bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blockade of peripheral α2‐adrenoceptors by L‐659,066 enhances glucose tolerance and insulin release in mice
Authors: Goldman M. E. , Pettibone D. J. , Reagan J. E. , Clineschmidt B. V. , Baldwin J. J. , Huff J. R. 
Published: January 2005

AbstractThe purpose of this study was to compare the effects of a peripherally selective (L‐659,066) vs. a centrally and peripherally active (L‐657,743; MK‐912) α2‐adrenergic antagonist on murine plasma glucose and insulin levels following fasting or administration of hyperglycemic agents (α2‐adrenergic agonists, glucose). The intravenous administration of L‐657,743 or L‐659,066 alone did not cause major alterations in plasma glucose or insulin levels. Pretreatment of mice with either of these agents, however, at selective α2‐adrenoceptor blocking doses (0.3–3 mg/kg) prevented the elevations of plasma glucose levels induced by the α2‐adrenoceptor agonists clonidine or 3,4‐dihydroxyphenylimino‐2‐imidazoline (DPl). Prazosin, an α1‐adrenergic antagonist, did not alter clonidine‐induced elevations of plasma glucose levels. Pretreatment of fasted mice with L‐657,743 or L‐659,066 (1 mg/kg) 5 min before receiving intravenous glucose resulted in higher plasma insulin levels and improved glucose tolerance compared to saline‐pretreated animals. Moreover, both α2‐adrenergic antagonists enhanced the acute insulin response to glucose. These findings indicate that, under conditions of hyperglycemia, insulin release is enhanced by the blockade of peripheral α2‐adrenoceptors α2‐Adrenoceptor antagonists, such as L‐657,743 or the peripherally selective agent L‐659,066, may prove effective in treating noninsulin‐dependent diabetes mellitus.
Pharmacology of receptors for excitatory amino acids
Authors: McLennan H. 
Published: January 2005

AbstractThe pharmacological evidence for the existence of three distinct neuronal receptors for the excitatory amino acids is reviewed. Although most or all central neurones respond to the eponymous agonists N‐methyl‐D‐aspartate (NMDA), quisqualate, and kainate, and the blockade of their effects is reasonably consistent throughout the neuraxis, subtle regional variations are detected when other agonists are tested. Thus, the tryptophan metabolite quinolinate is completely NMDA‐mimetic in the hippocampus and neocortex but is almost inactive in the spinal cord. L‐Homocysteate resembles NMDA in the cord and striatum but is quisqualate‐like in the hippocampus. There is good evidence for the involvement of amino acids in the mediation of excitatory synaptic events; however, the regional differences in the actions of the endogenous agonists make positive identification of the chemical species active at a particular synaptic site, at best, rather tentative.
Pharmacological regulation of the phencyclidine‐binding site associated with the N‐methyl‐D‐Aspartate receptor‐operated ion channel
Authors: Johnson Kenneth M. , Snell Lawrence D. , Sacaan Aida I. , Jones Susan M. 
Published: January 2005

AbstractThe ion channel operated by N‐methyl‐D‐aspartate (NMDA) receptor agonists is modified by several positive and negative effectors. A variety of chemical structures are known to antagonize the effects of NMDA agonists by preferentially binding with high affinity to the open state of the ion channel. Binding of two of these noncompetitive antagonists has been study extensively in recent months as a probe of NMDA receptor function. It has been found that NMDA agonists and antagonists increase and decrease, respectively, the binding of 3H‐TCP or 3H‐MK‐801 by altering the affinity of the putative phencyclidine (PCP) receptor localized within the ion channel. This affinity change is presumed to be correlated with the conformational change associated with channel opening. This model is also discussed in relationship to one in which binding is increased under nonequilibrium conditions because of a simple increased accessibility to the channel binding site. The modulatory effects of glycine, other amino acids, certain polyamines, and divalent cations on 3H‐TCP and/or 3H‐MK‐801 binding are discussed in relation to their effects on NMDA function in more intact, physiological preparations. It is concluded that the complexity of NMDA receptor regulation provides many possibilities for pharmacological intervention, and that the use of noncompetitive antagonists to probe NMDA receptor function could play a key role in drug development.
N‐methyl‐D‐aspartate receptors, synaptic plasticity, and Alzheimer's disease
Authors: Cotman C. W. , Monaghan D. T. , Geddes J. W. 
Published: January 2005

AbstractThe NMDA (N‐methyl‐D‐aspartate) excitatory amino acid receptor mediates a potent excitatory response in many regions of the CNS and plays a key role in excitotoxicity and synaptic plasticity. Results from radioligand‐binding studies indicate that NMDA agonists and antagonists preferentially bind to differing populations of NMDA receptors. The distribution of NMDA receptors as labeled by the agonist L‐[3H]glutamate differs from that obtained with the radiolabeled antagonist [3H]3‐((±2‐carboxypiperazine‐4‐yl)‐propyl‐1‐phosphonic acid ([3H]CPP)). In addition, NMDA agonists and antagonists display complementary regional variations in their ability to displace L‐[3H]glutamate binding. At least some of the differences between agonist and antagonist‐binding properties can be accounted for by suggesting that glycine converts the NMDA receptor from an antagonist‐preferring state into an agonist‐preferring state. Since NMDA and other excitatory amino acid receptor functions are necessary for synaptic function, certain forms of synaptic plasticity, and learning, we have evaluated their status in Alzheimer's disease (AD). Using radioligand‐binding techniques, we find that NMDA receptors are generally preserved in the course of AD pathology in the human hippocampus in spite of partial cell loss. Kainate receptors, on the other hand, display a radistribution within the hippocampus. This redistribution corresponds to an apparent synaptic reorganization owing to the loss of input from the entorhinal cortex. The response of both the NMDA and kainate receptor systems may be adaptive plastic responses that attempt to maintain hippocampal function that is compromised by AD. However, these mechanisms may also render the hippocampus more vulnerable to damage following excessive neuronal activation.
Neurochemical effects of pyritinol and their relevance for the treatment of brain function deficits in old age
Authors: Seyfried Christoph A. 
Published: January 2005

AbstractThis article reviews the neurochemical results obtained in rats treated with pyritinol, a drug used clinically in the treatment of brain function deficits in old age. Pyritinol can be characterized as an indirectly acting cholinergic drug in the CNS, although its precise mechanism and its primary site of action remains to be elucidated. Direct interactions with muscarinic receptors and influences on catecholaminergic or indolaminergic systems are unlikely. Other actions of pyritinol, i.e., increases in cerebral glucose utilization in rats and cerebral blood flow in man might be secondary to its activating actions on cholinergic neurons. Since pyritinol is reported to significantly improve memory and cognitive functions in patients, the results are considered as evidence that neurochemical measurements of cholinergic functions in animals provide useful and relevant information for these indications although, similar to other cholinergic drugs, the magnitude of its therapeutic effect remains limited.
Discriminative stimulus properties of the non‐sedative anxiolytic benzodiazepine receptor ligand RU 32698
Authors: Gardner Colin R. 
Published: January 2005

AbstractGardner, C.R.: Discriminative stimulus properties of the non‐sedative anxiolytic benzodi‐ azepine receptor ligand RU 32698. Drug Dev. Res. 18:ll–18, 1989.Rats were trained to discriminate RU 32698 (10 mg/kg p.o.) from vehicle using a fixed‐ratio 20 drug discrimination procedure. The characteristics of this cue were compared with that evoked by training rats to discriminate a low dose of chlordiazepoxide (CDZP, 5 mg/kg p.o.) from vehicle. Both cues were antagonized by the benzodiazepine inverse agonist FG 7142, and by the weak inverse agonist CGS 8216. Each training drug substituted for the cue induced by the other. Several benzodiazepine receptor ligands substituted for both cues at similar doses (zopiclone, zolpidem, ZK 91296, RU 43028), although there was a tendency for only partial generalization with ligands with only weak agonist activity (RU 39419, CGS 9896, RU 32514). CL 218872 partially substituted for the RU 32698 cue. Tracazolate partially substituted for both cues but buspirone showed little or no substitution for either cue. Thus, RU 32698 induces a cue via an action at benzodiazepine receptors. The RU 32698 cue is sensitive to low levels of agonism at benzodiazepine receptors and should be useful in the discovery of non‐sedative anxiolytic agents.
Discriminative stimulus properties of haloperidol
Authors: McElroy John F. , Stimmel Jay J. , O'Donnell James M. 
Published: January 2005

AbstractRats (N = 9) were trained to discriminate the antipsychotic drug haloperidol (0.05 mg/kg i.p.) from drug vehicle (0.25% acetic acid in 0.9% saline) using a water‐reinforced, fixed‐ratio 10 response operant procedure. Acquisition of discrimination required a mean of 45 trainingsessions (median value of 38 sessions). The discriminative stimulus was dose‐dependent with an ED50 value of 0.008 mg/kg. The total number of responses per 10‐min test session was significantly reduced at all doses of haloperidol that produced haloperidol lever selection. The antipsychotic drug chlorpromazine substituted for the haloperidol discriminative stimulus (ED50 = 0.38 mg/kg). The indirect dopaminergic agonists amphetamine (1.0 mg/kg) and cocaine (10 mg/kg) fully blocked the haloperidol discriminative stimulus. Taken together, these initial results suggest that the discriminative stimulus produced by haloperidol is mediated, at least in part, by an interaction with dopamine receptors.
Behavioral effects of non‐opioid antitussive anticonvulsants
Authors: Witkin Jeffrey M. , Tortella Frank C. 
Published: January 2005

AbstractMany of the currently used anticonvulsants possess a host of undesirable pharmacological properties. Several non‐opioid antitussives bind to high‐affinity [3H]dextromethorphan sites in brain and have novel anticonvulsants activity. Because these compounds may be useful in the treatment of some epilepsies, either alone or as adjuncts. Behavioral effects of these as well as clinically used anticonvulsant drugs were studied under a standard preclinical test of sedative‐hypnotic/anxiolytic activity which generally yieds positive results with standard anticonvulsants. Lever‐press responses of male Sprague‐Dawley rats were maintained under a multiple schedule of food presentation in which responses in one component were suppressed by brief electric shock (punishment) whereas responses in an alternate component were not punished. The drug doses tested were the ED50 and 2 X ED50 for anticonvulsant activity against maximal electroshock‐induced convulsions. The non‐opioid antitussive anticonvulsants, carbetapentane, caramiphen, dextromethorphan, as well as diphenylhydantoin, did not increase punished responding, Nonpunished responding was unaffected by ED50 does levels of these compounds. In contrast, diazepam increased punished responding to 800% of control levels and increased nonpunished responding at 1 mg/kg. Responding was typically decreased by the highest doses of all drugs studied except diphenylhydantion. Thus, the non‐opioid antitussive anticonvulsants were devoid of significant behavioral effects at the ED50 does and did not possess the anxiolytic activity of benzodiazepine or barbiturate anticonvulsants.
Antihypertensive activity and effects on blood flow of CL 115,999 (5‐lodo‐5,6‐dihydro‐15‐deoxy‐16‐hydroxy‐16‐vinyl‐prostacyclin methyl ester), a new potent orally and transdermally long‐acting prostacyclin analog
Authors: Chan Peter S. , Cervoni Peter , Ronsberg Margaret A. , Scully Patricia A. , Quirk Gerald J. , McLendon Trina K. 
Published: January 2005

AbstractCL 115,999 was found to be a very potent orally and transdermally active antihypertensive prostacyclin (PGl2) analog with a long duration of action. In conscious spontaneously hypertensive rats (SHR), CL 115,999 lowered mean arterial blood pressure (MABP) 16, 37, 47, and 54 mm Hg at 0.5, 1, 3, and 10 mg/kg orally, respectively. It lowered MABP 19, 28, and 50 mm Hg at 0.1, 0.3, and 1 mg/kg transdermally with durations of action of 2, >6, and >24 hr, respectively. In aorta‐coarcted, renin‐dependent, malignant hypertensive rats, and in deoxycorticosterone aceate (DOCA)‐salt‐induced (low renin) hypertensive rats, CL 115,999 at 3 mg/kg orally lowered MABP 54 and 66 mm Hg lasting longer than 6 and 5 hr, respectively. In conscious two‐kidney, one‐clip, Goldblatt hypertensive dogs, CL 115,999 decreased MABP 33 and 66 mm Hg at 1 (p.o.), and 0.5 (i.v.) mg/kg, respectively. CL 115,999 increased blood flows to renal, coronary, carotid, femoral, and superior mesenteric arterial beds in anesthetized dog when given intraarterially into the bed under study. These findings suggest that CL 115,999 produces potent vasodilation leading to lowering of blood pressure and may act like endogenous prostacyclin in the vasculatures and may be useful for the treatment of hypertension and other cardiovascular diseases in humans.
Memory impairment induced by CCK‐8 antagonists in passive avoidance response of the rat
Authors: Takashima Akira , Ltoh Shinji 
Published: January 2005

AbstractThe effect of novel potent CCK‐8 antagonists on a one‐trial passive avoidance response was investigated in the rat. Intracerebroventricular administration of L‐364,718 and CR 1409 in doses of 10 ng per rat or more and proglumide in doses of 100 ng per rat or more completely attenuated the passive avoidance response, when examined 24 hr after the injection. The effective doses of these antagonists did not cause any motility change, as tested by an open‐field situation at the same period of time after the central administration. The present findings, together with our previous results on an active avoidance response, suggests that endogenous CCK‐8 may be involved in memory processes.
In vivo hemodynamic effects of endothelium‐derived constricting factor in the dog
Authors: Hom Gary J. , Highsmith Robert F. , Pang David C. 
Published: January 2005

AbstractPrimary cultures of bovine thoracic aortic endothelial cells release an endothelium‐derived constricting factor (EDCF), which contracts isolated porcine, bovine, and canine coronary arteries and increases coronary perfusion pressure in isolated rabbit heart. We have tested the effect of theis EDCF on coronary and aortic flows, left ventricular dP/dt, and left ventricular end diastolic pressure, and mean arterial pressure in opern chest anesthetized dogs. Intracoronary administration of conditioned medium containing EDCF caused a reduction in coronary flow. The constrictor response was slow in onset, peaked 50 min after bolus injection, and was sustained during the rest of the observation period. Aortic flow, heart rate, left ventricular dP/dt, left ventricular end diastolic pressure, and mean arterial pressure were not significantly altered. Intracoronary administration of denatured conditioned medium or nonconditioned medium did not elicit any cardiovascular changes. The EDCF‐induced reduction in coronary flow was inhibited by intracoronary administration of nitroglycerin. These findings suggest that conditioned medium from bovine aortic endothelial cells produces coronary vasoconstriction in the intact, anesthetized dog.
Radioelectroencephalographic characterization of tenilsetam (CAS 997), a putative nootropic compound, in the freely behaving rat
Authors: Dimpfel Wilfried , Spüler Manfred , Schindler Ursula 
Published: January 2005

AbstractRecording, telemetric trandmission, and spectral analysis of field potentials from frontal cortex, hippocampus, striatum, and reticular formation of the rat brain were used to monitor the effect of tenilsetam (CAS 997) and piracetam on the central nervous in delta and alpha2 power in all brai areas. Dose‐dependent decreases in alpha1 power were seen in the frontal cortex, striatum, and reticular formation, whereas the hippocampal alpha1 activity increased (100 mg/kg) or remained unaffected. These effects were dose‐dependent and lasted for at least 90 min. In the presence of piracetam, changes in brain electrical activity were dominated by an overall decrease in alpha1 activity and by less pronounced effects on beta1 activity. The spectral pattern profile induced by tenilsetam was compared to the “fingerprints” of a great number of different drugs from our data base. Some similarities to the action of fluvoxamine and SK&F 38393 point to changes in serotonergic and dopaminergic transmission. The present data show the functional outcome of interactions with different aspects of neurotranmission and suggest that the “nootropic” drug tenilsetam enhances vigilance by shifting the balance of neurotransmission to a status resembling low serotonergic and, at the same time, high dopaminergic activity. These drugs obviously not only improve brain function under pathological conditions but can also affects electrical activity of the intact brain.
Reversal of chlordiazepoxide‐induced impairment in successive discrimination performance by RO 15‐1788
Authors: Cole Sherwood O. 
Published: January 2005

AbstractThe effects of chiordiazepoxide (CDP) alone and in combination with Ro 15‐1788 on the performance of a previously learned go‐no go successive discrimination were studied in male Sprague‐Dawley rats. CDP 10 mg/kg impaired discrimination performance in six sucessive sessions, with animals showing recovery in two post‐drug sessions. The impairment in disrcimination performance was due to an increase in responding during no go (waiting) periods of the task. The benzodizepine (BDZ) receptor antagonist Ro 15‐778 (5 and 10 mg/kg) reversed the impairment in discrimination performance in sessions 2‐6 (but not 1) when co‐administered with CDP. While the effectiveness of Ro 15‐1788 was not dose‐dependent, the reversal in discrimination impairment was due to a reduction in responding during no go periods of the task. These findings suggest that the impairment in discrimination performance produced by CDP is mediated by central BDZ receptor sites. When administered alone, Ro 15‐1788 10 mg/kg (but not 5mg/kg) produced a mild BDZ‐like impairment in discrimination performance and increase in a no go period responding. These findings suggest that Ro 15‐1788 is not a neutral antagonist but has some intrinsic action of its own.
Tissue plasminogen activator synthesis by trabecular cells and its implications for fibrinolytic therapy of the eye
Authors: Tripathi Ramesh C. , Park James K. , Tripathi Brenda J. , Ts'ao Chunghsin 
Published: January 2005

AbstractTissue plasminogen activator (t‐PA) has proved to be an effective drug for intravascular fibrinolysis. We have found that the trabecular meshwork system, which regulates the outflow of the aqueous humor in the eye, normally contains a significant amount of t‐PA (0.2 IU/mg protein). When we experimentally introduced 0.2 ml autologous plasma into the anterior chamber of dog eyes, the amount of t‐PA in the trabecular meshwork increased 2.5‐fold within 90 minutes. In cultured porcine trabecular meshwork cells, exposure to 10 U/ml thrombin for 24 hours caused a maximum rise in the concentration (0.82 ng/ml) and in the activity (0.63 IU/ml) of t‐PA. Despite this synthesis of t‐PA by the trabecular meshwork system and other structures of the eye, as well as its normal level in the aqueous humor, a delay in the dissolution of fibrin in the anterior chamber occurs in various clinical conditions, and this compromises the structural and functional integrity of the ocular tissues. Because the locally produced proteases are apparently insufficent to resolve rapidly the fibrin, and based on our present and previous investigations in the eye, we advocate the exogenous administration of t‐PA when rapid fibrinolysis must be behieved. We propose, with caution, a guideline for the therapeutic use of t‐PA in the eye.
Modification of morphine withdrawal in rats by alterations of the endogenous opioid system: Effects of actinonin and GEMSA
Authors: Dzoljic Eleonora D. , Dzoljic Mihailo R. 
Published: January 2005

AbstractThe results show that actinonin (50‐200 m̈g, i.c.v.), an inhibitor of the three enzymes involved in the biodergradation of enkephalins, attenuates, while guanidinoethylmercaptosuccinic acid (GEMSA 3‐12 m̈g, i.c.v.), an inhibitor of enkephalin‐synthesising carboxypeptidase, aggravates some naloxone‐precipitated withdrawal signs in chronic morphine‐dependent rats. The results suggest that alterations in the functional activity of the endogenous opioid system by drugs that affect enkephalin metabolism might have a significant effect on the severity of opiate withdrawal.
Novel approaches to study myocardial hypertrophy towards development of anti‐hypertensive drugs: Expression of myosin light chain genes during cardiac hypertrophy
Authors: Kumar C. Chandra 
Published: January 2005

AbstractMyocardial hypertrophy as an adaptive response to various physiological and pathological conditions is characterized by major alterations in the cellular restructuring of the heart as well as by many biochemical and genetic alterations. Hence, the development of hypertrophy provides a unique opportunity to study the various mechanisms underlying the functions of the normal and diseased heart, as well as to understand the molecular mechanisms that operate to regulate cardiac specific gene expression. Both the spontaneously hypertensive rat strain (SHR) and the myocardial cell culture system developed by Paul Simpson have been used as model systems to study cardiac specific gene expression. We have isolated and characterized in detail the rat ventricular specific myosin light chain (MLC)‐1 and MLC‐2 cDNA clones. Using a sensitives S1 nuclease analysis we have shown that while no MLC‐1 mRNA of the ventricular type is detectable in the normal and SHR atrial muscle, there is a selective increase in ventricular MLC‐2 mRNa in both 6 week old (prehypertensive stage) and 18 week old (hypertensive) SHR heart atria. The myocardial cell culture system has been used to examine the effects of α‐adrenergic stimulation on the accumulation of contractile units and the expression of MLC‐2 gene. Stimulation of α‐adrenergic receptors with norepinephrine results in an increase in cellular MLC‐2 protein content as well as an increase in steady‐state level of MLC‐2 mRNA. This increase in MLC‐2 mRNA is mediated in part by an increase in transcription of the MLC‐2 gene. In order to characterize the regulatory elements of the MLC‐2 gene, we have characterized in detail the genomic clone corresponding to rat cardiac MLC‐2 cDNA. The results show a complete conservation of exon and intron organizations between cardiac and skeletal MLC‐2 genes. There is also a strong conservation of DNA sequence elements upstream to the transcription initiation site between rat cardiac and chicken cardiac MLC‐2 genes. Analysis of the cis‐ and trans‐acting factors that regulate MLC‐2 gene expression during cardiac hypertrophy should prove very useful in understanding the molecular mechanisms involved in hypertropic response.