G. Egger

Albumin as one-way transport vehicle into sites of inflammation

Intravenously injected Evans blue combines with albumin. The resulting complex appears in the inflammatory exudate that collects in Sephadex G 200 subcutaneously injected into rats. A comparison between the concentrations of albumin and Evans blue in the blood and in the inflammatory exudate shows that the life-span of albumin in the Sephadex is drastically reduced. After decomposition of albumin, the combined Evans blue is liberated, accumulates in the Sephadex and, after 24 h, attains concentrations higher than in the blood. The experiment is a plausible model for transport and deposition of albumin-bound drugs into and at sites of inflammation.

The influence of a permanent isoproterenol (ISO) application on the dynamics of the Sephadex inflammation.

The influence of Isoproterenol on the number of the different types of white blood cells appearing during the course of the Sephadex inflammation was investigated in rats. Isoproterenol treatment causes a decrease of the number of the immigrating neutrophils within the first two days and an increase of the lymphocytes during almost the entire experiment. A sudden decrease of the number of these cell types, indicating a massive cell destruction, was followed by immigration of eosinophilic granulocytes after 24 hrs. Isoproterenol accelerated and augmented this immigration. We conclude, that perishing neutrophils and lymphocytes produce or mediate the production of factors which attract eosinophils and moreover that Isoproterenol enhances the production or the effect of these factors. The mechanism underlying this enhancement is not known. We suppose a specific beta-adrenergic influence, because we could not reproduce this increasing effect with adrenaline.

Modifications in the regression of the acute inflammation caused by a β-adrenergic effect unbalanced by the α-component (“biased β-effect”)

Summary A biased β -adrenergic effect was produced either by blocking the α -adrenergic component of endogenous catecholamines using phentolamine or by application of isoproterenol. Both experimental conditions led to a prolongation of the lymphocyte phase of the inflammatory process. A β -bias also curbed the activity of a substance (or substances) inhibiting the ingress of lymphocytes into the site of inflammation (subcutaneously injected Sephadex) around the fourth and fifth day after the onset of inflammation. This lack in activity is evidently connected with the prolonged lymphocyte phase.

In vivo demonstration of endogenous substances regulating the regression of the acute inflammation

Subcutaneous injection of Sephadex G 200 causes an acute inflammation in rats. Its course was estimated by the types and numbers of white cells which immigrated into the Sephadex implants during a period of 5 days. Adrenaline (ADR) as well as Isoproterenol (ISO) each alter the cell immigration in a characteristic pattern. Sephadex which has already induced inflammation in an animal causes a mitigated inflammatory process when transplanted to another animal. Sephadex originating from donor animals influenced by ADR or ISO causes different reactions. A comparison of the results of the original inflammatory response and of the transplantation experiments demonstrates that several distinct substances with apparently specific functions must participate in the regression of the acute inflammation. The process by which the acute inflammation subsides is controlled by the organisms endogenous antiinflammatory substances.

Adrenalinapplikation durch eine intraperitoneale Depotkapsel — Wirkungen auf das Herz

Abstract 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.

Salivary gland enlargement as a test for a new way of permanent isoproterenol application

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.

Changes in blood catecholamines, insulin, corticosterone and glucose during the course of the Sephadex inflammation.

During an acute inflammation, the blood levels of noradrenaline, dopamine and insulin increase uniformly until the fourth day, then reach a climax which for dopamine is above the norm, while the suppressed levels of noradrenaline and insulin approach the norm. All values decrease on the fifth day (end of the experiment). Glucose behaves inversely, showing a minimum on the fourth day. Corticosterone displays two peaks, on the first and fourth days. The adrenaline level differs distinctly from these patterns: it is elevated on the second, fourth and fifth days. By releasing each catecholamine independently, the organism can possibly influence the course of the inflammation.

The influence of a permanent adrenalin application on the renais, using a new method for determining clearances in the conscious rat

Summary In order to investigate the extent of a permanent adrenalin application on the kidneys, rats were given two doses of adrenalin by subcutaneous implantation of adrenalin tablets into the neck. Inulin and PAH-clearances were measured in conscious rats using an intraperitoneal depot for the clearance substances. 22 hours post implantation of the depots, glomerular filtration rate (GFR), p-aminohippuric acid (PAH) and urea clearance, Combur-8-test, s-glucose and triglyceride levels, water and food uptake and changes in body weight were measured. Histological and histochemical examinations were also carried out. Permanent adrenalin application causes a decrease of GFR, PAH and urea clearances. The data of the Combur-8-test indicate renal damages (glucosuria, proteinuria and haematuria). Histologic findings show a reduction of functional nephrons, fresh necroses of glomerula and symptoms of cell destruction. Beside the glomerular damages there are also tubular alterations, such as fat deposits or glycogen depletions. Glucose and triglyceride levels are in normal ranges.

Antiinflammatory substances appearing during an acute inflammation and the alteration of their properties by isoproterenol (ISO). An in vivo investigation in rats.

It could be demonstrated that antiinflammatory substances appear during the course of an acute inflammation. The inhibition of leucocyte immigration into the site of inflammation (caused by Sephadex) was taken as criterion for the antiinflammatory property. The highest quantity or effect of the antiinflammatory substances was found on the 3rd day after inflammation has started. Not only the absolute number of cells but also the composition of the cellular exudate (compared with a fresh inflammation) was changed: The percentage rate of the neutrophils was reduced, whereas the portion of the eosinophils and the lymphocytes was increased. A permanent ISO application on the animals altered the quantity of the composition of these substances, in consequence of which the immigration of eosinophils and lymphocytes was promoted. The reaction of the neutrophils was unaffected.

Inhibition of adrenalin depletion in hypoglycaemic rats following permanent adrenalin application by depot capsule

Chronic treatment of rats with adrenalin by means of a subcutaneous depot capsule (cont. 40 mg dry adrenalin/HCl, Merck, ca. 10 mg ascorbic acid and ca. 0.4 ml 0.9% NaCl, and sealed with a dialysis membrane to provide constant adrenalin output) leads after a primary hyperglycaemic phase to hypoglycaemia. At the onset of hypoglycaemia the adrenalin contents of the suprarenal glands decrease to levels of about one third of their normal state. Simultaneous glucose infusions by intraperitoneal depot capsules prevent hypoglycaemia as well as adrenalin depletion. The fact that adrenalin depletion does not always correspond with blood sugar levels below 80 mg/dl and that this depletion could be prevented by glucose infusions altogether seems to provide a strong hint that the mentioned depletion is due to hypersecretion and not to the blocking of adrenalin synthesis. If is true, then there must be no direct negative feed-back system between adrenalin secretion and its extraglandular level.