bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of the PAF antagonists bepafant and L‐659, 989 in endotoxic and septic shock
Authors: Tang Hai Ming , Teshima Dick Y. , Lum Bert K. B. 
Published: January 2005

AbstractMany of the pathophysiological effects of endotoxin (ETX) can be mimicked by the administration of platelet activating factor (PAF), and the latter has been implicated as a possible mediator of the derangements seen in endotoxic shock. In this investigation, two new potent PAF antagonists, bepafant (WEB‐2170) and L‐659,989, were studied for their effects in experimental endotoxic and septic shock in rats. Pretreatment with the PAF antagonists, 15 min prior to the iv administration of Escherichia coli endotoxin (ETX), was found to be highly effective in decreasing the mortality caused by the lipopolysaccharide. The antagonists were less effective in reducing mortality when given as post‐treatment 15 min after ETX, and were ineffective when post‐treatment was delayed until 30 min after ETX. Administration of ETX caused manifestations of disseminated intravascular coagulation (DIC), including thrombocytopenia, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT), hypofibrinogenemia, elevation of serum fibrin(ogen) degradation products (FDP), and gastrointestinal hemorrhage. With the exception of the thrombocytopenia, the PAF antagonists reduced or abolished all of the hematological manifestations of DIC caused by ETX. Septic shock was produced by ligation and puncture of the cecum in rats. The PAF antagonists, given as two iv doses (an initial 2.0 mg/kg dose administered 1.5 or 2.5 h after cecal puncture and a second dose given 5 h later), significantly reduced the cumulative 24‐h mortality. These results provide added evidence of the importance of PAF and DIC in the pathophysiology of ETX and suggest that PAF antagonists may be useful in the clinical management of septicemia/endotoxemia. © 1993 Wiley‐Liss, Inc.
Further characterization of the 5‐hydroxytryptamine1‐like receptors mediating the increase in external carotid blood flow in the dog
Authors: Villaón Carlos M. , Terrón José A. , Hong Enrique 
Published: January 2005

AbstractIt has recently been shown that the increase in external carotid blood flow (external CBF) produced by 5‐hydroxytryptamine (5‐HT) in the anaesthetized dog, being mimicked by 5‐carboxamidotryptamine, potently blocked by methiothepin and resistant to blockade by ritanserin and MDL 72222, is mediated by 5‐HT1‐like receptors. In the present investigation, we have further characterized these 5‐HT1‐like receptors. Like 5‐HT, 1 min intracarotid (i.c.) infusions of the 5‐HT1A receptor agonist, indorenate, produced an increase in external CBF without modifying mean arterial blood pressure or heart rate. Contrasting with indorenate, 1 min i.c. infusions of the 5‐HT1A receptor agonists, 8‐hydroxy‐2(di‐N‐propylamino)tetralin (8‐OH‐DPAT), buspirone and ipsapirone, or the 5‐HT1A/5‐HT1B receptor agonist, 5‐methoxy‐3‐[1,2,3,6‐tetrahydro‐4‐pyridinyl]‐1‐H‐indol succinate (RU 24969), resulted in dose‐dependent decreases in external CBF; furthermore, both the 5‐HT1C/5‐HT2 receptor agonist, 1‐(2,5‐dimethoxy‐4‐iodophenyl‐)‐aminopropane (DOI) and the 5‐HT3 receptor agonist, 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT), were essentially inactive. Thus, only indorenate increased the external CBF in the dog; this effect of indorenate was not antagonized by intravenous (i.v.) administration of the 5‐HT1 and 5‐HT2 receptor antagonist, methiothepin, or completely abolished after sympathectomy. Unlike methiothepin, the 5‐HT1A and 5‐HT1B receptor antagonist, (±)‐pindolol, did not block indorenate‐induced external carotid vasodilatation. Together, the above results support the notion that indorenate is acting on the 5‐HT1‐like receptors involved in the increase in external CBF in the dog. These receptors, which are probably located on carotid sympathetic nerve endings, do not seem to correspond to either the 5‐HT1A, 5‐HT1B, or 5‐HT1C binding sites. © 1993 Wiley‐Liss, Inc.
Alcohol‐induced reinforcement: Dopamine and 5‐HT3 receptor interactions in animals and humans
Authors: Johnson Bankole A. , Cowen Philip J. 
Published: January 2005

AbstractAlcohol abuse is a major health problem worldwide. Whatever the treatment goal, be it abstinence or “controlled” drinking, the outcome from both pharmacological and nonbiological treatments remains disappointing. Behavioural experiments in animals have suggested that the reinforcing properties of alcohol, like other drugs of abuse, are critical to drug‐seeking behaviour. Dopaminergic fibres running from the ventral tegmental area to the nucleus accumbens may play a central role in mediating the reinforcing effects of drugs of abuse including alcohol. Thus, alcohol increases extracellular levels of dopamine in the nucleus accumbens and dopamine receptor antagonists decrease alcohol consumption in a number of behavioural paradigms. A recently described subtype of serotonin (5‐HT) receptor, the 5‐HT3 receptor, appears to modulate the effects of alcohol on dopamine release in the nucleus accumbens. In rodents, 5‐HT3 receptor antagonists inhibit alcohol‐induced dopamine release in the nucleus accumbens. Further, in behavioural studies, 5‐HT3 receptor blockade decreases alcohol consumption in a free‐choice paradigm. In humans, reinforcement is difficult to measure directly. Nevertheless, the pleasurable subjective effects of alcohol are important behavioural correlates of the reinforcement process. Our preliminary findings in humans suggest that the 5‐HT3 receptor antagonist, ondansetron, can attenuate some of the pleasurable effects of a small dose of alcohol including the subjective desire to drink. We speculate, although we have no direct evidence for this at present, that in humans this effect could also be due to a blockade of alcohol‐induced dopamine release in the nucleus accumbens as has been demonstrated in animals. Further studies with clinical populations are required to assess the effects of 5‐HT3 receptor antagonists on drinking behaviour and to explore their potential in the management of alcohol abuse. © 1993 wiley‐Liss, Inc.
Intracerebroventricular nicotine and mecamylamine alter radial‐arm maze performance in rats
Authors: Brucato Frederic H. , Levin Edward D. , Rose Jed E. , Swartzwelder H. Scott 
Published: January 2005

AbstractIn rats, the effects of an intracerebroventricular (ICV) nicotinic agonist nicotine (NIC), the nicotinic antagonist mecamylamine (MEC), and combinations of NIC + MEC were assessed in a radial‐arm maze (RAM). In experiment 1, exploratory behavior was assessed in untrained rats (N = 13). The rats received 4 μg, 8.65 nmol NIC (NIC 4), 200 μg, 0.98 μmol MEC (MEC), and saline (SAL) ICV infusions. NIC 4 caused a significant increase in choice distribution compared to SAL (P < 0.025). In experiment 2, rats (N = 10) were trained to perform a working memory task for food reinforcement in the RAM. ICV doses of SAL, NIC 4, NIC 8, MEC, MECNIC 4, and MECNIC 8 were administered after completion of the training period. MEC caused a significant deficit in choice accuracy when compared to SAL (P < 0.025). This deficit was reversed when NIC 8 was coadministered with MEC (P < 0.05). There were no significant effects on choice latency for either study. The effects of ICV NIC and MEC on RAM performance are generally similar to their systemic effects in that NIC improves and MEC impairs choice accuracy. The reversal of the MEC‐induced choice deficit by ICV NIC administration has not been reported with systemic administration. ICV MEC induces a choice accuracy deficit without increasing choice latency. This has not been seen with systemic MEC administration. The current result implies that the MEC‐induced choice accuracy deficit did not result from MEC‐induced sedation. The data indicate that previously reported changes in choice accuracy from peripherally administered NIC and MEC result from their central effects. © 1994 Wiley‐Liss, Inc.
Nicotine interactions with dopamine agonists: Effects on working memory function
Authors: Levin Edward D. , Eisner Batya 
Published: January 2005

AbstractNicotine has been found to improve memory performance in a variety of tests including the radial‐arm maze. Nicotine may have effects mediated by promoting the release of dopamine. The present study was conducted to determine the interactions of nicotine with D1 and D2 agonists. Rats were acutely administered nicotine, the D1 agonist SKF 38393, and D2/D3 agonist quinpirole, and nicotine together with each of these agonists. Nicotine significantly improved choice accuracy in the radial‐arm maze. The D1 agonist SKF 38393 significantly impaired choice accuracy. Nicotine was effective in reversing this effect. The D2/D3 agonist quinpirole showed a trend toward potentiating the improvement in choice accuracy caused by 0.2 mg/kg (0.43 μmol/kg) of nicotine. These data show that, as with the nicotinic antagonist mecamylamine, there are significant interactions of dopamine systems with nicotine effects. © 1994 Wiley‐Liss, Inc.
Effects of anabaseine‐related analogs on rat brain nicotinic receptor binding and on avoidance behaviors
Authors: Meyer Edwin M. , de Fiebre Christopher M. , Hunter Bruce E. , Simpkins Christopher E. , Frauworth Neal , de Fiebre Nancy Ellen C. 
Published: January 2005

AbstractSeveral novel anabaseine‐derived compounds were investigated with respect to their ability to displace high affinity [3H]cytisine binding in rat brain membranes, as well as their ability to improve passive and active avoidance behaviors in nucleus basalis‐lesioned rats. The relative potencies for displacement of 1 nM [3H]cytisine binding IC50 in parentheses: anabaseine (70 nM) > DMAB (140 nM) = DMXB (150 nM) > anabasine (270 nM) > DMAC (420 nM). Passive avoidance behavior in bilaterally nucleus basalis‐lesioned rats was improved by each of these drugs to an extent comparable to that observed with (–)‐nicotine. The relative potencies of these compounds for improving this behavior exhibited a pattern very similar to their affinities for displacing [3H]cytisine binding (nicotine > anabaseine > DMXB > DMAB = DMAC > anabasine). Acquisition of active avoidance behavior was slower in unilaterally and bilaterally nucleus basalis‐lesioned rats than unlesioned controls; (−)‐nicotine improved acquisition behavior only in the former group. At doses that improved passive avoidance behavior, DMXB also improved acquisition of active avoidance behavior in unilaterally lesioned rats, while DMAB and DMAC did not. (−)Nicotine and DMXB had no effect on escape behavior in the active avoidance task at doses that improved retention of avoidance behavior itself. These results suggest that anabaseine and several of its analogs bind to brain α4β2 nicotinic receptors and mimic non‐spatial, memory‐related behaviors in a nicotine‐like manner. © 1994 Wiley‐Liss, Inc.
Alkyl‐modified side chain variants of anatoxin‐a: A series of potent nicotinic agonists
Authors: Thomas Philip , Brough Paul A. , Gallagher Timothy , Wonnacott Susan 
Published: January 2005

AbstractThe potent nicotinic agonist anatoxin‐a has a semi‐rigid structure amenable to chemical synthesis and modification, making it an attractive candidate for exploring the structure‐activity relationships of ligands at nicotinic acetylcholine receptors. Racemic anatoxin‐a and a series of three analogues with one or more methine or methylene units added to the acetyl sidechain were synthesised and designated homoanatoxin, propylanatoxin, and isopropylanatoxin. In competition binding assays on two neuronal nicotinic receptors in rat brain membranes, labelled with [3H]nicotine and [125I]αbungarotoxin, the analogues retained or exceeded the potency of the parent structure. Ki values for anatoxin‐a, homoanatoxin, propylanatoxin, and isopropylanatoxin were 19, 5.5, 24 and 7.5 nM, respectively, at the [3H]nicotine site and 900, 340, 40, and 120 nM, respectively, at the [125I]αbungarotoxin site. Thus propylanatoxin appears to show a preference for the latter receptor site. Functional potencies of homoanatoxin and isopropylanatoxin were determined at neuronal α7 nicotinic receptors reconstituted in Xenopus oocytes, by two electrode voltage clamp recording. EC50 values of 0.72 μM and 0.66 μM were determined, similar to that previously published for (+)anatoxin‐a. Molecular modelling of anatoxin‐a and its alkyl‐modified analogues shows them to have very similar energy profiles, consistent with their similar potencies. In the preferred (low energy) conformation, the enone moiety adopts an s‐trans arrangement, although this configuration does not fit the classical pharmacophore model for nicotinic ligands. This series of alkyl‐modified analogues based on anatoxin‐a provides some novel potent nicotinic agonists and with propylanatoxin, receptor subtype selectivity may be emerging. This rational approach to ligand design also enables us to explore further the requirements for ligand recognition through the application of computational chemistry. © 1994 Wiley‐Liss, Inc.
Effects of repeated treatments with an extract of Ginkgo biloba (EGb 761) and bilobalide on glucose uptake and glycogen synthesis in rat erythrocytes: An ex vivo study
Authors: Rapin Jean R. , Provost Philippe , DeFeudis Francis V. , Drieu Katy 
Published: January 2005

AbstractThe metabolic action of an extract of Ginkgo biloba (EGb 761) has been examined in an ex vivo study of rat erythrocytes. Oral administration of EGb 761 (100 mg/kg/day) for 5 days to Wistar rats caused an increase in the in vitro uptake of glucose by erythrocytes, especially in high‐glucose (13.32 mM) medium, an effect that was associated with an increase in intracellular energy metabolism and reflected as a significant reduction in free glucose concentration. In contrast, the lactate concentration of the erythrocytes and lactate release to the bathing medium were not modified. Conversion of glucose into glycogen was significantly increased in the erythrocytes of EGb 761‐treated animals. Taken together, these findings indicate that in vivo administration of EGb 761 exerts an action favoring the transformation of glucose into glycogen, its storage form. Oral administration of the EGb 761 constituent bilobalide (4 or 8 mg/kg/day) for 5 days caused similar changes in the uptake of glucose and its conversion into glycogen. However, in contrast to the total extract, bilobalide treatment did not increase the energy‐yielding consumption of glucose. © 1994 Wiley‐Liss, Inc.
Effects of linopirdine (DuP 996) and X9121 on age‐related memory impairments and on the cholinergic system
Authors: Baxter Mark G. , Rohrbach Kenneth W. , Tam S. William , Zaczek Robert , Frick Karyn M. , Golski Stephanie , Wan Rui‐Qian , Olton David S. 
Published: January 2005

AbstractLinopirdine (DuP 996) has been shown to enhance K+‐stimulated release of acetylcholine from cerebral cortex, striatum, and hippocampus of rats in vitro. X9121 is a structurally different compound identified as having similar release properties. The present experiments compare the effects of linopirdine and X9121 on cognitive deficits in aged rats, and on the pharmacological properties in young rats. For cognitive testing, aged male Fischer‐344 rats (24 months old, n = 116) received either vehicle or one of 5 doses of linopirdine or X9121 prior to behavioral testing; young rats (4 months old, n = 13) were controls and received vehicle prior to testing. Place discrimination and repeated acquisition were tested in the water maze, and a variety of sensorimotor tasks were given. Aging impaired performance in all tasks. Linopirdine (0.25, 2.5, and 8.5 mg/kg po [0.64, 7.4, and 25 μmol/kg]) and X9121 (0.85 and 8.5 mg/kg po [2.1 and 24 μmol/kg]) moderately improved place discrimination. None of the doses tested improved repeated acquisition or sensorimotor function. No behavioral indications of toxicity were observed. Acetylcholine release, acetylcholinesterase (AChE) inhibition, and nicotinic and muscarinic binding were measured in vitro in cerebral cortical tissue from young male Wistar rats (2 months old). Both linopirdine and X9121 enhanced K+‐stimulated release from cerebral cortex; X9121 produced greater release with a broader range of active concentrations. Linopirdine weakly inhibited AChE (1,000 × weaker than physostigmine) and X9121 did not. Neither drug bound significantly to muscarinic or nicotinic cholinergic receptors. These results support the hypothesis that linopirdine and X9121 have some cognition enhancing properties which may be due to enhancement of stimulation induced acetylcholine release. These results suggest that linopirdine and X9121 may be useful in treating disorders involving cognitive impairment. © 1994 Wiley‐Liss, Inc.
Mechanisms for the increase in electrically stimulated [3H]norepinephrine release from rat cortical slices by N‐(n‐propyl)‐N‐(4‐pyridinyl)‐1H‐indol‐1‐amine
Authors: Smith Craig P. , Petko Wayne W. , Kongsamut Sathapana , Roehr Joachim E. , Effland Richard C. , Klein Joseph T. , Huger Francis P. 
Published: January 2005

AbstractN‐(n‐propyl)‐N‐(4‐pyridinyl)‐1H‐indol‐1‐amine (HP 749) is currently in clinical trials for the treatment of Alzheimer's disease (AD). While HP 749 has many pharmacological properties, the biochemical basis for its efficacy in animal models for AD remains unexplained. To this end, we have investigated some biochemical properties of HP 749 as they relate to its effect on electrically stimulated [3H]norepinephrine (NE) release. HP 749 was found to inhibit both [3H]NE uptake and [3H]yohimbine binding to cortical μ2‐adrenergic receptors. Consistent with this profile, HP 749 (1 and 10 μM) enhanced electrically stimulated release of [3H]NE from rat cortical slices. Both clonidine (1 μM) and nomifensine (10 μM) inhibited the effect of HP 749 (1 μM). The enhancement of [3H]NE release produced by the μ2 adrenergic antagonist, idazoxan (0.1 μM), was completely reversed by the μ2 agonist, clonidine (1 μM), but was not affected by the NE uptake inhibitor, nomifensine (10 μM). These results indicate that the HP 749 enhancement of electrically stimulated [3H]NE release is due, at least in part, to a combination of presynaptic μ2‐adrenergic receptor antagonism and NE reuptake blockade. These mechanisms may contribute to some of the adrenergic effects of HP 749.
Characterization of arbutamine: A novel catecholamine stress agent for diagnosis of coronary artery disease
Authors: Young Mark , Pan Wei , Wiesner Jim , Bullough David , Browne Gene , Balow Guity , Potter Scott , Metzner Kurt , Mullane Kevin 
Published: January 2005

AbstractArbutamine, 1,2‐Benzenediol,4‐[1‐hydroxy‐2‐[[4‐(4‐hydroxyphenyl)butyl[amino]ethyl]rsqb;rsqb; hydrochloride, (R), is a new catecholamine being developed as a pharmacologic stress agent for the diagnosis of coronary artery disease and myocardial ischemia. The pharmacology of arbutamine was studied in vitro using receptor binding assays and functional bioassays of α‐ and β‐adrenoceptor activity, and in vivo using the hemodynamic responses to intravenous infusion in anesthetized and conscious dogs. In isolated membranes, receptor binding studies demonstrated Ki values of 196 ± 12 nM and 147 ± 11 nM for β1‐ and β2‐adrenoceptors, and 265 ± 4 nM and 867 ± 40 nM for α1‐ and β2‐adrenoceptors, suggesting that arbutamine is a mixed β1+2‐adrenoceptor agonist with significant affinity for β1‐adrenoceptors. This was supported by in vitro bioassay data, where arbutamine increased spontaneous atrial rate (β1‐activity, ED50 = 16 ± 6 nM), relaxed isolated tracheal rings (β2‐activity, ED50 = 13 ± 5 nM), and contracted aortic rings (α‐activity, ED50 = 430 ± 80 nM), indicating 25–30‐fold selectivity for β‐adrenoceptor activation. In conscious or anethetized dogs, arbutamine elicited dose‐dependent increases in heart rate and LV dP/dt with little fall in mean arterial pressure. The data demonstrate that arbutamine exhibits similar degrees of intropic and chronotropic activity, while eliciting less peripheral vasodialation than isoproteronal and less inotropic activity than dobutamine. Moreover, there was rapid termination of the tachycardia, as heart rate resolved to 50% of the maximal effect within 7.2 ± 1.1 min following arbutamine, compared to 5.5 ± 1.0 min following isoproterenol and 5.9 ± 1.4 min following dobutamine. This hemodynamic profile and rapid pharmacodynamic offset makes arbutamine ideally suited for use as a pharmacologic stress agent.
Species differences in ligand affinity at central A3‐adenosine receptors
Authors: Ji Xiao‐Duo , Lubitz Dag Von , Olah Mark E. , Stiles Gary L. , Jacobson Kenneth A. 
Published: January 2005

AbstractBinding affinities of purine derivatives at A3 adenosine receptors in different species were compared. Binding was carried out using the novel high affinity agonist ligand [125I]AB‐MECA (3‐iodo‐4‐aminobenzyladenosine‐5′‐N‐methyluronamide) in the presence of 1.0 μM XAC (8‐[4‐[[[[(2‐aminoethyl)amino]carbonyl]methyl]oxy]phenyl]‐1,3‐dipropylxanthin), an A1‐ and A2a‐adenosine antagonist. XAC was added to eliminate binding to non‐A3 receptors. In rat brain membranes [125I]AB‐MECA exhibited saturable, specific binding with a Kd of 2.28 nM and a Bmax of 43 fmol/mg protein. The affinity of [125I]AB‐MECA at the gerbil and rabbit brain A3‐receptors was similar to the rat, suggesting that the affinity of this agonist is not highly species dependent. The affinity of various xanthine derivatives was measured in [125I]AB‐MECA competition binding assays. Gerbil and rabbit brain A3‐receptors were similar in the affinity of antagonists whose potency order in both species was: BWA522 ≥ CPX > XCC, XAC, SPX, BWA1433 > theophylline. The affinities of 8‐arylxanthines at the rat, rabbit, and gerbil brain A3 receptors were considerably less than the previously reported affinities at cloned sheep and human A3 receptors. Species differences in agonist affinity were assessed by comparing Ki values at cloned rat brain A3 receptors expressed in CHO cells with cloned sheep and human A3 receptors. Human and rat brain A3 receptors were highly similar in the relative affinities of agonists, and sheep brain A3 receptors were unlike either human or rat A3 receptors in agonist affinity. © 1994 Wiley‐Liss, Inc.
Marine biodiversity as a source of chemical diversity
Authors: De Vries David J. , Hall Michael R. 
Published: January 2005

AbstractTotal global biodiversity is estimated at between 3 and 500 × 106 species of prokaryote and eukaryote organisms spread across 70 or more phyla. The marine macrofauna alone are estimated between 0.5 and 30 × 106 species and represents a broader range of taxonomic diversity than that found in the terrestrial environment, which has been the traditional source of natural products. With a typical eukaryote possessing 50,000 genes, the global marine macrofauna are the source of 2.5 × 1010 to 1.5 × 1012 primary products and an associated extensive range of secondary products. However, only a few thousand novel compounds from marine organisms have been described. These compounds have proven unique in chemical and pharmacological terms but, as yet, no therapeutic agents have resulted. Given a broader drug discovery strategy, and facilitated by technological advances, it is predicted that the characterisation of marine chemical diversity will be accelerated. Strategies for drug discovery from the virtually untapped chemical diversity of marine organisms are discussed. © 1994 Wiley‐Less, Inc.