bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractThe 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

AbstractAutoimmune 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

AbstractCompounds 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

AbstractAs 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

AbstractDiscriminative 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

AbstractThe 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

AbstractCholecystokinin 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

AbstractPropranolol 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

AbstractIn 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

AbstractThe 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

AbstractCurrent 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

AbstractLocomotor 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

AbstractThe 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

AbstractU‐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

AbstractThe 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

AbstractIndoramin 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.