Interaction of MK-801 with the nicotinic acetylcholine receptor-associated ion channel from electroplax.
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Animals↗
Biomedical subjects
E Weber
Publications and source records attributed to E Weber.
Effects of sulfated polysaccharides on inhibition of thrombus formation initiated by different stimuli.
To test the possibility that different doses of heparin or other sulfated polysaccharides are required to inhibit thrombosis initiated by different stimuli, we compared the effects of heparin (HEP), pentosan polysulfate (SP54) and dermatan sulfate (DS) on the inhibition of thrombus formation induced by either I) tissue thromboplastin; II) thrombin; or III) factor Xa. Inhibition of thrombus formation induced by the stimuli was measured in a rabbit jugular vein hypercoagulation/stasis model. First, we determined the minimum dose of each sulfated polysaccharide which inhibited tissue thromboplastin-induced thrombus formation by approximately 75%, and then compared the relative effectiveness of this dose to prevent thrombus formation initiated with the other two stimuli. HEP and SP54 were less effective when thrombin was the thrombogenic stimulus, while DS was more effective. HEP was the most effective agent when factor Xa was the stimulus. We conclude that the antithrombotic effectiveness of a given dose of a sulfated polysaccharide may vary depending on the stimulus which initiates thrombus formation.
Animals↗
Adrenal cortical foci and nodules in Sprague-Dawley rats treated with N-nitrosomorpholine. Light and electron microscopic findings.
Treatment of male Sprague-Dawley rats with N-nitrosomorpholine (NNM) in the drinking water at a dose of 120 mg/l for 7 weeks resulted in a subsequent enhanced development of focal and nodular lesions in the adrenal cortex. Sequential observation revealed that focal lesions in the zona reticularis/fasciculata or the zona glomerulosa developed both earlier and at a significantly higher incidence in animals treated with carcinogen than in untreated controls. Foci observed within or adjacent to the zona glomerulosa were all of pale cell appearance and contained large numbers of electron-dense cytoplasmic granules similar to those observed in normal granulosa cells. The foci and nodules which arose in the zona reticularis/fasciculata were, in contrast, characterized by a reduction or loss of the dense osmiophilic droplets normally seen in the cells of this region of the adrenal cortex, a pronounced increase in pleomorphic mitochondria of atypical appearance and the development of vacuoles.
Adrenal Cortex Neoplasms↗
Collecting duct origin of rat renal clear cell tumors.
The renal tubular segment from which clear cell tumors originate was investigated in the kidneys of rats treated with N-nitrosomorpholine. This tumor type, which in the rat closely resembles that in man, is made up of clear and granular acidophilic cells and arises from tubules lined by clear cells. The tubular origin of the tumors was established in serial sections by demonstrating connections between both clear cell tumors and tubules lined by clear cells, and renal tubules of normal appearance. In 45 clear cell lesions (17 tumors and 28 tubules) one or more such connections were identified which belonged to the collecting system. In accordance with their localisation in the kidney, the clear cell lesions were connected predominantly to tubules of the cortical collecting system and occasionally to outer medullary collecting ducts. As previously reported, oncocytic tubules and microoncocytomas were observed to originate from the same portions of the collecting system. Rarely, microadenomas and tubules consisting of both oncocytes and clear or granular acidophilic cells were also observed in the kidneys studied.
Adenocarcinoma↗
Pharmacokinetics of nicotinic acid-salicylic acid interaction.
Both nicotinic acid and salicylic acid undergo glycine conjugation in human beings. Competitive inhibition may therefore be possible when these substances are used concomitantly in patients with hyperlipidemic disorders. The aim of this study was to determine, in six healthy subjects, whether nicotinic acid steady-state levels and total clearance are affected by concomitant aspirin administration. Steady-state nicotinic acid concentrations were obtained in all six volunteers by infusion of nicotinic acid solutions at constant rates (0.075 to 0.100 mg/kg/min) for 6 hours; aspirin (1 gm) was administered orally 120 minutes after the beginning of the infusion of nicotinic acid. Plasma samples were analyzed for nicotinic acid, nicotinuric acid, and salicylic acid. After aspirin administration an immediate marked decrease of nicotinuric acid levels could be observed in all six volunteers, whereas nicotinic acid concentrations increased. We hypothesize that salicylic acid causes a concentration-dependent decrease of total nicotinic acid clearance that results in the saturation (and effective elimination) of the nicotinuric acid conjugation pathway.
Administration, Oral↗
Solubilization and characterization of sigma-receptors from guinea pig brain membranes.
The sigma-receptor, a distinct binding site in brain tissue that may mediate some of the psychotomimetic properties of benzomorphan opiates and phencyclidine, has been solubilized using the ionic detergent sodium cholate. Binding assays were performed with the solubilized receptor using vacuum filtration over polyethyleneimine-treated glass fiber filters. The pharmacological specificity of the solubilized binding site for sigma-receptor ligands is nearly identical to the membrane-bound form of the receptor, with the order of potencies for displacement of the selective sigma-ligand [3H]di-o-tolylguanidine ([3H]DTG) closely correlated. The stereoselectivity for (+)-benzomorphan opiate enantiomers was retained by the solubilized receptor. The soluble receptor retained high affinity for binding of [3H]DTG (KD = 28 +/- 0.5 nM) and (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-[3H]3-PPP] (KD = 36 +/- 2 nM). Photoaffinity labeling of the solubilized receptor by [3H]p-azido-DTG, a sigma-selective photoaffinity label, resulted in labeling of a 29-kilodalton polypeptide identical in size to that labeled in intact membranes. Estimation of the Stokes radius of the [3H]DTG binding site was obtained by Sepharose CL-6B chromatography in the presence of 20 mM cholate and calculated to be 8.7 nm. This value was identical to the molecular size found for the binding sites of the sigma-selective ligands (+)-[3H]3-PPP and (+)-[3H]SKF-10,047, supporting the hypothesis that all three ligands bind to the same macromolecular complex.
Affinity Labels↗
Endocrinology of benign breast disease in relation to the severity of radiological dysplasia.
A link between benign breast disease and hormonal imbalance has not been conclusively determined. In women suffering from severe radiological dysplasia, it was found to be correlated with slightly raised serum hormone binding globulin (SHBG) binding capacity. SHBG is an oestrogen-sensitive protein, which may be a marker of enhanced oestrogen bioactivity. Such abnormality was not, however, detected by the measurement of peripheral steroid hormones.
Breast Diseases↗
Hormonal and non-hormonal medical therapy of benign breast disease.
Mastopathy or nodular painful breast can be managed by several non-hormonal and hormonal treatments. Little data exist for effectiveness of the former. Whilst the hormonal treatments are considered to be very effective, their use can be limited by unpleasant side effects.
Breast Diseases↗
Significance of sequential cellular changes inside and outside foci of altered hepatocytes during hepatocarcinogenesis.
A variety of phenotypic cellular changes emerge in the liver of different species prior to the appearance of hepatocellular adenomas and carcinomas induced by carcinogenic agents (chemicals, radiation, hepadna viruses) or develop "spontaneously." Foci of altered hepatocytes have been studied most extensively in rats treated with chemical carcinogens; they are considered preneoplastic lesions and have been used in several laboratories as endpoints in carcinogenicity testing. The principles and problems of the morphological classification of foci of altered hepatocytes are presented. In addition to the 4 types of foci generally accepted (clear, acidophilic, basophilic and mixed cell foci), further subtypes (intermediate cell foci) or other types of foci, namely tigroid cell foci and amphophilic cell foci, have more recently been separated as distinct pathomorphological entities. Whereas the amphophilic foci might result from a modulation of clear and acidophilic cell foci, the tigroid cell foci apparently represent a stage in a separate cell lineage leading to hepatocellular adenomas. It remains open whether the tigroid cell foci may also progress to carcinomas. Extrafocal phenotypic changes of hepatocytes might also be involved in hepatocarcinogenesis. The cellular phenotypes within foci also depend strongly, among many other factors, on the dose and duration of the carcinogenic treatment. Cytomorphological, cytochemical, microbiochemical and stereological studies suggest that the predominant sequence of cellular changes during hepatocarcinogenesis leads from the clear and acidophilic cell foci storing glycogen in excess through mixed cell foci and nodules to basophilic cell populations prevailing in hepatocellular carcinomas. A multitude of metabolic aberrations is associated with the sequential cellular changes. Aberrations in carbohydrate metabolism are particularly prominent and might be causally related to the neoplastic transformation of the hepatocytes.
Animals↗
Immunocytochemical demonstration of cytochrome c oxidase as a marker for renal oncocytes and oncocytomas.
Using an antibody raised against the mitochondrial enzyme cytochrome c oxidase (EC 1.9.3.1), it was possible to visualize microoncocytomas, oncocytic tubules and even single oncocytes in the renal cortex of rats treated with N-nitrosomorpholine, and to localize the lesions to the collecting duct of the nephron. In human specimens, the antibody also stained oncocytomas and oncocytic tubules in the surrounding macroscopically unaffected cortex. Thus, this antibody may be used for detection as well as for investigation of the development of oncocytic lesions in various species.
Animals↗
The isolation, identification and structure of a new hydroxylated metabolite of benzbromarone in man.
1. The metabolic fate of the uricosuric drug, benzbromarone, in man was reinvestigated. Plasma and urine samples obtained from healthy subjects after administration of a single oral dose of 100 mg were analysed by h.p.l.c. and g.l.c.-mass spectrometry; bromobenzarone and benzarone, previously assumed to be the debrominated metabolites of benzbromarone, were not detectable. 2. Instead, two metabolites (M1 and M2) were present in plasma samples, which had plasma elimination rates lower than those of the parent drug. 3. One of the metabolites (M1) was identified as 1'-hydroxy-benzbromarone using g.l.c.-mass spectrometric analysis of trimethylsilylated and methylated extracts. Chromatographic and spectroscopic data for this metabolite were identical to those of the synthetic compound.
Adult↗
Vessel wall reactivity and 13-hydroxy-octadecadienoic acid synthesis.
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Blood Platelets↗
Sigma receptors regulate contractions of the guinea pig ileum longitudinal muscle/myenteric plexus preparation elicited by both electrical stimulation and exogenous serotonin.
Sigma receptors are specific, highly localized binding sites in limbic and sensorimotor structures of the brain that interact with many psychotropic drugs. These agents include the psychotomimetic benzomorphan opiates, the psychotomimetic drug phencyclidine and its analogs, as well as numerous typical and atypical antipsychotics such as haloperidol, chlorpromazine, and the novel drugs BMY 14802 and rimcazole. So far, no physiological function has been assigned to these binding sites. We have synthesized a number of novel sigma receptor-active drugs derived from the selective sigma ligand N,N'-di(o-tolyl)guanidine (DTG). DTG and its congeners were found to inhibit contractions of the guinea pig ileal longitudinal muscle/myenteric plexus (LMMP) preparation evoked by electrical stimulation. In addition, the sigma ligands noncompetitively antagonized contractions of the LMMP preparation evoked by serotonin (5-HT). The 5-HT-evoked contractions were found to be largely due to 5-HT's activation of 5-HT3 receptors to release ACh. The activity of DTG congeners in inhibiting electrically or 5-HT-evoked contractions of the LMMP highly correlated with their potency to inhibit binding of both 3H-DTG and (+)3H-3-PPP [3(3-OH-phenyl)-N-(1-propyl)piperidine] to sigma receptors in guinea pig brain homogenates. Two DTG congeners that did not bind to sigma receptors also showed no activity in the bioassay. Many other (but not all) sigma receptor ligands showed a high correlation between their potency to inhibit electrically evoked contractions of the LMMP and their sigma receptor binding affinity. The benzomorphans (+)SKF 10,047 and (+)cyclazocine potentiated electrically evoked contractions of the LMMP. Sigma ligands also inhibited the contractions of the LMMP in the presence of the opiate antagonist naloxone and in preparations in which opioid receptors had been inactivated by treatment with the irreversible opiate antagonist beta-chlornaltrexamine. Control experiments suggested that the sigma ligands act via a neuronal mechanism to inhibit ACh release evoked by electrical stimulation or by stimulation with 5-HT. These results suggest that there are functional sigma receptors on cholinergic nerve terminals or within the myenteric plexus and that these receptors can inhibit stimulated ACh release through an opioid receptor-independent mechanism. However, sigma receptor activation in the ileum has the same effect on ACh release as activation of naloxone-sensitive opioid receptors. The LMMP may be an in vitro bioassay system for characterizing the mechanism of action of sigma receptors and for determining the biological efficacy of drugs known to bind to sigma receptors in radioligand binding assays.
Animals↗
1,3-Di(2-tolyl)guanidine blocks nicotinic response in guinea pig myenteric neurons.
Ditolylguanidine (DTG) is a ligand which binds with high affinity to neuronal sigma receptors. Activation of sigma receptors inhibits the release of acetylcholine (ACh) from guinea pig ileum myenteric plexus preparations. A study was therefore undertaken to investigate the action of sigma receptor ligands on single neurons. Nicotinic responses to locally applied ACh onto single neurons of the guinea pig ileum myenteric plexus were studied using intracellular recording techniques. DTG and (+)-SKF10047 (N-allylnormetazocine) produced a concentration-dependent suppression of the depolarization of enteric neurons evoked by ionophoresis of ACh. The EC50 values for DTG and (+)-SKF10047 were 4.7 and 3.8 microM, respectively, and were similar to that for hexamethonium (3.2 microM). The inhibition of the ACh-depolarization was not mediated at sigma receptors because (-)SKF10047 and Bridge-DPG (2-imino-1,3H-dibenzo[d,f]-[1,3]-diazepine), which are inactive at sigma receptors, were as potent as DTG and (+)-SKF10047. DTG and hexamethonium (each at 1 microM) were more effective blockers of ACh-induced inward currents at a holding potential of -100 mV than at -40 mV. This voltage dependence is consistent with a channel blocking mechanism. DTG (10 microM) did not affect the depolarization (mediated by 5-HT3 receptors) induced by pressure application of 5-HT onto single neurons. DTG and Bridge-DPG inhibited contractures of the longitudinal muscle-myenteric plexus preparation elicited by dimethylphenylpiperazinium noncompetitively (EC50 values were 8.0 and 12.3 microM, respectively) whereas DTG but not Bridge-DPG inhibited 5-HT-induced contractions of the longitudinal muscle-myenteric plexus noncompetitively.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Neuroleptic-sensitive binding sites in the nigrostriatal system: evidence for differential distribution of sigma sites in the substantia nigra, pars compacta of the cat.
The sigma site is a recently described binding site to which dextrorotary isomers of certain psychotomimetic benzomorphans bind specifically. Classical and nonclassical neuroleptics also have high affinity for the sigma site, including neuroleptics known to bind to the D2 dopamine receptor. The affinity of some D2-binding neuroleptics for the sigma site has raised the possibility that certain important effects of antipsychotic drugs may relate to the sigma site. Left unresolved has been the question of how these actions could relate to dopaminergic systems. To explore this issue we carried out an autoradiographic binding study of the distribution of the sigma-selective ligand 3H-DTG in the nigrostriatal system. We report here that haloperidol-displaceable 3H-DTG binding sites are densely concentrated in an anatomically discrete subdivision of the cat's substantia nigra pars compacta. This zone, identifiable as the striosome-projecting densocellular zone of the pars compacta, also shows heightened D2-related ligand binding but has reduced D1-related ligand binding relative to other parts of the nigral complex. This evidence suggests that sigma-mediated interactions with dopaminergic systems may occur in the substantia nigra pars compacta and that the functional effects of these interactions may influence the nigrostriatal projection to striosomes differentially.
Animals↗
Interaction of 6-cyano-7-nitroquinoxaline-2,3-dione with the N-methyl-D-aspartate receptor-associated glycine binding site.
The interaction of newly described antagonist of the non-NMDA glutamate receptor 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) with the glycine site of the NMDA receptor complex has been investigated. In whole-cell patch recordings from hippocampal neurons maintained in culture, currents induced by N-methyl-D-aspartate (NMDA) were dependent on extracellular glycine. Responses to both NMDA (30 microM) and kainate (20 microM) were reduced by CNQX (10-30 microM). The antagonism by CNQX of NMDA, but not kainate, receptor-mediated responses could be reversed by increasing the concentration of glycine in the external medium. Glycine concentration-response curves constructed in the presence of 30 microM NMDA were shifted to the right by CNQX, suggesting that CNQX was competing with glycine for the glycine binding site. However, even at high concentrations of glycine (300 microM) the maximal NMDA current obtained in the presence of CNQX (10-30 microM) was not restored to control levels. Because CNQX had no effect on responses produced by supramaximal concentrations of NMDA (500 microM) and glycine (300 microM), it is suggested that CNQX also interacts with the NMDA recognition site. The antagonism of currents induced by NMDA was not dependent on the membrane potential, and the rapid onset and offset of the block suggested that there was little or no use dependence. Radioligand binding experiments were performed using [3H]glycine to label the strychnine-insensitive glycine regulatory site of the NMDA receptor complex in guinea pig brain frontal cortex membranes. CNQX displaced [3H]glycine binding in a concentration-dependent manner (IC50 = 5.7 microM). Scatchard analysis of the inhibition showed a decrease in the affinity (increase in Kd) of [3H]glycine binding, but no change in the number of binding sites (Bmax) in the presence of 5 microM CNQX, suggesting a competitive interaction. These data provide evidence that CNQX antagonizes NMDA receptor-mediated responses by competing with glycine for a modulatory site associated with the NMDA receptor complex. Furthermore, the results indicate that CNQX may not be as selective an antagonist for non-NMDA receptors as initially described, although its selectivity will depend on the concentration of the NMDA receptor ligand and may be enhanced by increasing the extracellular concentration of glycine.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
The influence of different formula diets and different pharmaceutical formulations on the systemic availability of paracetamol, gallbladder size, and plasma glucose.
The influence of two liquid formula diets on the systemic availability of paracetamol was investigated in 12 healthy normal volunteers using a liquid and a solid paracetamol dosage form. The diets contained the same balanced amounts, but different patterns of nutrients and different amounts of dietary fiber. Plasma glucose and gallbladder response to the standard meal were used as indicators of gastric emptying. Paracetamol plasma concentrations following application of the liquid dosage form also served as a marker for the gastroduodenal transport of liquid gastric contents. For the liquid dosage form, the plasma concentration time curves did not vary with diet composition. However, with the tablets, a differential effect was observed. Following coingestion with the fiber depleted diet, the rate of systemic availability was reduced more than with the liquid preparation. A further delay was obvious, when the tablets were combined with the meal enriched in dietary fiber. Plasma glucose and gallbladder response did not vary with diet composition. Variations of gastric emptying are unlikely to account for the variability of food effects. Consequently our results illustrate that an interaction of certain meal components with a particular drug dosage form determines the rate of intragastric release of the active compound. This could be shown due to a high standardization of nutrition by using liquid formula diets. Because of the variation of drug release, paracetamol cannot be used as a marker of gastric emptying without taking into account the vehicle necessary for drug application. In contrast to previous studies, our data provide evidence that even balanced test meals retard paracetamol absorption.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetaminophen↗
Preliminary results of an induction combination regimen including fractionated anthracycline.
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Aclarubicin↗