia and glomerula which is more expressed in the inner part of the renal cortex. Hyalinisation begins in the vas afferens and juxtaglomerular cells and extends to the glomerulus. Electron microscopic examination of the vas afferens shows vasoconstriction and beginning cellular degeneration of this vessel. Vasoconstriction is considered to be responsible for the decrease in kidney function.

A 24 h lasting long term adrenaline application in the form of subcutaneously implanted retard-tablets causes functional and morphological changes in the kidney, which are dose dependent and either reversible or irreversible. Animals in the V 15 group received one 15 mg and in the V 30 group two 15 mg adrenaline tablets resp. The tablets were removed after 24 h and a clearance depot capsule was implanted in the abdominal cavity. The test period extended from 22 h after removal of the retard tabl. to 21 d thereafter. Inulin (except the V 30 grp.), PAH and urea clearance are showing no significant differences. The data of urine gamma-GT activity, urea and urea-N in serum and urine, S-glucose, S-triglycerides, Combur-8-test, Na+ and K+ levels are in normal ranges. Morphological changes were found in the glomerula and tubular regions. Both the number of damaged nephrons and the extent of the damage depend upon the doses of adrenaline given. All glomerula with visible serious changes are irreversibly damaged; this was not true in case of the tubule. In the latter, after 7 d, the fatty deposits had diminished or disappeared.

A new method has been developed for the simultaneous measurement of Inulin and PAH clearance in small laboratory animals (rats). An implantable Inulin/p-aminohippuric-acid matrix-retard tablet based on Eudragit was tested with the purpose to estimate renal clearances. Sufficiently high serum and urine levels of both substances can thus be maintained up to 12-48 hours. The advantage of the method is that it can be used for renal clearance tests in small conscious animals, able to move freely within their cages without serious handling stress.

Twice a day, rats were exposed to handling stress by sham i.p. injections during a period of five days. This procedure progressively drove up the basic blood levels of free adrenaline, noradrenaline and dopamine, while insulin decreased to below normal. Blood glucose returned successively from hyperglycemia during the beginning of the experiment to normal later on. If rats subjected to acute inflammation were handled, the parameters blood catecholamines, glucose and the lymphocyte ingress into the site of inflammation all showed the same patterns of changes, suggesting a certain synchronization of the metabolic events. This synchronization failed to occur in animals with inflammation, but without handling. In any case, the disturbed metabolism of handled animals did not normalize during the test period of five days. Therefore, application of test substances by repeated injections is a useless method for the correct investigation of chronic exogenous influences.

A combined method of tissue culture and storage in liquid nitrogen is described, which is suitable for covering the root surface of transplantable teeth with a dense cell layer: after an initial period of 10 days in tissue culture the teeth are stored in liquid nitrogen. 10 days before a transplantation the teeth are thawed and cultured again for 10 days. By this pretransplantation treatment a densely grown periodontal cell layer as well as an unlimited storage time are achieved.

Investigations were performed with the aim of establishing the influence of various environmental conditions (such as steady field conditions, climatized laboratories, Faraday's cage) on a number of enzymic activities in the rat (including glutamic oxaloacetic tic transaminase, glutamic pyruvic transaminase, lactic dehydrogenase, gamma-glutamyl transpeptidase, acid phosphatase), as well as the serum concentrations of triglycerides, the oxygen consumption of hepatic parenchyma cells, and the influence on the incorporation of 3H-thymidine (following partial hepatectomy). In the steady field, the activities of the cytoplasmic enzymes (GOT, GPT, LDH) were higher then under Faraday conditions. The same applies both to the hepatic oxygen consumption and to the neutral fat serum levels. The control values always remained within the range of the results obtained under steady field or Faraday conditions. In the structure-linked enzymes (gamma-glutamyl transpeptidase, acid phosphatase) the results were not uniform. Following partial hepatectomy, and under steady field conditions, the serum triglyceride concentrations showed a less pronounced drop than they did in the controls. Under selected environmental conditions, the results obtained lie within the physiological range. The present findings, therefore, do not permit definite conclusions to be drawn on favourable or unfavourable effects exerted by the different types of electroclimates.

Summary Not only insulin application but also permanent treatment with adrenalin leads to adrenalin depletion of the adrenal medulla. Unilateral sympathectomy and subsequent treatment with insulin or adrenalin shows that in both cases adrenalin depletion is triggered by hypoglycaemia and activation of the sympathico-adrenal system. Therefore, a permanent elevation of the adrenalin level is sufficient to achieve depletion of the adrenal medulla, without necessitating a rise in the level of an additional hormone (insulin).

Summary Adrenal depletion in rats due to hypoglycemia was effected by prolonged administration of adrenalin, without artificial increase of insulin levels. In spite of significantly enhanced catecholamine turnover in this stadium Golgi complexes - which are usually reported to develop hypertrophy during adrenal depletion using insulin induced hypoglycaemia - could never be observed. This leads to the conclusions, that firstly the presence of hypertrophic Golgi complexes is not necessarily linked with increased catecholamine turnover and secondly that permanent adrenalin application suppresses and insulin application promotes the formation of Golgi systems. Moreover, our electromicrographs do strongly suggest, that catecholamine turnover is linked with the rough endoplasmatic reticulum.