Norepinephrine triggers medullar epinephrine depletion during normoglycemia.

Our experiments did show that chronic 12 hours administration of norepinephrine (NE) to rats by means of subcutaneously implantable retard tablets, led to a highly significant epinephrine (E) depletion of the adrenal medulla during normoglycemia. The expected rise of free plasma NE at 6 and 12 hours was accompanied by increased free plasma E values at 12 hours. At this very time point the liver contents of glycogen and free intracellular glucose showed their most pronounced decrease. Since at 12 hours both liver glycogen and medullar E values were at their lowest, a second experiment was performed to examine a possible causal relationship. In order to curb the breakdown of liver glycogen, rats were force fed with 50% glucose solution 9 hours after NE tablet implantation. Glucose feeding not only caused a much less pronounced liver glycogen fall at 12 hours, but, at the same time also prevented E depletion of the adrenal medulla. These observations suggested that rapid fall of liver glycogen and/or liver intracellular free glucose might be the trigger for medullar E depletion, even before hypoglycemia.

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.

[Implantable repository adrenaline tablets for long-term studies on rats]. / Implantierbare Adrenalin-retard-Tabletten zur Langzeituntersuchung in Ratten.

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).

[Development of combined inulin/p-aminohippuric acid (PAH) slow release implantation tablets for clearance determination in awake rats]. / Entwicklung kombinierter Inulin/p-Aminohippursäure (PAH) Retard-Implantationstabletten zur Bestimmung der Clearance an wachen Ratten.

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.

Determination of efficacy of linotroban by inducing a reduction of renal inulin/para-aminohippuric acid clearances with the thromboxane A2 mimetic U-46619 in the conscious female rat.

Linotroban (CAS 141443-73-4), a potent and selective thromboxane (TXA2) receptor antagonist, is known as a novel antithrombotic agent. It is suggested that pharmacological inhibition of TXA2 synthesis or action merits continued evaluation in the treatment of a variety of renal diseases. The aim of this study was the determination of efficacy of this new TXA2 receptor antagonist by assessing its effect on the reduction in inulin and para-aminohippuric acid (PAH) clearances induced by the TX/prostaglandin endoperoxide mimetic U-46619 in the conscious female rats. The following doses (3, 10, 30 mg/kg/24 h) of linotroban mixed with 720 micrograms TX-mimetic U-46619/kg/24 h were administered via osmotic pumps at a delivery rate of 10 microliters/h, implanted s.c. during 72 h. Rats of the U-46619 group were administered 720 micrograms U-46619/kg/24 h alone as described above, controls received 3.5% NaHCO3, respectively. Inulin/PAH clearances were determined at the end of the 4-h clearance period (68 h-72 h). Summarizing the data, glomerular filtration rate (GFR) and PAH clearances were reduced significantly by U-46619. When linotroban (3, 10 or 30 mg/kg/24 h) was added to U-46619 the GFR and PAH clearance were reversed to values that showed no significant differences to the controls.

Critical comments on the classic concept of hypoglycemia induced epinephrine secretion.

Our experiments showed that a continuous chronic administration of norepinephrine (NE) to rats for 20 h by means of subcutaneously implantable retard tablets, led to a highly significant epinephrine(E) depletion of the adrenal medulla during normoglycemia. The rise of free plasma NE was accompanied by increased free plasma E values at 12 hours. At this time the liver contents of glycogen and free intracellular glucose showed their most pronounced decrease. At 12 and 20 hours both liver glycogen and medullar E values were very low. To check a possible causal relationship between those two events another experiment was performed in which the breakdown of liver glycogen should be inhibited. NE treated rats were force fed with 50% glucose solution 9 h after tablet implantation. This resulted in only mild glycogen depletion, which was no more able to trigger E liberation from the medulla. Therefore we conclude that pronounced liver glycogen depletion possesses a triggering ability for medullar E output by which hypoglycemia could be prevented.

Effects of the novel thromboxane (TXA2) receptor antagonist linotroban on inulin and para-aminohippuric acid clearances in the conscious male and female rat.

This paper reports the results of experiments designed to determine the effect of linotroban (CAS 141443-73-4) a selective thromboxane (TXA2) receptor antagonist with novel antithrombotic activity, on renal function in conscious male and female rats. Linotroban was administered subcutaneously at doses of 0, 6, 24, 48 and 96 mg/kg/24 h by osmotic minipumps over 6 days. Inulin (Inutest) and para-aminohippuric acid (PAH) clearances were determined on the last day of linotroban treatment. These agents were delivered by a slow release tablet planted s.c. five days after the start of the linotroban treatment. Linotroban did not significantly alter renal functions, although there was a significant difference in GFR (glomerular filtration rate) for male and female rats receiving the highest dose. Linotroban is well tolerated but the difference in renal function between male and female rats at the highest dose may reflect a threshold of renal tolerance.

Adrenal depletion during hypoglycemia without participation of the Golgi apparatus.

Adrenal depletion in rats due to hypoglycemia was effected by prolonged administration of adrenaline, without artificial increase in 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.

Long-term intraspinal infusions of opioids with a new implantable medication pump.

Experiences with long-term intraspinal infusion of opioid drugs using the new implantable medication pump VIP 30 in patients with chronic non-malignant pain are reported. During a 19-month period 10 patients with chronic pain--mainly mixed nociceptive-neuropathic pain--underwent implantation of the medication pump for long-term treatment. The mean follow-up period was 9.5 months. Pain relief was classified as very good in 22.2%, good in 44.4%, moderate in 22.2% and poor in 11.1%. In 88.9% of the cases the patients stated they would undergo the same procedure again. Technical problems (catheter dislocation) developed in 1/10 patients could be surgically corrected. One pump including catheter was explanted because of an infected seroma within the pocket area. Long-term intrathecal application of opioids with the VIP 30 pumps is an effective and safe treatment in patients with chronic non-malignant pain.

Perioperative catecholamine changes in cardiac risk patients.

BACKGROUND: It has previously been found that in cardiac risk patients undergoing non-cardiac surgery post-operative cardiac complications are correlated with high post-operative serum levels of troponin T (TNT) and troponin I (TNI). We investigated whether perioperative changes in the release of free (fCAs) and conjugated catecholamines (cCAs) correlate with the increased serum level of TN (TN upward arrow). MATERIALS AND METHODS: Plasma levels of CAs were determined in 28 patients at risk for or with definite coronary artery disease. Blood sampling was performed in the morning on the day before surgery, on the day of surgery before induction of anaesthesia and until the fifth post-operative day for measurement of CAs by high-performance liquid chromatography. RESULTS: The plasma concentrations of free and conjugated noradrenaline (fNA and cNA) as well as of free and conjugated adrenaline (fA and cA) were increased significantly in TN upward arrow patients post-operatively. The plasma levels of free as well as of conjugated NA and A in TN upward arrow patients were significantly higher than in TN0 patients over the whole post-operative period. CONCLUSION: This study demonstrates that increased post-operative release of fNA and fA as well as of cNA and cA correlates with high post-operative serum levels of troponins in cardiac risk patients undergoing non-cardiac surgery.

Laboratory handling and its influence on hormonal and metabolic parameters during acute inflammation in rats. A critique of long-term treatment by repeated injections.

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.

Long-term adrenergic beta-action decreases and alpha-action enhances corticosterone levels in rats.

A 20 h hyperadrenalinemia in rats was produced by subcutaneously implanted A-retard tablets with an output rate of 1.8 micrograms/min/250 g. This caused a moderate (6 h, 20 h) to expressed (12 h) rise in Corticosterone. Concomitant beta-blockade leads to equal (12 h, 20 h) or even more expressed (6 h) enhancement of plasma corticosterone, while A + alpha-blockade lowers those levels significantly against A or A + Prop treated animals. At 6 and 20 h they are even significantly lower than control values. We therefore conclude that enhanced alpha-adrenergic influence increases and beta-adrenergic influence decreases plasma Corticosterone levels in rats.

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.

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.