A. Sadjak

Nephrotoxicity of Fumaric Acid Monoethylester (FA ME)

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.

Long-term application of some catecholamines elevates levels of other catecholamines in rats

Male Sprague-Dawley rats were treated during 20 h with subcutaneously implanted tablets (controlled release systems) containing either adrenaline (A), noradrenaline (NA), isoprenaline (ISO) or just placebos. Levels of the exogenously administered catecholamines (CA) in plasma and liver homogenate were significantly higher than in controls throughout the test time. During NA application endogeneous A and dopamine (DA) plasma values rose considerably, while ISO application enhanced endogenous NA and A levels. Adrenaline application increased NA and DA plasma levels. Several possibilities for this phenomenon are discussed, and it is concluded that previous papers dealing with observations of long term action of CAs should be reevaluated unless the influence of the artificially given CA on the elevation of endogenous CAs has been already taken into consideration.

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.

Peculiar long-term effects of catecholamines and their blockers in rats on insulin, glucose and pancreas*

To be able to study the long-term effects of moderately enhanced catecholamine levels in rats, we developed subcutaneously implantable retard systems, granting a linear output of various agents throughout the test time. Adrenaline application leads to hyperglycemia without elevation of serum immune-reactive-insulin (IRI) during 20 h of uninterrupted adrenaline (A) action. This we call an A-induced diabetes like reaction. It could be completely abolished by simultaneous application of low phentolamine (Regitin) doses. Simultaneous application of propranolol (P) gradually diminished blood glucose levels from about 200 mg/dl after 6 h to 120 mg/dl after 20 h. Since here insulin levels are uniformly low, decline of blood glucose could not be due to enhanced insulin-action. The moderate hyperglycemia after 6 h isoprenaline (ISO)-treatment alone goes with a hyperinsulinemia at the same time. Obviously this hyperinsulinemia cannot cope with the increased blood glucose probably due to enhanced liver-glycogenolysis by intact alpha-action. Later on insulin--despite of beta-action on pancreas--declines strictly proportional with diminishing blood-glucose-levels. A comparison between the action of catecholamines and their blockers showed that alpha-blockers tend to diminish blood glucose levels by two independent ways, namely by the inhibitory action on pancreas and the inhibitory action on liver glycogenolysis.

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.

The suitability of a combined inulin/PAH retard tablet for measuring renal functions in the conscious rat

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.

Adrenaline application by controlled release system shows that it does play a physiological role in glycogenolysis

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 in the fact that Sokal , Sarcione and Henderson (1964) diminished the glycogenolytic action of adrenaline by blocking its alpha-component for the reason of an easier perfusion, and they further diminished its glycogenolytic action by omitting corticosterone, which is well known for its permissive role in adrenaline induced glycogenolysis in vivo.

Vasoconstriction of the vasa afferentia in the rat kidney after long-term adrenaline application

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 hyalinization of the vasa afferentia and glomerula which is more expressed in the inner part of the renal cortex. Hyalinization begins in the vas afferents and juxtaglomerular cells and extends to the glomerulus. Electron microscopic examination of the vas afferents shows vasoconstriction and beginning cellular degeneration of this vessel. Vasoconstriction is considered to be responsible for the decrease in kidney function.