bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alpha adrenergic activity and renal function in two‐kidney deoxycorticosterone‐acetate hypertensive swine
Authors: Zambraski Edward J. , Ciccone Charles D. 
Published: January 2005

AbstractTo evaluate the role of alpha‐adrenergic activity in deoxycorticosterone‐acetate (DOCA) hypertensive swine, eight two‐kidney Yucatan miniature swine were implanted with DOCA silicone strips (100 mg/kg) for 12–16 weeks. Mean arterial pressure (MAP) in these animals increased progressively from control values of approximately 1 15 mm Hg to 173 ± 5 mm Hg. Treatment of four conscious animals with phenoxybenzamine (POB) (1 mg/kg) resulted in a significant decrease in MAP from 190 ± 3 to 157 ± 5 mm Hg (P < 0.05). This decline was due to a 21% decrease in total peripheral resistance (TPR) (P < 0.05), while cardiac output (CO) and heart rate (HR) remained unchanged. Pentobarbital anesthesia caused a small insignificant decrease in MAP to 165 ± 5 mm Hg. While under anesthesia, infusion of POB into the left renal artery (0.04 μg/kg/min) caused a slight increase in left renal blood flow (P > 0.05), without affecting MAP, HR, TPR, or CO. Left kidney urine flow and sodium excretion also increased during intra‐renal POB infusion. Potassium excretion was unchanged and GFR decreased slightly. When POB (1 mg/kg) was infused systemically during anesthesia, MAP decreased to 82 ± 6 mmHg (P < 0.05). This was due to a 34% and 14% decrease in TPR and CO, respectively (P < 0.05). Whole animal urine flow, sodium excretion, and GFR all decreased significantly with systemic POB. These findings suggest that alpha‐adrenergic activity plays a role in the maintenance MAP and the determination of renal function in DOCA hypertensive swine.
Effects of antidepressants on isolated, electrically stimulated rat epididymal fat pads
Authors: Light Kim E. , Maickel Roger P. 
Published: January 2005

AbstractThe isolated, electrically stimulated rat epididymal fat pad in vitro was tested under various conditions as a model for neuronally induced lipolysis. A 24‐hr fast, or a preincubation without electrical stimulation, decreased spontaneous lipolysis as measured by glycerol release; however, only slight alterations were seen in the response of the pads during a 40‐min period of electrical stimulation. Spontaneous (nonstimulated) lipolysis was reduced by pretreatment with alpha‐methyl‐paratyrosine‐methylester and increased by pretreatment with reserpine; both of these treatments abolished the response to stimulation. The effects of addition of a variety of agents to the incubation medium confirm the role of a sympathetic nervous‐cyclic 3′,5′‐adenosine‐monphosphate mediated response system.
Studies on the efficacy and depressant potential of muscle relaxants in mice
Authors: Novack Gary D. 
Published: January 2005

AbstractThe present study was undertaken to confirm and extend previous observations on the use of morphine‐induced Straub tail and rotarod performance in mice as a means of assessing the efficacy of a compound as a muscle relaxant and its potential for depressant side‐effects, respectively. The ratio of the rotarod to Straub tail ED50s was calculated as an index of specificity. Our results generally confirmed previous reports in the case of diazepam, chlordiazepoxide and dantrolene. Additionally, the recently introduced muscle relaxants, cyclobenzaprine, baclofen, and DS 103‐282 were found effective in blocking Straub tail and their reported clinical specificity was reflected by the specificity observed in the mouse tests. DS 103–282 was found to be the most potent and specific. It is concluded that muscle relaxants with specificity ratios significantly greater than 1.0 appear to have comparatively few depressant effects at therapeutic doses. The relatively simple methods used in the present study appear to be useful in the initial assessment of compounds as potential muscle relaxants.
The effects of depolarizing agents and neuropeptides on dopamine release from striatal synaptosomes
Authors: VonVoigtlander Philip F. , Losey Elizabeth G. 
Published: January 2005

AbstractSynaptosomes (isolated nerve endings) from rat corpus striatum responded to several depolarizing agents by releasing dopamine. Among these agents were KCl, glutamic acid, ouabain, and veratrine. Substance P hexapeptide (SP6) also caused dopamine release, but the magnitude of this effect was small and variable. A number of other neuropeptides (cholecystokinin 1–8, des‐Tyr‐γ‐endorphin, Leu5‐β‐endorphin and substance P) did not alter dopamine release. SP6‐induced dopamine release may result from substance P receptor‐induced depolarization; however, the lack of robustness of the response in this preparation makes it unsuitable for studying agonists and antagonists of substance P.
The effects of lidocaine and hexamethonium on prostaglandin F2α‐ and histamine‐induced bronchoconstriction in normal and ASCARIS‐sensitive dogs
Authors: Malo Peter E. , Wasserman Martin A. , Griffin Robert L. 
Published: January 2005

AbstractThe effects of local deposition of the topical anesthetic, lidocaine, and ganglionic blockade by hexamethonium were investigated in canine models of pharmacologic‐ and antigen‐induced bronchoconstriction. Control bronchopulmonary provocations, i.e., increases in pulmonary resistance (RL) and decreases in dynamic lung compliance (CDYN), were accomplished by aerosols of prostaglandin F2α (PGF2α) and histamine (HIST) in normal, pentobarbital‐anesthetized beagles. Pretreatment with an aerosol of lidocaine (2%, 30 breaths) significantly inhibited PGF2α‐ and HIST‐induced changes in RL by 43.9 ± 6.5% and 58.0 ± 10.9%, respectively, and significantly reduced CDYN changes due to an aerosol challenge with HIST by 43.6 ± 9.2%. An i.v. infusion of hexamethonium (10 mg/kg) significantly inhibited PGF2α‐ induced changes in RL (36.5 ± 10.4%), while inhibiting changes in both RL and CDYN produced by HIST (57.8 ± 7.5% and 63.1 ± 6.5%, respectively). In Ascaris‐sensitive animals, neither lidocaine nor hexamethonium had any statistically significant effect on the bronchopulmonary responses to antigen challenge. These results suggest that a portion of the bronchoconstrictive response to PGF2α and HIST in dogs may involve an indirect, vagal‐mediated reflex, which is sensitive to lidocaine at the afferent cholinergic pathway and to hexamethonium at the ganglion. In antigen‐induced bronchoconstriction, these reflex pathways may be of lesser importance.
Lithium and central monoamine neurotransmitter systems
Authors: Ahluwalia Pardeep , Singhal Radhey L. 
Published: January 2005

AbstractLithium salts have been in use in psychiatric medicine for the past three decades, but their mechanism of action is still unknown. Studies using a model of mania to delineate the means by which they exert their therapeutic effect have been hampered by the lack of a suitable animal analogue, although attempts have been made to induce a “manic” state in rodents. For this reason, most investigations of the neurochemical basis of lithium action have used normal animals, and have focused primarily on the monoaminergic neurotransmitters, mainly because of the predominant theory of affective disorders (the “biogenic amine hypothesis”). Data indicate that these neurotransmitter substances are affected by lithium administration, although the findings are not always consistent and it is therefore difficult to determine exactly their role in the antimanic effect of lithium and the pathogenesis of the bipolar affective disorder. While animal studies have confirmed the existence of a “withdrawal” phenomenon, the involvement of biogenic amines or of central Y‐aminobutyric acid (GABA)minergic system in the rapid recurrence of psychotic symptoms soon after cessation of lithium therapy is still equivocal.
Psychotropic actions of BW 234U in the treatment of inpatient schizophrenics: A dose‐range study
Authors: Guy W. , Manov G. , Wilson W. H. , Ban T. A. , Fjetland O. K. , Manberg P. J. , Dren A. T. 
Published: January 2005

AbstractIn a 28‐day, dose‐range study, 11 chronic schizophrenic inpatients newly admitted to the hospital with acute exacerbations were administered a new antipsychotic, BW 234U, in daily doses ranging from 100 to 400 mg/day on a fixed/flexible schedule to determine therapeutic dose range, safety, and psychotropic activity with special regard to possible antiaggressive action. The results of weekly assessments with standard psychiatric rating instruments indicate that BW 234U has dual psychotropic action—an antipsychotic and an activating effect—that may have potential value in the treatment of depressive illness. The drug appears to be relatively free from neurologic, cardiovascular, anticholinergic, and CNS‐depressant side effects.
An improved model for assessment of positive inotropic activity in vitro
Authors: Anderson William G. 
Published: January 2005

AbstractResponses of guinea pig paced left atria to positive inotropic agents that probably act by different mechanisms were compared at two different calcium concentrations in vitro (1.25 and 2.50 mM). Consistently good results were obtained with isoproterenol, ouabain, amrinone, and 3‐isobutyl‐1‐methylxanthine only at the lower calcium concentration, which resulted in a greater percentage of responsive preparations, greater response discrimination, lower incidence of spontaneous and drug‐induced arrhythmias, and therefore a better quantitative assessment of concentration‐response relationships. Satisfactory responses were also obtained with the indirect‐acting agent tyramine and with the new agent, vardax. An excellent correlation between the magnitude of tension developed and the maximum rate of tension development was obtained for various inotropic stimuli. The partial beta agonists, prenalterol and dichloroisoproterenol, gave relatively poor responses under both sets of experimental conditions. It is concluded that the use of a low calcium concentration in the bathing medium enhances responsiveness to a variety of inotropic agents acting by different mechanisms, providing a useful and more reliable model for testing in vitro. It is suggested that a low external calcium concentration results in a smaller predrug sarcolemmal calcium flux, which may be markedly enhanced by inotropic agents.
Acute cardiovascular effects of bepridil in anesthetized mongrel dogs
Authors: Jandhyala Bhagavan S. , Steenberg Marie L. , Buckley Joseph P. 
Published: January 2005

AbstractThe cardiovascular effects of bepridil, a calcium antagonist, were investigated in pentobarbital‐anesthetized dogs. The intravenous administration of bepridil, 5 mg/kg, produced significant reductions in heart rate, cardiac output, and cardiac contractility. There was an initial transient marked increase in coronary blood flow and a significant increase in oxygen consumption which was followed by a decrease in oxygen consumption 5 min after administration of bepridil. The progressive and significant reductions in heart rate, cardiac contractility, cardiac output, and left ventricular minute work could be responsible for the secondary reduction in oxygen consumption. Coronary hemodynamic effects appeared to be independent of other cardiac effects since there appears to be no temporal correlation between these two phenomena. The coronary vasodilator property of bepridil was specific since there was an initial decrease in renal, femoral, and mesenteric blood flows.
The antihypertensive effect of a selective central muscarinic cholinergic antagonist: N‐(4‐diethylamino‐2‐butynyl)‐succinimide
Authors: Coram Willie Mae , Brezenoff Henry E. 
Published: January 2005

AbstractN‐(4‐Diethylamino‐2‐butynyl)‐succinimide (DKJ‐21), a cholinergic antagonist selective for muscarinic receptors in the central nervous system, has an antihypertensive effect in conscious spontaneously hypertensive rats (SHR) but not in normotensive Wistar‐Kyoto (WKY) control rats. Intravenous doses over a range of 3.1 to 25.0 mg/kg produced a dose‐dependent decrease in systolic blood pressure. This effect was still apparent 24 hr after drug administration, but blood pressure returned to predrug levels by 48 hr after injection of DKJ‐21. In a dose–response study, the maximum antihypertensive response in a group receiving 25.0 mg/kg was 43 ± 8 mm Hg. Marked variability of the maximum response was observed in all age groups and with all doses. Decreases in blood pressure up to 75 mm Hg were obtained in individual animals. The magnitude of the antihypertensive effect is not age related since 10‐, 15‐, 22‐, and 36‐week‐old SHR responded to the same degree after injection of 25 mg/kg DKJ‐21. Smaller doses (50 μg) of DKJ‐21 decreased blood pressure when administered into the lateral cerebral ventricle of SHR. Vascular responses to norepinephrine, acetylcholine, dimethylphenylpiperazinium, angiotensin I, and tyramine were not inhibited by i.v. injection of DKJ‐21; however, the centrally mediated pressor response to physostigmine was reduced by 60%.
Antagonism of discriminative stimuli produced by anxiogenic drugs as a novel approach to bioassay anxiolytics
Authors: Lal Harbans , Fielding Stuart 
Published: January 2005

AbstractAntagonism of selected agonist‐type drugs is an approach commonly employed to identify new drug activity. In the search for new anxiolytics, drug antagonism has not been a drug development tool in the past because of the lack of a suitable anxiogenic agonist for routine use. Recently, a number of anxiogenic drugs have been described. Pentylenetetrazol is one of those drugs. This review provides a critical examination of pentylenetetrazol with regard to its suitability as an agonist of anxiety that may be used routinely to predict and bioassay anxiolytic activity of novel molecules. In addition, drug discrimination is presented as a novel tool to measure objectively a specific animal activity which shows the same pharmacological properties as the subjectively perceived symptom of anxiety in human subjects. It is believed that the antagonism of an interoceptive discriminative stimulus produced by pentylenetetrazol may be a reliable and sensitive procedure to identify anxiolytic drugs of the future.
Vascular serotonin receptors and blood pressure regulation
Authors: Cohen Marlene L. 
Published: January 2005

AbstractIn most vascular beds, receptors mediating contraction to serotonin are of the 5HT2 type (defined by [3H]‐spiperone binding in brain tissue). Research on vascular serotonin receptors has been prompted by the development of ketanserin, a potent 5HT2‐receptor antagonist. Recent data suggest that ketanserin also possesses α‐receptor antagonist activity and that this property accounts for its antihypertensive activity in spontaneously hypertensive rats (SHR). The multiple blocking activities of ketanserin have prompted a search for more selective 5HT2‐receptor antagonists to elucidate the role of vascular serotonin receptors in blood pressure regulation. Consequently, 1‐(1‐naphthyl)piperazine (1‐NP) and LY53857, an ergoline derivative, have been identified as potent and highly selective 5HT2‐receptor antagonists in vascular tissue. 1‐(1‐napthyl)piperazine and LY53857 show approximately 2,000‐ and 300,000‐fold greater affinity, respectively, for 5HT2‐receptors than for α‐receptors compared to a 60‐fold selectivity of ketanserin. However, neither 1‐NP nor LY53857 lowered blood pressure in the SHR in doses that markedly shifted the pressor response to serotonin but did not antagonize α‐adrenergic receptors. Furthermore, blood pressure reduction in the SHR correlated poorly with the ability of several “5HT2‐receptor antagonists” to bind to 5HT2‐receptors and correlated extremely well with the binding of these agents to α‐receptors. Thus, in SHR, 1) antihypertensive activity of ketanserin occurred in doses that block α‐receptors and not at lower doses that block serotonin receptors, 2) more specific serotonin antagonists that did not block α‐receptors in vivo did not lower blood pressure, and 3) the reduction in blood pressure produced by a series of serotonin receptor antagonists correlated with their ability to block α‐receptors but not 5HT2‐receptors.
The state of the art of the science of drug discovery—an opinion
Authors: Maxwell R. A. 
Published: January 2005

AbstractThe discovery of drugs (and their subsequent development) is a difficult subspeciality in pharmacology that, in conjunction with clinical medicine, generates the vitality underlying the entire pharmacologic‐therapeutic enterprise. The drug discovery process is unique among biomedical sciences in that it takes place almost solely in industrial research institutions rather than in nonindustrial institutions—i.e., academic and government laboratories. The conventional view of drug discovery is that, since it is mission‐oriented and pharmacological, it is derivative on the basic pharmacological research carried out in nonindustrial research institutions. It is argued by the author that this model is oversimplistic and is not applicable to pharmaceutical research: It is very frequently the case that drugs are developed first and thus precede “basic” knowledge and in fact are the source of new academic findings, especially in pharmacology. In addition, new drugs are useful tools in physiology and biochemistry. Thus, the discovery of an innovative drug is per se a basic contribution. A more reasonable model of the relationship between drug discovery (and development) and nonindustrial research—physiological, biochemical, and pharmacological—is that of symbiosis with each segment nurturing the other to mutual benefit.The problems of pharmacologists involved in drug development are more complex than those of nonindustrial pharmacologists in that the end points of their work—successful clinical trial and marketing—demand more than an interesting pharmacological action; the action must be of therapeutic significance and be resident in a molecule which has been determined to be nontoxic, bioavailable, patentable, and commercially viable. The differences in goals between academic (non‐mission‐oriented) and industrial (mission‐oriented) pharmacological research and the consequent demands in the latter for specified kinds of results often leads to differing patterns of research and research judgments that can be a source of misunderstandings and confusion between industrial and nonindustrial pharmacologists.
Cholinergic hypothesis of human memory: Review of basic and clinical studies
Authors: Sitaram Natraj 
Published: January 2005

AbstractRecent neurochemical data from autopsy and biopsy studies of Alzheimer patients lends strong support for a selective impairment of cholinergic functioning. A number of pharmacological trials are described testing the effects of cholinergic agonists and antagonists on cognitive functions of both young normal volunteers as well as geriatric, demented patients. Paradigms included prelearning and postlearning pharmacological manipulations as well as testing the effect of a combination of a cholinergic precursor (lecithin) plus an anticholinesterase (tetrahydroaminoacridine). The results indicated great variability of responses among subjects, with mild‐to‐moderate enhancement of memory recall in specific subgroups of normal controls and demented patients. Further research should be aimed at developing reliable in vivo cholinergic markers and validation of these measures as response predictors of specific cholinergic treatments in patients with dementia.
Hormonal mediation of the memory disorder in depression
Authors: Reus Victor I. 
Published: January 2005

AbstractMany patients with major depression show deficits in information processing to a degree that parallels the severity of the mood disorder. Parallel findings of alteration in hormonal systems known to modulate memory functions suggest that the biological and cognitive changes described may be functionally linked. A specific goal for norepinephrine and the limbic hypothalamic‐pituitary‐adrenal axis is hypothesized and related to specific components of the alteration in information processing. The cognitive and mood effects of stimulant compounds in normal and depressed patient populations and parallels between the biologic and cognitive changes seen in normal aging and those observed in depression are considered.
Nootropic drugs: Animal models for studying effects on cognition
Authors: Schindler U. , Rush D. K. , Fielding S. 
Published: January 2005

AbstractThe term “nootropic” refers to compounds that act on cognitive functions. These drugs should facilitate learning and memory and prevent impairment of cognitive functions induced by diseases and brain insults. In animal models of impaired cognitive functions, the effects of several nootropic substances were investigated. Learning and retention in passive avoidance, and positive reinforcement paradigms were disrupted by hypoxia, cerebral ischemia and amnesia‐inducing agents. Piracetam and several other novel nootropic compounds were shown to improve performance in these animal models. These results indicate that experimentally induced cognitive dysfunction in animals can be attenuated with drug treatment.
Comparative activity of antihypertensive drugs as determined by the indirect measurement of blood pressure
Authors: Yaden Senka , Palmer Ralph T. , Elko Edward E. , Lal Harbans 
Published: January 2005

AbstractMany protocols for studying blood pressure over a long period of time in the same animal involve direct measurement via arterial cannulation. Chronic cannulations are not only stressful but also cause a high rate of mortality. In rats, the most common procedure other than permanent catheterization consists of transitory occlusion and reinstatement of blood flow in the tail to record systolic blood pressure. In this technique, animals are warmed individually to increase blood flow, which often results in stress to the animal and high variability in the results. Recently, an automated version of testing equipment for indirect measurement of blood pressure has become available. Utilizing this system, a number of atithypertensive drugs were tested in spontaneously hypertensive rats in order to (1) determine the sensitivity and reliability of measurements made by the automated system and (2) evaluate relative potency and efficacy of antihypertensive drug therapy. The ED50 and confidence limits were determined for the following antihypertensive drugs: clonidine, guanabenz, para‐aminoclonidine, hydralazine, minoxidil, prazosin, and aceperone. Systolic blood pressure was measured by means of tail cuffs with built‐in photoelectric sensors in 12 rats concurrently. It is concluded that the use of the automated equipment provides reliable and reproducible measurement of blood pressure and permits testing of the effects of antihypertensive drugs repeatedly in a larger number of rats.
Inhibition of ultrasonic distress vocalizations in rat pups by chlordiazepoxide and diazepam
Authors: Gardner C. R. 
Published: January 2005

AbstractWistar rat pups emit ultrasonic distress cries when placed on a cold plate or when held by the tail. More sounds were induced by tail holding than by placing on the cold plate, but in both cases the number emitted was relatively constant from 7 to 13 days of age. Chlordiazepoxide and diazepam inhibited the sounds, and their activity was only associated with sedation and muscle relaxation at higher doses. The muscle relaxant mephenesin had little effect. Prazosin induced sedation and hypothermia and inhibited sounds induced by tail holding more than those on the cold plate. Clonidine induced hypothermia and weak sedation and increased sound emission weakly for the tail holding response but markedly for responses on the plate. This separation of responses may result from potentiation of responses on the plate by drug‐induced hypothermia. Although sedative effects result in decreased ultrasounds, the benzodiazepines continue to reduce sounds at doses showing little or no sedation. It is suggested that the benzodiazepines may reduce the sound via their anxiolytic action.