[Automatic, electronic determination of resting time in small laboratory animals and the effect of psychopharmaceuticals]. / Automatisierte, elektronische Bestimmung der Ruhezeit am kleinen Labortier und Einfluss von Psychopharmaka.

The free movements of a small laboratory animal on the bottom of a cage, containing capacitive sensors, are measured as electrical signals which are then amplified, classified in a classification device and counted. With reference to the class of the highest sensitivity and by the choice of appropriate device parameters, signals are only counted during the time in which animal movements are below a level defined as rest. By this, the resting time can be determined which expresses the time in which animals are in the defined rest during the whole test time. The ED50, namely the doses after which the resting time increases by 50% during the first 10 min of the exploration phase of mice has been determined of diazepam, chlordiazepoxide, haloperidol, droperidol, fluphenazine, butaperazine, 7-fluorobutaperazine, and chlorpromazine and it was compared with the ED 50 determined in the contact bottom plates motimeter according to Knoll et al. in mice and in the catalepsy test according to Wirth et al. in rats. respectively. The method of resting time determination has proved as to be striking more sensitive (5- to 10-fold) than the other methods.

Nonspecific action of glucocorticosteroids after high-dose pulse therapy?

The original view of glucocorticoid effects as being divided into physiological and pharmacological ones is no longer acceptable, i.e. all glucocorticoid effects are apparently mediated by receptor occupation which triggers RNA protein synthesis. The concentrations needed for receptor-mediated effects are low, e.g. the KD value for dexamethasone is in the nanomolar range. The high-dose pulse glucocorticoid therapy results in blood concentrations much higher than those necessary for receptor saturation. This makes sense only when nonspecific effects may be expected to occur which necessitate concentrations higher than 10(-6) mol.l-1. In this paper the question of nonspecific glucocorticoid effects in adjuvant arthritis and carrageenin paw edema of rats was investigated using the glucocorticoid receptor antagonist RU 38486 and by injecting the RNA/protein synthesis inhibitors actinomycin D or cycloheximide. We did not find convincing evidence for nonspecific glucocorticoid mechanisms.

Acute phase reaction in rats: independent change of acute phase protein plasma concentration and macroscopic inflammation in primary rat adjuvant inflammation.

Experiments in rats suffering from primary acute adjuvant inflammation showed independent changes in serum acute phase protein concentration and macroscopic paw inflammation during antiinflammatory treatment: soybean trypsin inhibitor and horse-radish peroxidase caused antiinflammatory effects but simultaneously produced increased alpha 2 macroglobulin levels. On the other hand, cycloheximide significantly inhibited the increase of alpha 2 macroglobulin concentration in adjuvant inflammation, however, it had no antiinflammatory effect. All forms of treatment caused even some change in protein plasma levels of healthy rats which probably relates to an activation of cells producing interleukin-1, interleukin-6, and/or hepatocyte stimulating factor which trigger the synthesis of acute phase proteins in the liver. In inflamed rats, the snake venom batroxobin caused a significant decrease in the fibrinogen level whereas the paw swelling remained completely unaffected. Therefore, it seems to be doubtful whether acute phase proteins essentially contribute to the modulation of acute inflammatory reaction in primary rat adjuvant inflammation.

Influence of flavonoids and lanthanides on kappa-carrageenin rat tail thrombosis.

Rat tail thrombosis (RTT) induced by i.v. injection of kappa-carrageenin was not inhibited by p.o. or i.p. administration of the aglucon of rutin, quercetin, but it was slightly inhibited by rutoside-containing Venoruton. The RTT was significantly inhibited by didymlaevulinate, Helodym 88, whereas samarium-containing Phlogosol gave inconsistent results because of the solvent propylene glycol. The RTT model is suitable to detect substances of the flavonoid and lanthanide types with weak antithrombotic activity.

[The effect of drugs on electronically determined movement profile (movement profile analysis)]. / Beeinflussung des elektronisch erfassten Bewegungsprofils von Mäusen durch Pharmaka (Bewegungsprofilanalyse).

In the movement profile analysis, movements of small laboratory animals, according to both intensity and direction (amplitude and polarity), are electronically measured by means of capacitive sensors. The electrical signals are amplified, classified into 13 classes in a classification device and depicted as frequency distribution. The obtained distribution corresponds to a Gaussian distribution if normal control mice are used (normal movement profile, MP). The normal MP is characteristically changed by drugs. By centrally depressing drugs (droperidol, chlorpromazine, diazepam, medazepam) distribution classes of weak movements are dose-dependently increased while classes of strong movements are decreased. Stimulating drugs (dexphenmetrazine, methamphetamine, caffeine) gave opposite changes of the MP. A certain time after a stimulating drug the change of the MP can turn to the MP of depressing drugs obviously as the result of exhaustion of the animal. After low doses of echinoramine I a MP with the characteristics of a depressing drug was found, after high doses the MP was that of a stimulating drug, perhaps as the result of subtoxic effects. After apomorphine (1, 5, and 10 mg/kg) no clear dose-dependence could be found. The movement profile analysis can be useful in the specified analysis of movements-influencing drugs.

Reactivity of resistance blood vessels ex vivo after administration of toxic chemicals to laboratory animals: arteriolotoxicity.

Three vasotoxic metals (arsenic, lead, cadmium) were investigated for their arteriolotoxicity in rats. A perfused hindleg preparation from control and treated animals was used to determine the vasoreactivity to norepinephrine. After 2 and 4 weeks of treatment with arsenic trioxide (15 mg/kg p.o.) and after 4 weeks of treatment with lead acetate (100 mg/kg p.o.), there was a significant reduction in vasoreactivity (10 20%) expressed as the maximum increase in perfusion pressure (EAmax). A single dose of cadmium chloride (1 mg/kg i.p.) caused a non-significant reduction of 12% in EAmax. We conclude that this method is suitable for detecting arteriolotoxic effects of chemicals in small laboratory animals.

[Movement profile analysis--automatic registration and evaluation of the movement patterns of small animals]. / Bewegungsprofilanalyse--automatische Registrierung und Auswertung des Bewegungsmusters kleiner Versuchstiere.

A method is described, in which small laboratory animals are freely moving in the field of analogous capacitive sensors. The electrical signals induced by animal movements which, according to amplitude and polarity, contain informations on intensity and direction of movements are conveyed to a classification device and classified according to well-defined classes. By measuring during a fixed time (e.g. 10 min) or for a previously determined number of signals (e.g. 2000) a distribution of class frequencies, the movement profile, is obtained. Parameters of movement profile of mice in the orientation phase and factors of influence are reported on. The method allows the continuously automatic registration of movement profiles.

[The pharmacology of the lipoxygenase inhibitors oxphaman (1-(2,5-dihydroxybenzylidene)aminoadamantane) and oxphalin (1-(3,4-dihydroxybenzylidene)-2,4,6-trimethylaniline]. / Zur Pharmakologie der Lipoxygenasehemmer Oxphaman, 1-(2,5-Dihydroxybenzyliden)aminoadamanten, und Oxphalin, 1-(3,4-Dihydroxybenzyliden)-2,4,6-trimethylanilin.

Oxphaman and particularly oxphalin, among other phenolic azomethines, have been proven as strong inhibitors of lipoxygenases (LOX) from reticulocytes, soybean, thrombocytes as well as of quasi-LOX (hemoglobin) with IC50 values which correspond with those of known LOX inhibitors. The 5-LOX is likewise strongly, the cyclooxygenase of sheep seminal vesicles only weakly inhibited. Nevertheless, antiinflammatory effectivity was found in some carrageenin-induced inflammatory models of the rat as well as in the arachidonic acid- and croton oil-induced ear oedema of the mouse. Adjuvant arthritis, experimental pain, skin permeability and allergy models (anaphylactic paw oedema, cutaneous anaphylaxis, asthma, picryl chloride ear oedema) were not, only weakly or irregularly influenced. In the guinea pig ileum a certain antihistaminic, anticholinergic and leukotriene antagonistic activity was found. An inflammation-induced vasodepression (anaphylactic shock, dextran paw oedema. UV irradiation) was dose-dependently prevented or even reversed, obviously on the basis of oxygen radical scavenging.

Vasodepression ex vivo after administration of inflammatory mediators in vivo in the rat.

When rats were pretreated by intraplantar or i.v. injection of various inflammatory mediators, the vasopressor effect of i.a. norepinephrine in the subsequently isolated perfused hindlegs of the rats was found to be partly depressed. This vasodepression could also be detected if mediators were directly co-perfused in the isolated hindlegs. The vasodepressor effect was strongest following histamine pretreatment and co-perfusion, respectively, whereas endotoxin 0111:B4, PAF-acether, PGE1, and LTD4 were less effective. Only weak or no vasodepression could be induced by bradykinin, serotonin, lysolecithin, and substance P (1-11). The significance of the results is discussed with respect to anaphylactic disorders.

Pharmacological modulation of neurogenic inflammation.

A neurogenic inflammation was induced by electrical stimulation of the exposed saphenous or sciatic nerve of male rats. The increase in paw weight of the stimulated leg was used as parameter for degree of inflammation. The content of substance P decreased significantly in the skin supplied by the antidromic stimulated nerves. Substances were tested whose effectivity in neurogenic inflammation is as yet unknown. Inhibition of the angiotensin converting enzyme by the inhibitor captopril did not yield an indirect reference for a causative role of substance P in neurogenic inflammation. The activity of catecholamines refers to the possible importance of blood vessel and/or cyclic nucleotide level alteration in this special type of inflammation.

[The effect of cyclo-oxygenase and lipoxygenase inhibitors on anaphylactic vasodepression ex vivo in mice and rats]. / Einfluss von Cyclooxygenase- und Lipoxygenase-Inhibitoren auf die anaphylaktische Vasodepression ex vivo an Maus und Ratte.

Cyclooxygenase inhibitors (diclofenac, indomethacin, piroxicam) does not or only hardly inhibit anaphylactic vasodepression, except acetylsalicylic acid which could act as an oxygen free radical scavenger. However, the dual blocker BW 755 c strongly improves vasodepression. Pure lipoxygenase inhibitors (nordihydroguajaretic acid, oxphaman) only moderately improve vasodepression, the leukotriene antagonist FPL 55,712 is hardly effective. Obviously, endogenous prostaglandins do not and leukotrienes do take little part in the pathogenesis of anaphylactic vasodepression in the mouse and rat.

[Inhibition of arachidonic acid-induced ear edema in the mouse with lipoxygenase-, cyclo-oxygenase- and dual inhibitors]. / Hemmung des Arachidonsäure-induzierten Ohrödems der Maus durch Lipoxygenase-,Cyclooxygenase- und Dualhemmer.

The ear edema of the mouse induced by local application of arachidonic acid is suitable for in vivo differentiation of lipoxygenase (LOX) and cyclooxygenase (COX) inhibitors. LOX blockers inhibit initially and plateau-like during the first hour of the course of the edema, while COX-blockers do so mostly only initially. For practice we recommend the measurement about 60 min following edema provocation. The dual blocker of LOX and COX, BW 755 c, acts like a LOX inhibitor.