Endotoxin administration stimulates cerebral catecholamine release in freely moving rats as assessed by microdialysis.

In vivo microdialysis was used to measure changes in extracellular concentrations of catecholamines and indolamines in freely moving rats in response to administration of endotoxin (lipopolysaccharide, LPS). Dialysis probes were placed stereotaxically in either the medial hypothalamus or the medial prefrontal cortex. We used a repeated-measures design in which each rat received LPS or saline, and each subject was retested with the other treatment one week later. With the dialysis probes in the medial hypothalamus, intraperitoneal (ip) administration of LPS (5 micrograms) increased dialysate concentrations of norepinephrine (NE, 187%), dopamine (DA, 119%), and all their measured catabolites, except normetanephrine. Dialysate concentrations of NE and DA were elevated significantly in the fourth or fifth (20 min) collection period with a peak response at around 2 hr. They returned to baseline by about 4 hr. When the dialysis probes were placed in the medial prefrontal cortex, the same dose of LPS also elevated dialysate concentrations of NE and DA, but the increases were much smaller (ca. 20%). However, a dose of 100 micrograms LPS increased dialysate concentrations of NE and DA from the medial prefrontal cortex to an extent comparable to that of the 5 micrograms dose in the hypothalamus, and the response was more prolonged. Dialysate concentrations of serotonin could not be measured reliably, but those of its catabolite, 5-hydroxyindoleacetic acid (5-HIAA), were also elevated in both regions. The peak of 5-HIAA occurred at around 4 hr. Pretreatment of the rats with indomethacin (10 mg/kg ip) completely prevented the changes due to 100 micrograms LPS in the medial prefrontal cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in cardiac beta-adrenoceptors in human heart diseases: relationship to the degree of heart failure and further evidence for etiology-related regulation of beta 1 and beta 2 subtypes.

Radioligand binding studies were performed to investigate total beta-adrenoceptor density (Bmax) and beta 1 and beta 2 subtype distribution in left ventricular biopsies obtained from 8 prospective transplant donors serving as controls and from 143 patients with different degrees of heart failure (NYHA class II to IV) undergoing aortic or mitral valve surgery due to aortic or mitral stenosis, aortic or mitral regurgitation, as well as combined aortic or mitral valve lesions (stenosis and regurgitation). In 13 other patients, heart failure was due to hypertrophic obstructive cardiomyopathy (N = 6, NYHA III), tetralogy of Fallot (N = 4, NYHA III), or Becker's muscular dystrophy (N = 3, NYHA IV). Bmax was assessed by (-)-(125I)-iodocyanopindolol used as radioligand. Competition experiments with the highly selective beta 1-adrenoceptor antagonist CGP 20712A were performed for determination of beta 1- and beta 2-adrenoceptor subtypes. In biopsies taken from transplant donors, the Bmax was found to be 70.1 +/- 5.8 fmol/mg protein. In all groups investigated the extent of total beta-adrenoceptor downregulation was related to the degree of heart failure. The decrease in Bmax was found to be about 20% (NYHA II), 45% (NYHA III), and 60% (NYHA IV) when compared with controls. There was no significant difference in the reduction of total beta-adrenoceptor density between isolated aortic or mitral valve diseases and combined valve lesions. Independent of the degree of heart failure, selective downregulation of the beta 1 subtype was found in patients with isolated or combined aortic valve diseases, hypertrophic obstructive cardiomyopathy, and Becker's muscular dystrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

Corticotropin-releasing factor stimulates catecholamine release in hypothalamus and prefrontal cortex in freely moving rats as assessed by microdialysis.

In vivo microdialysis was used to measure changes in extracellular concentrations of catecholamines and indoleamines in freely moving rats in response to administration of corticotropin-releasing factor (CRF). Dialysis probes were placed stereotaxically in either the medial hypothalamus or the medial prefrontal cortex. We used a repeated-measures design in which each rat received artificial CSF or one dose of CRF 3-4 h apart, and each subject was retested with the same treatments in the reverse order 5-7 days later. With the dialysis probe in the hypothalamus, intracerebroventricular administration of CRF (17 or 330 pmol) dose-dependently increased dialysate concentrations of norepinephrine (NE), dopamine (DA), and all their measurable catabolites except normetanephrine. The effects on NE were substantially greater than those on DA. Dialysate concentrations of serotonin could not be measured reliably, but those of its catabolite, 5-hydroxyindoleacetic acid, were also elevated. Concentrations of NE and DA were elevated within the first one or two (20 min) collection periods, with a peak response at approximately 1-2 h. Dialysate concentrations of catecholamines and metabolites normally returned to baseline within 3 h. Similar data were obtained with dialysis probes in the medial prefrontal cortex after intracerebroventricular administration of 17 or 167 pmol of CRF, except that the increases in DA exceeded those of NE in this region. Intraperitoneal administration of CRF (1 nmol) similarly elevated dialysate concentrations of NE, DA, 5-hydroxyindoleacetic acid, and all catecholamine catabolites except normetanephrine in both medial hypothalamus and medial prefrontal cortex. These results support earlier neurochemical data suggesting that CRF administered both centrally and peripherally stimulates the release of both DA and NE in the brain.

Cardiac alpha 1-adrenoceptor densities in different mammalian species.

1. alpha 1-Adrenoceptor densities were studied in cardiac membrane preparations from several mammalian species including human failing hearts under identical experiment conditions; the alpha 1-adrenoceptor antagonist, [3H]-prazosin, was used as radioligand. End-stage heart failure (NYHA IV) in human hearts was due to idiopathic dilated cardiomyopathy. 2. The ventricular alpha 1-adrenoceptor densities were not significantly different in guinea-pig, mouse, pig, calf, and man (11 to 18 fmol mg-1 protein) but about 5 to 8 fold smaller than in rat (about 90 fmol mg-1 protein). Right and left ventricular receptor densities were similar in these species. 3. A sufficient amount of right and left atrial tissue was obtained from rabbit, pig, calf, and man only. The alpha 1-adrenoceptor densities in both atria of these species were found to be at the detection limit of the method used (less than 8 fmol mg-1 protein). 4. The equilibrium dissociation constant (KD) was similar in all species studied ranging from 0.047 +/- 0.006 to 0.063 +/- 0.007 nmol l-1. 5. It is concluded that differences in alpha 1-adrenoceptor density between atria and ventricles may exist in mammalian species. The exceptionally high density of these receptors in rat ventricles seem to be a particular feature in these animals.

Apparent inter-channel interference in dual-electrode electrochemical detection.

During the course of routine high-performance liquid chromatographic analyses of brain catecholamines using dual-electrode electrochemical detection, we encountered an unusual negative peak in the lower-voltage channel. Subsequent investigations suggested that this peak was caused by tyrosine which produced a positive peak in the higher-voltage channel. Our investigations indicate that compounds that generate a peak in one channel appear to be responsible for complex peaks in a second channel set at a lower voltage, close to or below that necessary for oxidation. The complex peaks are biphasic; a sharp negative peak coinciding with the positive peak on the higher-voltage channel, followed by a positive peak. This effect was not specific for tyrosine, but was observed on the lower-voltage channel with all compounds tested that produced signals on the high-voltage channel. The cause of the problem is unknown, but it appears to be an artifact of the electrical coupling of the two electrode channels in a dual-channel system.

Regional distribution of beta 1- and beta 2-adrenoceptors in the failing and nonfailing human heart.

Total beta-adrenoceptor density and beta 1- and beta 2-subtype distribution in right and left atria and in different ventricular regions from 14 failing and seven nonfailing human hearts have been compared. End-stage heart failure was due to idiopathic dilated cardiomyopathy (n = 8) or ischaemic cardiomyopathy (n = 6). In nonfailing hearts the total beta-adrenoceptor density was similar in the right and left atria and in all the ventricular regions studied (about 70 to 80 fmol/mg protein). The beta 1:beta 2-adrenoceptor ratio in both nonfailing atria was similar (about 70:30%) and was significantly smaller than in the different regions of both ventricles (about 80:20%). The beta 1-subtype density was similar in nonfailing atria and ventricles (about 55 fmol/mg protein). The beta 2-subtype density was significantly higher in the right and left atrium (about 25 fmol/mg protein) than in both ventricles (about 15 fmol/mg protein). In patients with end-stage heart failure due to idiopathic dilated cardiomyopathy or ischaemic cardiomyopathy the total beta-adrenoceptor density was reduced by 50-60% in all regions. On the other hand, the beta 1- and beta 2-subtype distribution differed with the cause of heart failure. In patients with idiopathic dilated cardiomyopathy, the beta 1-adrenoceptor density was not significantly reduced. In patients with ischaemic cardiomyopathy both beta 1- and beta 2-adrenoceptors were reduced in all regions. It is concluded that downregulation of beta-adrenoceptors in patients with end-stage idiopathic dilated cardiomyopathy or ischaemic cardiomyopathy occurs uniformly throughout the heart. The results support the hypothesis that changes in beta-adrenoceptor subtypes may be related to the cause of heart failure.

Different stressors and blood lipid peroxidation.

Elevation of lipid peroxidation (LOX) was observed in rabbits and mice after the intravenous administration of 0.2 micrograms.kg-1 of lipopolysaccharide (LPS) and 100 micrograms.kg-1 of peptidoglycan (MP). The peak was reached sooner after peptidoglycan, and 2-4 h after LPS administration. The trends of lipid peroxidation were the same in both species. 8-10 h later original LOX blood levels were reached. Mild horizontal vibration (1 h) induced in both species a significant lowering of LOX. This appeared already immediately after the vibration. Original values were gained again after 8-10 h. The difference between the internal stressors, LPS and MP, and the external stressor, vibration, are discussed.

Vibration stress and pharmacokinetics of rifampicin.

The influence of horizontal vibration stress on pharmacokinetics of rifampicin (RFP) 20 mg.kg-1 on rabbits was investigated. RFP was given orally or intravenously. The experiments were repeated one week later. The drug was administered immediately after 60 min of vibration like in control experiments on the same animals. Another group of animals was exposed to daily vibration for two weeks. The arrangement otherwise was the same as above. Serum levels of orally administered RFP were significantly decreased after a single vibration session. Repeated vibration exposure abolished the observed differences. The single vibration session had no effect on the pharmacokinetics of intravenously applied RFP.

The effects of peptidoglycan, a pyrogenic constituent of gram-positive microorganisms, on the pharmacokinetics of rifampicin.

Pharmacokinetics of rifampicin (20 mg/kg orally or i.v.) was determined in calves and rabbits. Seven days later a model pyrogen was administered i.v. to the same animals and 1 hr later the rifampicin administration was repeated. The pharmacokinetic analysis of oral rifampicin was performed using a one-compartment open model with absorption. Intravenously administered rifampicin was analysed by a two-compartment intravascular model. Injection of peptidoglycan in pyrogenic doses led to a significant increase of orally applied rifampicin serum levels in both animal species. The i.v. administration of rifampicin had the same parameters in the control and peptidoglycan experiments. Daily pretreatment of rabbits with small doses of peptidoglycan induced tolerance to the pyrogenic effect. In tolerant animals we did not observe any changes of rifampicin serum levels. Elevated temperature alone was not responsible for observed pharmacokinetic changes leading to the increase of bioavailability of oral rifampicin since another pyrogenic substance (endotoxin) had an opposite effect on pharmacokinetics of previously tested drugs.

Bacterial pyrogens of different origin and pharmacokinetics of rifampicin.

Changes of pharmacokinetics of rifampicin (RFP, Rifadin were investigated on endotoxin pretreated still not ruminant calves. The animals served as their own controls and drug administration twice in a 1-week interval gave the same results. Endotoxin 0.02 micrograms kg-1 given intravenously 1 h prior to the oral administration of RFP (20 mg kg-1) induced considerable pharmacokinetic changes. The serum levels of the total drug were significantly lower after the endotoxin administration. The pharmacokinetic analysis revealed significant changes mainly in the distribution phase. When both toxin and drug were administered intravenously, the drug levels were higher. The results are discussed with reference to the pathophysiological endotoxin changes. After the toxin administration the bioavailability of oral RFP was 4-fold lower.

Changes of pharmacokinetics of trimethoprim after pretreatment with streptococcal peptidoglycan.

Trimethoprim (TMP) 10 mg.kg-1 was given orally to calves and rabbits. Two to three weeks later the animals were pretreated by i.v. Peptidoglycan (Pt) 20 micrograms.kg-1. One hour later TMP was administered as above. To other animals under otherwise identical conditions TMP was injected intravenously. The pretreatment with Peptidoglycan induced in both species a significant increase of TMP serum levels positively correlated with temperature elevation. Peptidoglycan pretreatment increased the bioavailability of TMP.

[Efficacy of levimasole and nilverm on gastrointestinal nematodes in cattle and their effect on milk yield]. / Die Wirksamkeit von Levamisol und Nilverm auf gastrointestinale Nematoden des Rindes und ihr Einfluss auf die Milchleistung.

Effect of Levamisole and Nilverm on gastrointestinal nematodes in cattle and on the milk yield. The effect of Levamisole--pure substance and the preparation Nilverm on the milk yield of cattle was experimentally tested, however, significant positive results were not recorded. Following Nilverm application and after the experiments had been terminated, t-test showed significant daily decrease (2.5 l) in milk yield in the treated animals when compared to the controls. This decrease was directly proportional to the resumed increase in the extensity of invasion with gastrointestinal nematodes recorded after the treatment had been terminated. Regarding that the possibility of reinvasion of animals in cow sheds could be excluded and that the extensity of invasion with gastrointestinal nematodes was higher in the treated cows than in the controls at the end of the experiments, we assume that following the eradication of adult nematodes with anthelmintics activation of hypobiotic worm larvae occurred in the mucosa.

Endotoxin and pharmacokinetics of rifampicin.

Changes of pharmacokinetics of rifampicin (20 mg . kg-1 orally) were seen in rabbits pretreated with 0.02, 0.2 and 2.0 micrograms . kg-1 of endotoxin S. typhimurium given intravenously. The animals served as their own controls. The two higher endotoxin doses induced significantly lower plasma levels and changes in the absorption and elimination phase. After the lowest endotoxin dose the results were variable. Tolerance to pyrogenicity of endotoxin, produced by daily toxin administration abolished the otherwise induced changes in rifampicin pharmacokinetics.