bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of aniracetam and the benzodiazepine receptor partial inverse agonist Ro 15‐3505 on cerebral glucose utilization and cognitive function after lesioning of cholinergic forebrain nuclei in the rat
Authors: Lorez Hans‐Peter , Martin James R. , Keller Hans H. , Cumin Rudolf
Published: January 2005

Regional cerebral [3H]2‐deoxyglucose uptake, choline acetyltransferase (ChAT) activity, monoamine levels, and cognitive performance—and the modulation thereof by drugs—were studied in rats after electrolytic lesion of the nucleus basalis magnocellularis (NBM) and septum. The animals showed long‐lasting memory impairment in a passive avoidance task as well as degeneration of cholinergic and monoaminergic nerve terminals in the neocortex (after NBM lesion) and hippocampus (after septum lesion). The denervated regions showed a long‐lasting reduction of the uptake of [3H]2‐deoxyglucose, indicating a decreased glucose utilization rate. The pyrrolidinone derivative aniracetam (Ro 13‐5057) and the benzodiazepine receptor partial inverse agonist Ro 15‐3505 improve cognitive functions in various animal tests. Rats with bilateral NBM lesions that typically exhibited passive avoidance learning, but no retention 24 hr later, were administered aniracetam, Ro 15‐3505, physostigmine, or tetrahydroaminoacridine after the acquisition phase. Ro 15‐3505 and physostigmine produced the most convincing ameliorative effects. Aniracetam did not change the cerebral glucose utilization in either control rats or in NBM or septumlesioned rats. In contrast, Ro 15‐3505 increased glucose use in various brain regions of control animals by 10–30% and partially reversed the deficit in lesioned animals. The effect of Ro 15‐3505 on glucose utilization and passive avoidance retention may be related to the disinhibition of various neuronal circuits; however, fully intact cholinergic and monoaminergic innervation of the cerebral cortex and hippocampus is not a prerequisite.
Beneficial effects of idebenone on memory impairment in rats
Authors: Nagaoka A. , Nagai Y. , Yamazaki N. , Miyamoto M. , Kiyota Y.
Published: January 2005

Idebenone showed beneficial effects on memory impairments in the passive avoidance, radial maze, and T‐maze tests in rats with cerebral ischemia, cerebral infarction, basal forebrain lesions, and treatment with an anticholinergic drug. The drug ameliorated neurological deficits following the onset of cerebrovascular lesions in strokeprone rats. In the neurochemical study, idebenone normalized reduced levels of 5‐hydroxy indole acetic acid (5‐HIAA) and acetylcholine (ACh) in various regions of the brain and inhibited the decrease in adenosine triphosphate (ATP) and the increase in lactate that occurs after cerebral ischemia. Furthermore, the drug activates mitochondrial respiratory function and inhibits lipid peroxidation in brain tissue. From these results, it is suggested that idebenone primarily ameliorates the energy failures in damaged brain tissues, partially normalizes the altered neural transmission in the tissues, and improves memory disturbance in rats.
Vascular and cardiac effects of HP 406 and nifedipine in vitro and in conscious spontaneously hypertensive rats and renal hypertensive dogs
Authors: Hubbard John W. , Kapples Joan F. , Nordstrom Scott T. , Matson Laura C. , Wilson Sandy J. , Ress Rudyard J. , Kosley Raymond W. , Cherill Robert J. , Huger Francis P. , Fielding Stuart
Published: January 2005

The cardiovascular effects of the calcium antagonists HP 406 and nifedipine were assessed in a series of in vitro and in vivo studies. HP 406 was found to display moderate affinity for dihydropyridine binding sites, as determined by the inhibition of [3H]‐nitrendipine binding on rat ventricular membranes. HP 406 was found to have an IC50 of 1.3 × 10−7 M as compared to nifedipine with an IC50 of 7.0 × 10−9 M. Additional in vitro studies were conducted with isolated spontaneously contracting and electrically paced guinea pig atria and rabbit aortic rings. HP 406 was found to have minimal effects on cardiac chronotropic and inotropic activity in isolated guinea pig atria. In contrast, nifedipine caused significant dose‐related reductions in heart rate and myocardial contractile force. Rabbit aortic rings were precontracted with potassium chloride (KCI) or norepinephrine (NE), and HP 406 or nifedipine was added to tissue baths in a cumulative dose range. HP 406 and nifedipine both caused dose‐related relaxation of KCI‐ and NE‐contracted rings; however, the IC50's against KCI were found to be significantly lower than those against NE for both compounds. The IC50's against NE were found to be 4.8 × 10−8 M and 5.9 × 10−8 M for HP 406 and nifedipine, respectively. The IC50's against NE were 1.9 × 10−5 M for HP 406 and 4.4 × 10−5M for nifedipine. Finally, the antihypertensive activity of HP 406 and nifedipine were compared in the spontaneously hypertensive rat (SHR) and renal hypertensive dog. Both compounds produced significant reductions in mean arterial pressure at 1 mgikg p.o. in the SHR and at 3 mgikg p.o. in the renal hypertensive dog. Nifedipine was also found to cause a significantly greater tachycardia compared to HP 406. The results of this study show that HP 406 is a potent antihypertensive agent with minimal direct or reflex‐mediated chronotropic effects. The mechanism of this antihypertensive activity appears to result from calcium‐channel antagonism and vascular dilation.
Behavioral approach to probe altered neurotransmission in autoimmune NZB/BINJ mice: Implications for investigations of cognitive dysfunctions
Authors: Retz Konrad C. , Forster Michael J. , Lal Harbans
Published: January 2005

Autoimmune NZB/BlNJ mice exhibit deficits in learning and memory that show accelerated appearance with age relative to nonautoimmune mice. NZB/BlNJ mice also exhibit an accelerated age‐dependent increase in brain‐reactive antibodies (BRA). The authors review studies employing neuropharmacological probes to examine whether or not autoimmune NZB/BlNJ mice exhibit abnormalities of neurotransmission that would be consistent with learning and memory deficits. NZB/BINJ mice exhibited abnormal responses when tested for motor activity and hypothermia following cholinomimetics and showed accelerated age‐related changes in sensitivity to diazepam. Overall, the experiments reviewed suggest the presence of altered neurological functions in autoimmune NZB/BINJ mice.
Interference of antimycotics and other drugs with methohexital hypnosis in rats
Authors: Awouters Frans , Niemegeers Carlos J. E. , Janssen Paul A. J.
Published: January 2005

Compounds of various pharmacological and chemical classes were studied for their interaction with methohexital hypnosis. Rats were treated daily for 5 days with an oral dose of a test compound or solvent. On days 1, 5, and 8 methohexital was injected intraperitoneally and the duration of hypnosis was measured. Three types of interaction with methohexital hypnosis were observed. Acute prolongation of hypnosis on day 1 was the most marked effect of fluconazole (median effective dose, ED50: 8.66 mg/kg), but this occurred also with phenobarbital (ED50: 26.4 mg/kg) and diphenylhydantion (ED50: ∼ 160 mg/kg). Tolerance to prolongation, i.e., a decrease of the hypnosis time by more than 50% from day 1 to day 5, was most marked with phenobarbital (ED50: 12.6 mg/kg) and diphenylhydantion (ED50: 113 mg/kg) but was also found with fluconazole (ED50: 22.6 mg/kg). Shortened hypnosis times on day 8 occurred with phenobarbital (ED50: ∼ 40.0 mg/kg) and diphenylhydantoin (ED50: ∼ 160 mg/kg). The antimycotic itraconazole, the antidiarrheal loperamide, the thymosthenic agent ritanserin, and the antiallergics astemizole and levocabastine were devoid of interactions with methohexital. When compared with the basic activity of the tested compounds in rats, interference with methohexital hypnosis was most pronounced with phenobarbital (ratio 3.13) followed by fluconazole (ratio: 3.28) and diphenylhydantoin (ratio: 5.07).
Characteristics of a discrimination among two doses of morphine and saline in pigeons
Authors: Young Alice M. , Walton Maureen A. , Perkins Ann N.
Published: January 2005

As reported by Gauvin and Young [1987], a robust discrimination can be established among saline, 10 mg/kg morphine, and 1.8 mg/kg morphine. The present experiment further examined the pharmacological characteristics of this discrimination. Pigeons were trained to discriminate among i.m. injections of saline, 1.8 mg/kg morphine (the low‐dose, or LD, stimulus), and 10 mg/kg morphine (the high‐dose, or HD, stimulus). Performance was maintained under FR 30 schedules of food delivery in 30‐min experimental sessions. After establishment of stimulus control, various doses of morphine, the agonist‐antagonist nalbuphine, and the nonopioid pentobarbital were tested for generalization to the LD and HD stimuli. For morphine itself, generalization of the LD and HD stimuli varied as a function of dose. A dose of 0.10 mg/kg morphien occasioned responses to only the saline key. As the dose of morphine was increased to 1.8 mg/kg, the proportion of responses to the LD key increased from 0 to 100%. As the dose was increased further, the proportion of responses to the LD key decreased, with a commensurate increase in responses to the HD key. Complete HD generalization occurred at 5.6 or 10 mg/kg morphine. In contrast, the opioid agonist‐antagonist nalbuphine (1.0 to 56 mg/kg) evoked generalization to only the LD stimulus. The highest dose of nalbuphine markedly suppressed response rates. The nonopioid pentobarbital (0.1 to 18 mg/kg) evoked neither LD nor HD generalization. This pattern of generalization suggests that the discrimination among saline and two doses of morphine may provide a fruitful assay for the agonist efficacy of novel opioids.
Subjectively experienced cannabis effects in animals
Authors: Järbe Torbjörn U. C. , Hiltunen Arto J. , Mechoulam Raphael
Published: January 2005

Discriminative stimulus properties of tetrahydrocannabinol (THC) are reviewed. The cue induced by δ9‐THC is pharmacologically specific. Generally, only cannabimimetics have been found to substitute for the THC cue, including hashish‐smoke. Combination tests with naturally occurring cannabinoids indicate interactions that, however, may be species specific. Among the THC metabolites examined, the 11‐OH‐THC is more potent than the parent compound. Other metabolites were much less active. (+)–δ–THC are much less active than the (–) natural enantiomer indicating stereoselectivity. Absolute stereospecificity was seen with the enantiomers of the dimethylheptyl homologs of 11‐OH‐δ8‐THC, the (–)‐isomer being at least 70 times more active than (–)‐δ9‐THC; the (+)‐isomer did not generalize even at doses a thousand times higher than those of the ED50 of the (–)‐enantiomer. Additional stereochemical aspects of the THC cue are indicated.
Discriminative stimulus properties of intracranial administration of delta‐9‐tetrahydrocannabinol
Authors: Mokler David J. , Rosecrans John A.
Published: January 2005

The purpose of the present experiment was to determine the possible brain areas involved in the discriminative stimulus properties of delta‐9‐tetrahydrocannabinol (THC). Male Sprague‐Dawley rats were trained in a fixed‐ratio 10 operant paradigm in a standard 2‐lever operant task to discriminate 3.0 mg/kg THC (i.p.) from its vehicle. After acquisition of the discrimination, animals were implanted with either unilateral or bilateral intracranial cannulae into the prefrontal cortex, dorsal hippocampus, or reticular formation. Intracranial (i.c.) infusions were made with the use of a microsyringe in a volume of 0.5 μl per cannula over 45 sec. The discrimination session was begun immediately after the infusion was completed. When the animals were accustomed to the procedure, 0.5 μl of vehicle (10% emulphor:ethanol) was administered i.c. Following this, doses of either 5 or 10 μg THC were infused into each cannula. Responses were not consistent from animal to animal. Of the 6 animals tested with infusion of THC into the prefrontal cortex, 2 showed drug‐appropriate responding following i.c. administration of THC with 1 additional rat showing a partial generalization to THC. Of the 6 animals implanted with cannulae into the dorsal hippocampus, 2 showed drug‐appropriate resonding following THC administration intracranially. Two other animals showed a partial generalization following THC infusion into the dorsal hippocampus. All animals with cannulae implanted into the reticular formation showed drug‐appropriate responding; this was accompanied, however, with drug‐appropriate responding following infusion of the vehicle. These data suggest that the discriminative stimulus properties of THC may involve actions of THC in discrete brain areas. They do not support the hypothesis that THC acts at a select site in the brain; rather, they support the idea that THC acts at multiple sites. The results with infusions into the reticular formation would support the hypothesis that nonspecific stimulation of this brain site may lead to THC‐like stimuli.
Effect of cholecystokinin octapeptide antagonists on the extinction of an active avoidance task in the rat
Authors: Itoh Shinji , Takashima Akira
Published: January 2005

Cholecystokinin octapeptide (CCK‐8) has been shown to be involved in memory processes. For example, in the absence of endogenous CCK‐8 in the brain, memory processes are imparied. In order to extend the understanding of this relationship, the present study observed the effect of novel potent CCK‐8 antagonists, L‐364,718 and CR 1409, on active avoidance responding in the rat. These antagonists caused marked impairment in the performance of the learned task when administered intracerebroventricularly immediately after the learning trials. The results suggest that CCK‐8 is indispensable for memory processes.
Propranolol induces hyperreactivity in lung parenchyma strips from sensitized guinea pigs
Authors: Vargas Mario H. , Montaño Luis M. , Vanda Beatriz , Selman Moisés
Published: January 2005

Propranolol causes airway hyperreactivity to agonists or antigenic challenge in vivo, but its mechanisms are still debated. In this study we found that the addition of propranolol (10 μ/ml) to lung parenchyma strips from sensitized guinea pigs enhanced the sensitivity and maximum contraction to antigenic challenge (ovalbumin, 0.01–100 μ/ml) and the sensitivity to histamine (1 × 10−7 to 1.7 × 10−4 M), determined through concentration‐response curves. In contrast, tracheal chains from sensitized guinea pigs were unaffected. These results in in vitro preparations strongly suggest that, at least in lung parenchyma tissue, other mechanisms different from beta‐blockade are present in propranolol‐induced airway hyperreactivity.
Pharmacologic modulation by cetirizine 2 HCl and loratadine of the histamine‐induced skin reaction in mice and in humans
Authors: Coulie P. , De Vos C. , Ghys L. , Rihoux J. P.
Published: January 2005

In mice, the histamine‐induced cutaneous reaction is inhibited by cetirizine with an approached ED50 of 0.04 mg/kg and by loratadine with an approached ED50 of 0.38 mg/kg, both drugsadministered intraperitoneally. At these doses, cetirizine' s onset of activity seems to be more rapid, although both compounds show the same duration for at least 7 hr. Nine healthy volunteers received orally either cetirizine or loratadine (10 mg single dose) or placebo in a double‐blind randomized and cross‐over study design. Both drugswere significantly more effective than placebo (except loratadine at the 2nd and 24th hr for the wheal with 1 and 10 μg histamine, and at the 2nd hr for the flare with 1 μg histamine). At all times and withboth agonists' concentrations, cetirizine was significantly more potent than loratadine (except at the 24th hr for the wheal with 1 μghistamine). Neither numerous nor marked side effects were found.
Antihypertensive property of a novel uricosuric diuretic, S‐8666, in rats
Authors: Matsuda Saburo , Ishii Mitsuo , Kitajiri Naoko , Yahara Isao , Harada Hiroshi , Yonetani Yukio
Published: January 2005

The antihypertensive, diuretic, and toxicological effects of S‐8666 were studied in rats. At doses of more than 60 mg/kg/day, p.o., S‐8666 was antihypertensive in DOCA‐salt hypertensive rats with a potency corresponding to 1/20 of that of trichlormethiazide. The antihypertensive effect was dose‐dependent, and, at the higher doses, S‐8666 had a more potent depressor effect than trichlormethiazide. The antihypertensive activity of S‐8666 was shown predominantly by the S‐(−)‐enantiomer, with the R‐(+)‐enantiomer being only slightly active. A similar dose‐dependent antihypertensive effect was shown by furosemide, tienilic acid, or indacrinone, but the therapeutic index (LD50/minimum effective dose) of S‐8666 was the highest among them. The acute diuretic and natriuretic effects of S‐8666 after oral administration of 60–200 mg/kg to DOCA‐salt hypertensive rats correlated well with its antihypertensive effect, although such diuretic and natriuretic effects in normotensive rats had no effect on blood pressure. S‐8666, like trichlormethiazide, showed a prophylactic effect on the development of hypertension in DOCA‐salt hypertensive rats, salt‐loaded spontaneously hypertensive rats (SHR), and salt‐loaded Dahl‐S rats, though it was much less potent. Moreover, the combination of S‐8666 with captopril in SHR enhanced the depressor effect of captopril like hydrochlorothiazide. These results indicate that S‐8666 can be an effective nonthiazide diuretic for use as an antihypertensive agent.
New n‐methyl‐d‐aspartate antagonists for the treatment of stroke
Authors: Porsche‐Wiebking Elena
Published: January 2005

Current research indicates that the neurotoxicity of the excitatory amino acid neurotransmitter glutamate contributes to the cell loss associated with a variety of neurological disease states. In particular, glutamate neurotoxicity has been proposed to play a key role in ischemic/hypoxic neuronal cell death and the development of ischemic brain damage. Certain N‐methyl‐D‐aspartate (NMDA) receptor/channel complex antagonists have been shown to protect against experimentally induced hypoxic/ischemic injury. Concepts for the development of novel NMDA antagonists for the treatment of stroke are discussed.
Effects of chronic imipramine and haloperidol treatment on apomorphine‐induced motility in rats
Authors: Pradhan Nityananda , Moro Sulochana D. , Srinivasan Aruna S.
Published: January 2005

Locomotor behavior was studied with the use of automated devices in chronic imipramine‐ and haloperidol‐treated Sprague Dawley rats. The biphasic response to apomorphine was only preserved in the control rats. The response to low dose apomorphine challenge was attenuated by chronic imipramine and haloperidol administration. There were no significant changes in motility responses to high dose apomorphine challenges between the control and experimental groups. The results suggest the involvement of postsynaptic Dopamine receptors (D2) in the loss of response to low dose apomorphine.
Biochemical and pharmacological characterization of the putative dopamine autoreceptor agonist benzopyranopyridine, CGS 15873A
Authors: Glaeser Bruce S. , Liebman Jeffrey M. , Sills Matthew A. , Hutchison Alan J. , Lovell Richard A. , Welch James , Jarvis Michael F. , Bennett Debra A. , Williams Michael
Published: January 2005

The substituted benzopyranopyridine, CGS 15873A (± trans‐1,3,4,4a,4,10b‐hexahydro‐4‐propyl‐2H‐[1]benzopyrano[3,4‐b]‐pyridine‐70olmonohydrochloride), was evaluated for its dopamine receptor agonist and other properties in biochemical and behavioral test procedures. In the γ‐butyrolactone (GBL) model of dopamine autoreceptor function, CGS 15873A i.p. had an ED50 value of 1.83 m̈mole/kg indicating that the compound had dopamine autoreceptor agonist activity. The corresponding p.o. value was 2.11 m̈mole/kg, indicating reasonable oral bioavailability. The compound exhibited a shallow competition curve in displacing [3H] ADTN from dopamine recognition sites in a biphasic manner with IC50 values of 6 and 234 nM, respectively. At the dopamine D2 receptor defined by [3H] spiperone binding, CGS 15873A had an IC50 value of 234 nM. The compound had negligible activity (IC50 > 1 m̈M) in binding assays for dopamine D1, serotonin (5HT1A, 5HT1B, 5HT2), and α1‐adrenergic binding sites. Moderate activity was, however, observed in α2‐adrenoceptor binding (IC50 = 77 nM).

CGS 15873A had a weak effect on stereotyped behavior (ED50 > 106 μmole/kg i.p.), an indication of postsynaptic activity, but showed partial generalization in a clonidine discrimination paradigm, indicating that it was a partiall α2 agonist. CGs 15873A appears to be a relatively selective dopmine agonist with preferentia activity at presynaptic autoreceptors and, as such, may represent a novel agent for treatment of disorders such as schizophreniaand Parkinsonism.
Relationship of anticonvulsant activity to brain concentrations of the chiral anticonvulsant U‐54494A
Authors: Von Voigtlander Philip F. , Althaus John S. , Lewis Richard A. , Green Donnella S.
Published: January 2005

U‐54494A and its enantiomers were administered to mice orally, intravenously, and intracerebroventricularly, and the anticonvulsant time anticonvuslant time courses were assessed by determination of electroshock seizure thresholds. The time courses of brain concentrations of the administered compounds were also assessed by an HPLC‐electrochemical detection assay. The recemate (U‐54494A) and both enantiomers were found to be long‐acting anticonvulsants with high oral apparent bioavailabilities. However, this was not reflected by the brain concentrations of administered compound; during the protracted anticonvulsant time courses, the drugs were present at only very low levels in the brain. This suggests the possibility of active metabolites contribting to the antoconvulsant effects of U‐54494A. However, both the enantiomers and the racemate are intrinsically active as indicated by anticonvulsant effects elicited via intracerebroventricular administration. Thus, both of the enantiomers and metabolites thereof contribute to the anticonvulsant effects of U‐54494A.
Sodium‐Calcium exchange: A possible target for drug development
Authors: Reeves John P.
Published: January 2005

The Na+‐Ca2+ exchange system is a carrier‐mediated transport process which couples the transmembrane movement of Ca2+ ions to the movement of Na+ ions in the opposite direction. It functions primarily as a Ca2+ extrusion process in cardiac cells and is thought to be an important mechanism for altering myocardial contractility through changes in intracellular [Na+]. We khave investigated the properties of the cardiac Na+‐Ca2+ exchange system using a subcellular preparation of membrane vesicles derived from the cardiac sarcolemma. Vesicle studies have been useful in investigating the kinetics of Na+‐Ca2+ exchange activity and in establishin the stoichiometry of the exchange process as 3 Na+ per Ca2+. The kinetec results are most easily interpreted in terms of a model for the Na+‐Ca2+ exchange carrier which features two types of cation binding sites: a divalent site for which Ca2+ and 1‐2 Na+ ions compete and a second, monovalent site which binds the third Na+ involved in Na+‐Ca2+ exchange. Na+‐Ca2+ exchange activity in vesicles is stimulated by a variety of agents or treatments, including limited proteolysis, phospholipase treatment, redox reagents, anionic amphiphiles, and intravesicular Ca2+, all of which lower the apparent Km for Ca2+. The physiological significance of these modes of regulation of exchange activity is at present uncertain. Progress in identifying and purifying the exchange carrier has been hampered by the lack of specific high‐affinity probes that could be used in labelling studies. Indirect estimates of the number of exchange carriers in sarcolemmal vesicles suggest that there are 10‐20 pmol of exchanger per mg of membrane protein and that the exchange system has a maximal turnover of approximately 103 sec−1. Studies are under way in several laboratories to clone a cDNA for the exchange carrier using oocytes of Xenopus laevis as an expression system.
Cutaneous arterial and venous alpha receptor blocking activity following intraduodenal indoramin to dogs
Authors: Greenberg Stan , Touhey Beatrix
Published: January 2005

Indoramin is a selective α1 receptor antagonist, with pharmacologic activity similar to prazosin. However, indoramin differs from prazosin in that indoramin has membrane stabilizing activity; does not cause reflex tachycardia, first dose syncope, or orthostatic hypotension; and requires several days for onset of its antihypertensive action. Thus, indoramin may lower blood pressure independent of arterial or venous α1 adrenoceptor blockade. This study compares the relative arterial and venous α1 adrenoceptor blocking activity of indoramin and prazosin, following intraduodenal (id) administration, in the canine hindpaw preparation perfused at constant flow, to their blood pressure lowering activity. Indoramin (5 and 20 mg/kg, id) inhibited the arterial and venous pressor responses to sympathetic nerve stimulation (SNS) and norepinephrine (NE). No significant differences in the magnitude of arterial and venous blockade existed. Blockade of α1 adrenoceptors was maximal at 5 mg/kg of indormin. In contrast, 20 mg/kg of indoramin lowered mean arterial blood pressure (MAP) but did not affect paw perfusion pressure (PP). Prazosin (0.25 and 1.0 mg/kg, id) produced both dose‐related α1 adrenoceptor blockade and reduction of MAP. Prazosin was more effective as an inhibitor of venous vs. arterial responses to SNS, and produced a different profile of inhibition of SNS than indoramin. Thus, indoramin differs from prazosin as an inhibitor of α1 adrenoceptors of the canine paw. Since indoramin does not lower MAP in doses which block α1 adrenoceptors of the paw and does not lower PP in the decentralized paw in doses which lower MAP, we conclude that indoramin acutely lowers MAP in the dog by a mechanism unrelated to postsynaptic α1 receptor blockade, and may inhibit a subtype of α1 adrenoceptor different from that inhibited by prazosin.
Adenosine transporters in vascular smooth muscle and endothelium: Multiple [3H]Nitrobenzylthioinosine binding sites in human umbilical vein endothelium
Authors: Williams Evan F. , Harris‐Hooker Sandra , Gordon Portia B.
Published: January 2005

Cultured vascular smooth muscle and endothelial cells may be useful models for studying the cardiovascular adenosine transport system and metabolism. We have quantified the nucleoside transporter elements of cultured primate vascular smooth muscle, bovine aortic endothelial, and human umbilical vein endothelial cells by radioligand binding and by using membrane preparations of these cells and the nucleoside transporter probe nitrobenzylthioinosine ([3H]NBMPR), a potent and tightly bound inhibitor of nucleoside transport. The binding was rapid, reversible, saturable, and site‐specific. Scatchard analysis of the saturation data showed that [3H]NBMPR bound to high and low affinity binding sites in human umbilical vein endothelial cell membranes with apparent binding affinities (KD) of 0.093±0.01 nM 1.92±0.1 nM, and binding site densities (Bmax values) of 13.48±1.2 and 69+5.3 fmol/mg protein, respectively. In contrast, the binding to primate vascular smooth muscle and bovine aortic endothelial cell membranes occurred to an apparently high affinity single class of binding sites at which the KD was 1.4±0.3nM and 0.28±0.05nM, respectively, and which had Bmax values of 1,977±163 and 1,284±267 fmol/mg protein, respectively. Scatchard analysis of the binding inhibition by dipyridamole showed a mixed type inhibition, while NBMPR inhibited the binding competitively. Several recognized nucleoside transport inhibitors and vasodilators inhibited the binding with an order of potency similar to that observed for the inhibition of [3H]NBMPR binding to guinea pig cardiac membranes.
Newer aspects of antiarrhythmic drug development: Introduction
Authors: Steinberg Mitchell I. , Cervoni Peter
Published: January 2005

Although cardiac arrhythmias remain a serious clinical problem in many patients with heart disease, the exact role of antiarrhythmic drug therapy is currently under intense evaluation. Within the last several years it has become clear that there are significant risks as well as potential benefits associated with existing agents. Ongoing studies in large patient populations should help determine the benefit/risk ratio of traditional therapy. Regardless of the outcome of these trials, current electrophysiological dogma will have to be re‐evaluated and newer concepts evolve for drug development to make further progress. The goal of this symposium is to exchange information among basic and clinical investigators so as to facilitate the emergence of novel electrophysiological concepts that will form the basis for future generations of antiarrhythmic drugs.
Fibroblast growth factor in the eye and prospects for its therapeutic use
Authors: Tripathi Ramesh C. , Kolli Susmitha P. , Tripathi Brenda J.
Published: January 2005

Fibroblast growth factor (FGF) is a monomeric mitogenic protein that exists as an acidic and a basic form and is distributed widely in tissues of the eye. Because FGF interacts with the cells and with the extracellular matrix, it has potential as a therapeutic agent, either alone or in combination with other agents such as epidermal growth factor, in promoting healing of corneal wounds, in restoring corneal endothelial cell loss due to dystrophic, degenerative, and surgical insults, as well as in regenerating lens cells after cataract surgery. Excess FGF probably plays a significant role in the pathogenesis of blinding disorders of the eye such as neovascular glaucoma, age‐related macular degeneration, and proliferative diabetic vitreoretinopathy, as well as failure of surgical filtering procedures for glaucoma. The use of transforming growth factor‐beta, anti‐FGF antibodies, and other blocking agents in the treatment of such diseases seems logical.
Comparison of the effects of secobarbital and diazepam on the repeated acquisition of response sequences in humans
Authors: Higgins Stephen T. , Stitzer Maxine L.
Published: January 2005

The present study was conducted to compare the acute effects of secobarbital (0–300 mg) and diazepam (0–30 mg) on learning in normal volunteers. The repeated acquisition of behavioral chains procedure was used to assess learning. Subjects were exposed to varying doses of secobarbital, diazepam, and placebo under double‐blind conditions. Both compounds increased overall percent errors and decreased overall response rates as an orderly function of dose. No statistically significant differences were observed between these two compounds in onset, magnitude, or duration of effects. As expected, potency differences were observed with diazepam being approximately 10 times more potent than secobarbital. Overall these results indicate that secobarbital and diazepam produce a comparable profile of effects in humans responding under a repeated acquisition of behavioral chains procedure. Thus, with regard to learning impairment, the liability associated with using or abusing secobarbital vs. diazepam appears to be the same.
Titration of duration discrimination in behavioral pharmacology and toxicology
Authors: Daniel Stephen A. , Evans Hugh L.
Published: January 2005

This study investigated a discrete‐trial, titration duration discrimination procedure in behavioral pharmacology. Pentobarbital and d‐amphetamine, measured with this procedure, selectively affected discrimination more than response tendencies. Pentobarbital also tended to affect selectively discrimination of longer durations, whereas d‐amphetamine did not. Further experiments showed that (1) other algorithms for modulating stimulus duration are useful in behavioral pharmacology and toxicology, (2) threshold estimates are similar with the method of constant stimuli and the method of titration, and (3) this titration procedure permits the separate examination of drug effects upon discrimination and upon response tendencies; the fixed‐interval procedure does not. Baseline variability was an important correlate of drug effects in that the endpoints with more variable baselines were also more sensitive to drugs.
Mild ethanol intoxication may enhance pavlovian conditioning
Authors: Hernandez Linda L. , Valentine James D.
Published: January 2005

Evidence is reviewed showing that low doses of ethanol (∼200–400 mg/kg), administered prior to training, can facilitate aversive Pavlovian conditioning and delay subsequent extinction of Pavlovian conditioned responses in both rabbits and rats. The effect of ethanol during Pavlovian training occurs during later testing in both intoxicated and sober animals and is stronger for Pavlovian than for comparable instrumental conditioned responses. New data are reported showing that the facilitatory effect of ethanol on Pavlovian conditioned suppression in rats interacts with both the extent of Pavlovian training and the reinforcement schedule used to maintain the operant baseline but also resembles the effect of more extended Pavlovian training in saline‐treated animals. Together, these findings suggest that facilitation of Pavlovian conditioning may be a general effect of mild ethanol intoxication. Possible behavioral mechanisms of this effect are discussed.
Antihypertensive, vasodilating, and sympatholytic activities of ofornine® in spontaneously hypertensive rats
Authors: Defelice Albert , Lape Harlan , Horan Patrick , Frering Richard , Brousseau Armand , O'Connor Bernard , Herrmann John , Bailey Denis
Published: January 2005

This study of spontaneously hypertensive (SH) rats documents oral antihypertensive activity of the vasodilator Ofornine®, an anthranilamide whose effect was sustained, at least in part, by suppression of compensatory renal and neurohumoral responses. Doses of 2.5 to 100 μg/kg p.0. reduced systolic blood pressure (BP) by up to 75 mm Hg. Effect lasted 6‐24 hr and did not diminish during a 16 day (25 μg/kg/day) regimen. Metoclopramide (10.0 μg/kg)and haloperidol (3.0 μg/kg) antagonized the antihypertensive effect. Antihypertensive activity was confirmed by direct (arterial cannula) monitoring where 0.001‐1.O μg/kg i.v. reduced mean BP by 6‐47% without tachycardia. Doses of 1‐10 ag/kg i.a. reduced perfusion pressure of the SH rat hindquarters by 35‐74 mm Hg. A dose of 5.0 μg/kg p.0. reduced BP and urine norepinephrine levels of SH rats by 58 mm Hg and approximately 50% without raising plasma renin activity or causing sodium retention. How‐ ever, Ofornine® (25 μg/kg p.0. daily for 6 days) did not affect reflex bradycardic or tachy‐ cardic effects of phenylephrine and sodium nitroprusside in SH rats. These and other results indicate that Ofornine@ reduces SH rat blood pressure through vasodilating and presynaptic adrenolytic activities, and that a dopaminergic mechanism may be involved.
Effects of chronic torbafylline treatment on energy metabolism of ischemic skeletal muscle
Authors: Comte Jane , Gautheron Danièle C. , Godinot Catherine , Okyayuz‐Baklouti Ismahan
Published: January 2005

This study investigates the effects of chronic oral treatment with Torbafylline, a xanthine derivative, on the energy metabolism of chronically ischemic skeletal muscle of the rat. Blood flow to one hindlimb was reduced by unilateral femoral artery ligation. One group of animals received 5 ml/kg body weight saline while the other group received 25 mg/kg Torbafylline dissolved in the same volume of saline. Treatment was pursued for 5 weeks, 2 times a day, except during the weekends. In NaCI‐treated rats, ischemia leads to muscle atrophy as measured by a decrease in muscle weights and to a concomitant decrease in lactate dehydrogenase and creatine kinase activities, while adenine nucleotide contents remain unchanged. Chronic administration of Torbafyllin almost totally prevented these changes. In isolated mitochondria from ischemic and non‐ischemic muscles, treated or not with Torbafylline, no significant changes were measured in malate dehydrogenase, citrate synthase, creatine kinase, cytochrome oxidase and oligomycin‐sensitive ATPase. However, in mitochondria prepared from NaCI‐treated muscles with limited flow, an increase of substrate oxidation was observed after formation of endogenous ATP (final state 4 of oxidation). This increase can be interpreted as an indication of a deviation from the normal use of ATP, e.g., non‐efficient energy production. Torbafylline treatment prevented this apparent waste of energy.
Anticonvulsant potency and toxicity of 5,5‐diphenyl‐2,4‐oxazolidinedione
Authors: Jones Gary L.
Published: January 2005

The anticonvulsant ED50 of 5,5‐diphenyl‐2,4‐oxazolidinedione (DPO) was determined in male CF#1 mice by a standard maximal electroshock method, and compared with that for phenytoin (PHT) and phenobarbital (PB). Acute neurotoxicity (TD50) and acute lethality (LD50) were also determined. These parameters are reported with respect to i.p. dosage, and blood and brain concentrations. The anticonvulsant ED50 (308 mg/kg) of DPO was significantly less than that of either PHT (7.1 mg/kg) or PB (19.0 mg/kg). The same order of potency was observed when expressed in terms of blood or brain concentrations, although important quantitative differences were noted. Neurotoxicity was observed with doses of DPO required for anticonvulsant action (TD50 = 335 mg/kg). Furthermore, acute lethality (LD 50 = 373 mg/kg) was observed at doses not significantly different (P≥.05) than the ED50. Doses between the ED50 and LD50 produced profound motor incoordination, seizures, and coma. Because of its extremely narrow margin of safety, DPO would not be considered a likely candidate for evaluation as a therapeutic agent in man. However, a greater understanding of its pharmacology is desirable because, in spite of its structural similarity to PHT, it contrasts sharply in certain properties.
Preclinical profile of Wy‐49,051: A new H1‐antagonist
Authors: Abou‐Gharbia Magid , Nielsen Susan T. , Andree Terrance H. , Tasse Rene , Leventer Steven
Published: January 2005

In an effort to develop an orally active, non‐sedating H1‐antagonist, compound Wy‐49,051 was synthesized and examined in various in vivo and in vitro assays. In vitro, the compound possessed high affinity for H1 receptors (IC50 = 44 nM) and was found to competitively antagonize histamine‐induced guinea pig ileum contraction. At a concentration of 1 × 10−10 M, Wy‐49,051 shifted the histamine dose‐response curve to the right in a parallel fashion. Wy‐49,051 demonstrated H1 antagonism in a variety of in vivo tests. Wy‐49,051 (s.c.) protected against histamine‐induced death (guinea pig) in a dose‐dependent manner and with a longer duration of action than terfenadine. In addition, Wy‐49,051 effectively antagonized histamine‐induced wheal formation (administered up to 18 hr prior to challenge) and was more potent than astemizole and chlorpheniramine. At a dose of 5 mg/kg (p.o.), Wy‐49,051 produced less inhibition of in vivo brain [3H]pyrilamine binding than ebastine (5 mg/kg, p.o.), terfenadine (20 mg/kg, p.o.), and chlorpheniramine (100 mg/kg, p.o.). Importantly, Wy‐49,051 did not exhibit H2‐antagonist activity (as indicated by a lack of effect on gastric acid secretion in the pylorus‐ligated rat) and did not affect histamine‐induced changes in blood pressure and heart rate in the anesthetized guinea pig. Although Wy‐49,051 displayed significant alpha1‐receptor affinity in vitro (IC50 =8 nM), it did not alter blood pressure or heart rate in SHR rats at doses examined above its projected therapeutic dose for H1‐receptor antagonism. Wy‐49,051 did not affect carbachol‐induced guinea pig ileum contraction and possessed little affinity for M2 muscarinic receptors (IC50 = 7.3 μ). Taken together with the previously mentioned in vivo [3H]pyrilamine binding data, these data indicate that Wy‐49,051 is a long‐acting, potent H1‐antagonist with less potential for sedative and anticholinergic side effects than many common antihistamines including chlorpheniramine.
Cardiovascular effects of medorinone in β‐adrenoreceptor‐blocked and non‐blocked anesthetized dogs
Authors: Lee King C. , Ezrin Alan M. , Pagani Edward D. , Canniff Paul C. , Hamel Douglas W. , Fort Dorothy J. , Silver Paul J.
Published: January 2005

The hemodynamic effects of the low Km cAMP peak III PDE inhibitor medorinone (0.01–0.3 mg/kg, i. v. ) were evaluated in anesthetized dogs in the presence and absence of β‐adrenoreceptor blocked. Medorinone increased the peak derivative of left ventricular pressure (+ dP/dt) in non‐blocked (all doses) and β‐blocked dogs (≥0.03 mg/kg) (2,766±259 and 1,403±262 mm Hg/sec, respectice max. changes). Heart rate (HR) was increased by medorinone in non‐blocked (≥0.1 mg/kg) and β‐blocked dogs (≥0.03 mg/kg) (77.4±8.9 and 25.5±4.3 beats/min, respective max. changes). In non‐blocked dogs only, medorinone (all doses) decreased left ventricular end‐diastolic pressure (LVEDP) (7.7±1.7 mm Hg, max. change). Mean arterial pressure (MAP) was similarly decreased by medorinone (<0.03 mg/kg) in β‐blocked and non‐blocked dogs (max. approx. −27 mm Hg). Medorinone did not affect cardiac output or renal blood flow. The hemodynamics of medorinone and milrinone (another peak III PDE inhibitor) in non‐blocked dogs were similar, except meddorinone was less potent in increasing +dP/dt (2,766±259 vs. 3,747±388, max. changes) and more potent in reducing LVEDP (−7.7±1.7 vs. −1.8±1.2 mm Hg, max. changes). In conclusion, medorinone similarly reduced MAP, but more effectively decreased preload, increased inotropy and chronotropy in non‐blocked than β‐blocked anesthetized dogs. Medorinone is more potent in reducing preload, but less potent in enhancing inotropy when compared to milrinone in anesthetized dogs.
Synthesis and metabolic profile of Cl‐966: A potent, orally‐active inhibitor of GABA uptake
Authors: Bjorge Susan , Black Ann , Bockbrader Howard , Chang Tsun , Gregor Vlad E. , Lobbestael Sandra J. , Nugiel David , Pavia Michael R. , Radulovic Louis , Woolf Thomas
Published: January 2005

A lipophilic derivative of the known GABA uptake inhibitor guvacine has been prepared. The synthesis of this compound, [1‐]2‐bis 4‐(trifluoromethyl)]phenyl[‐methoxy]ethyl[‐ 1,2,5,6‐tet‐rahydro‐3‐pyridine carboxylic acid, monohydrochloride, Cl‐966, is described. Studies were carried out to determine the metabolic profile of Cl‐966, in rats. Two metabolites, one less polar and the other more polar than Cl‐966, were identified and their structures assigned by spectroscopic methods and confirmed by comparison to synthetic material.
Assessment of zolpidem and Cl‐966 for anxiolytic and anxiogenic properties by using the discrimination of pentylenetetrazole by rats
Authors: Emmett‐Oglesby M. W. , Abdel‐Malek S. L.
Published: January 2005

This experiment determined if two novel compounds, zolpidem and CI‐966, would show anxiogenic or anxiolytic activity in an animal model of anxiety based upon the discrimination of pentylentetrazole (PTZ). Rats were trained to detect the anxiogenic drug PTZ, 20 mg/kg, and tested with zolpidem (an agonist at omega [benzodiazepine] receptors) and CI‐966 (a GABA‐uptake inhibitor). Zolpidem did not substitute for PTZ. This drug blocked the PTZ stimulus in a dose‐related manner (0.32–5.0 mg/kg), although only partial blockade was obtained even at the highest dose that could be tested. These data suggest that zolpidem may have weak efficacy as an anxiolytic drug. CI‐966 partially substituted for PTZ at 3 to 6 hr post injection of doses of 16.0 and 32.0 mg/kg. Lower doses of CI‐966 produced a slight, but non‐significant, blockade of the PTZ stimulus, which appeared to be additive with the blocking effects of diazepam upon this discrimination. Because CI‐966 has been shown to block PTZ seizures in mice, the present data suggest that the discriminative stimulus produced by PTZ is not related to its ability to produce convulsions. The partial substitution of CI‐966 given in high doses is consistent with clinical reports that this compound may produce anxiogenic effects.
General pharmacology of CK‐2130: A new selective positive inotrope
Authors: Greenberg Stanley S. , Paul Jeff , Luisi Alan
Published: January 2005

CK‐2130 is a new imidazolone developed to treat congestive heart failure. We compared CK‐2130 to four inodilators and ouabain in several pharmacologic models. Intravenous (i.v.) administration of CK‐2130 to pentobarbital‐anesthetized dogs (0.03 to 1 mg/kg) relatively selectively increased myocardial dP/dT when compared to the dual positive inotropic and vasodilator activity of milrinone, enoximone, imazodan, and piroximone. Milrinone and piroximone (600 mg/kg, p.o., and 30‐300 mg/kg, i.p.) were central nervous system depressants in mice. CK‐2130 (100 mg/kg, i.v. and 600 mg/kg, i.p. and p.o.) was not depressant. Gastric acid secretion in the guinea pig was not affected by CK‐2130 (1 mg/kg, i.v.) and was inhibited by milrinone (1 mg/kg, i.v.) and enhanced by enoximone (1 mg/kg, i.v.). CK‐2130 and milrinone (0.03‐1 mg/kg, i.v.) did not affect rabbit sciatic nerve‐gastrocnemius muscle function. CK‐2130, piroximone, imazodan, and milrinone (100 μM) did not affect sympathetic neurotransmission, postsynaptic receptors, or guinea‐pig nonvascular smooth muscles but relaxed canine arteries and veins. Ouabain (1‐100 μM) initially facilitated, then inhibited, sympathetic neurotransmission, contracted vascular and non‐vascular smooth muscles, enhanced the vas deferens contraction to norepinephrine, and inhibited uterine contractions to bradykinin (10 μM). CK‐2130, milrinone, piroximone, and imazodan (0.1 to 100 μM) inhibited human platelet aggregation produced by adenosine diphosphate and sodium arachidonate. Thus, CK‐2130, a relatively selective positive inotrope, should be devoid of adverse central nervous system; neural, smooth, and skeletal muscle; and gastrointestinal side effects associated with digitalis and enoximone therapy.
Antihypertensive effect of metoprolol in diuretic‐treated, mild primary hypertension
Authors: Mahapatra Rajat , Hunter Kenneth W. , Mahapatra Dipta , Yaden Senka , Lal Harbans
Published: January 2005

Metoprolol tartrate was administered to 41 patients with mild essential hypertension already treated with a diuretic for a period of 2 weeks. In the majority of those patients, other step 2 antihypertensive agents either failed to control high blood pressure or caused adverse reactions. All other antihypertensive agents except diuretics were discontinued during the 2‐week wash‐out period. Patients with a diastolic blood pressure of 95 to 104 mmHg (inclusive) received oral metoprolol at a dose of 50mg twice daily for 2 weeks. Subsequently, metoprolol titration was individualized on a bi‐weekly basis until either the diastolic blood pressure was = 90 mmHg and/or a maximal daily dose of 300mg of metroprolol was reached. The analysis of efficacy and safety was done for a total period of 14 weeks. Diastolic blood pressure and heart rates were significantly reduced (P≤0.05) in all treatment groups. Minor adverse reactions such as mild fatigue in 11 patients, nervousness in 2, and leg cramps in 2 patients were reported. Transient skin rash, dizziness, headache, chest pain, insomnia, and cold extremities were also reported in one patient each. It is concluded from the present study that metropolol (in twice daily dose) in combination with a diuretic is safe, effective, and well tolerated in the treatment of mild hypertension.