bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiovascular pharmacology of FK664, a novel venodilator with cardiotonic properties
Authors: Sudo Yuji , Maeda Kazuhiro , Ozaki Tohru , Takai Masaki , Sakata Yoshihiko , Nishida Keiko , Matsuo Noriko , Nakajima Hiromi , Enda Emiko , Esumi Kimio 
Published: January 2005

AbstractThe cardiovascular effects of FK664, [6‐(3, 4‐dimethoxyphenyl)‐1‐ethyl‐4‐mesitylimino‐3‐methyl‐3, 4‐dihydro‐2 (1H)‐pyrimidinone], were examined in both in vitro and in vivo preparations. FK664 is an orally effective noncatechol and nonglycoside cardiotonic agent. FK664 has vasodilating activity not only in resistance vessels but also in capacitance vessels in both in vitro and in vivo studies (venodilation). This venodilating effect of FK664 has been observed at much lower concentrations than those required to produce an inotropic response. FK664 is effective in the conscious dog at 1 mg/kg (2.5 μmol/kg) orally and in a dog model of congestive heart failure at 3.2 μg/kg/min (7.8 nmol/kg/min), intravenously. The vasodilating and positive‐inotropic activities of FK664 are mainly due to an increase in cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) levels due to inhibition of cyclic AMP phosphodiesterase. Moreover, FK664 does not affect the balance between myocardial oxygen supply and demand due to a significant increase in coronary blood flow, though the agent does increase myocardial oxygen consumption. In conclusion, the agent produces potent preload reduction and mild cardiac stimulation. This unique pharmacological profile may be beneficial in the management of congestive heart failure. © 1993 Wiley‐Liss, Inc.
Effect of silymarin and silybinin on oxygen radicals
Authors: Pascual Carlos , Gonz Ricardo , Armesto Julio , Muriel Pablo 
Published: January 2005

AbstractThe aim of this work was to study the scavenging action of the flavonoids, silymarin and silybinin (two well known hepatoprotective agents) against different types of oxygen radicals which were generated by specific chemical reactions and detected by luminol‐sensitized chemiluminescence. A well known scavenger for each radical was used as control for the paradigm and for comparing its effect with those of the flavonoids. It was found that 0.8 μg/ml of silymarin and 5.5 mg/ml of silybinin produced the same effect as 3.2 ng/ml superoxide dismutase (SOD). An alkoxy radical scavenging effect similar to the one produced by 0.35 ng/ml of vitamin E was caused by 2 μ/ml silymarin and 1.6 ng/ml silybinin. Silybinin was evaluated as a scavenger of hydroxyl radicals by determining the inhibition of the chemiluminescence produced by the Fenton reaction with luminol; this was compared with the results obtained from a more conventional method which determines the inhibition of the damage to 2‐deoxyribose by the Fenton reaction. In both methods, inhibition was observed at a relatively high concentration of the flavonoid as compared with ethanol. The action of silymarin and silybinin as scavengers of oxygen radicals may explain the protective effect of these flavonoids in certain forms of liver disease where free radicals are involved. However, other properties of these compounds cannot be discarded for their hepatoprotective actions. © 1993 Wiley‐Liss, Inc.
PDGF‐receptor protein tyrosine kinase activity in carotid artery is enhanced by injury and inhibited in vivo by tyrphostin RG 13291
Authors: Bilder Glenda E. , Kasiewski Charles J. , Walczak Edward M. , Perrone Mark H. 
Published: January 2005

AbstractTyrphostins (TKI) are synthetic low molecular weight compounds which inhibit in vitro platelet‐derived growth factor (PDGF) mitogenesis by blocking PDGF receptor protein tyrosine kinase activity (PDGF R‐PTK). To determine whether TKIs act by this mechanism in vivo, a rat model of vascular injury was used. Rat carotid arteries were injured by implantation of a tygon cuff machined so that 1 mm of each end touched the artery. PDGF R‐PTK was measured ex vivo by incubation of the excised denuded artery with porcine PDGF followed by homogenization and Western blotting with antiphosphotyrosine/antiPDGF‐R antisera. In arteries from control rats, PDGF produced a maximal 2‐fold increase in R‐PTK at 120 ng/ml. In cuffed arteries, PDGF stimulated R‐PTK in a dose‐related manner after one day of injury; R‐PTK remained elevated for 4–5 days post injury (6‐fold increase in R‐PTK activity at 180 ng/ml). A similar response to PDGF was also evident in contralateral uncuffed arteries. Intraperitoneal injection (+ 2 h) of TKI RG 13291 inhibited PDGF R‐PTK of cuffed artery with an IC50 value of ∽ 2 mg/kg and of the uncuffed artery with IC50 value of ∽ 30 mg/kg. It is concluded that TKIs are potential in vivo inhibitors of injury‐induced PDGF R‐PTK activity and may be useful as inhibitors of PDGF‐dependent effects such as proliferation. © 1993 Wiley‐Liss, Inc.
Inhibition of synovial LTB4 production by a specific leukotriene biosynthesis inhibitor, MK‐0591, in a rabbit model of joint inflammation
Authors: Brideau Christine , Chan Chi‐Chung , Guevremont Diane , Hutchinson John H. , McDonnell Joseph , Moore Vernon 
Published: January 2005

AbstractThe effect of a leukotriene biosynthesis inhibitor (MK‐0591) on LTB4 synthesis was examined in a rabbit model of joint inflammation. Intra‐articular (ia) injection of human recombinant interleukin‐1β (rlL‐1β, 50–400 ng/joint) resulted in dose‐dependent infiltration of leukocytes into the synovium but produced only background levels of LTB4 over a time course of 14–16 h, suggesting that the leukocytes were not activated with respect to LTB4 metabolism. The influx of leukocytes in the synovial space was not inhibited by MK‐0591. Injection of A23187 (100 nmol/joint, ia) in addition to rlL‐1β elicited significant LTB4 release in the synovial fluid. MK‐0591 given iv 30 min before A23187 significantly inhibited the release of LTB4 (ED50 = 0.3 mg/kg), without affecting the number of leukocytes in the synovium. In rabbit whole blood challenged with A23187 in vitro, MK‐0591 also potently inhibited LTB4 synthesis (IC50 = 126 ± 29 nM). The in vivo inhibitory action of MK‐0591 was in good agreement with the plasma levels of the compound (0.62 μM in the group treated with MK‐0591 at 3 mg/kg) and its biochemical efficacy in vitro (100% inhibition of LTB4 synthesis). The effect of MK‐0591 was comparable to that of another leukotriene biosynthesis inhibitor, MK‐886. Indomethacin at dose up to 3 mg/kg iv did not affect the production of LTB4 in the joint. The present study demonstrates that MK‐0591 inhibits LTB4 biosynthesis with high potency in the rabbit synovium, a microenvironment rich in protein and leukocytes. It would be of interest to determine whether such an action would be beneficial in the management of rheumatoid arthritis or other inflammatory conditions in humans. ©1993 Wiley‐Liss, Inc.
Use of neuroendocrine effects in discrimination between CNS‐active drugs in the rat
Authors: Albinsson Agneta , Lundstedt Torbjörn , Andersson Gunnar 
Published: January 2005

AbstractDifferent psychotropic drugs were investigated in order to determine their effect on the release of prolactin and corticosterone and their influence on the tuberoinfundibular dopamine (TIDA) neuron activity. The results were used in a principal component analysis, which grouped the psychotropic drugs into different clusters. In the plot showing these clusters the anxiolytic drugs were found to be grouped together and differ from the antidepressant drugs by their potent ability to increase plasma corticosterone. The antipsychotic drugs formed a separate group being clustered together. Typical neuroleptic and atypical antipsychotic drugs could be separated within the cluster by their different effects on plasma prolactin and corticosterone and on TIDA neuron activity. The results indicate that the neuroendocrine profiles of antidepressant and anxiolytic drugs are different from those of antipsychotic drugs and that the neuroendocrine measurements could be a useful tool in the early classification of psychotropic drugs. © 1993 Wiley‐Liss, Inc.
Effects of antiglaucoma drugs on ocular blood flow in ocular hypertensive rabbits
Authors: Hong Show‐Jen , Chiou George C. Y. 
Published: January 2005

AbstractIn search of antiglaucoma agents which can increase the ocular blood flow and effectively lower the intraocular pressure (IOP), numerous antiglaucoma drugs were investigated to determine their ability to increase the ocular pulsatile blood flow in ocular hypertensive rabbits with the intraocular pressure artificially raised to 40 mmHg. It was found that various antiglaucoma drugs increased ocular pulsatile flow; these included (with percent increase) ethoxzolamine (36–56%), pilocarpine (65%), physostigmine (43–83%), echothiophate (23–62%), timolol (28–42%), levobunolol (37–55%), betaxolol (35%), and epinephrine (61%). Metipranolol, metoprolol, and clonidine had no effect on pulsatile blood flow. These results indicate that most antiglaucoma drugs, with the exception of a few, can enhance the ocular pulsatile blood flow in ocular hypertensive rabbits. © 1993 Wiley‐Liss, Inc.
Effects of artilide on spontaneous and induced ventricular arrhythmias in 24‐hour canine myocardial infarction
Authors: Buchanan Lewis V. , Kabell Glenn , Turcotte Uta M. , Brunden Marshall N. , Gibson John K. 
Published: January 2005

AbstractThe electrophysiologic and antiarrhythmic effects of artilide were evaluated in dogs 24 h after myocardial infarction. Artilide (0.1 to 3.0 mg/kg or 0.2 to 7.0 μuM/kg iv) prevented programmed stimulation induced ventricular arrhythmias in 9 out of 9 dogs that had demonstrated inducibe ventricular arrhythmias prior to treatment. This antiarrhythmic action was associated with significant increases in ventricular refractoriness and monophasic action potential duration. Lower doses of artilide tended to reduce the incidence of spontaneous ventricular arrhythmias but these effects were not significant. These results are consistent with the concept that spontaneous and pacing induced ventricular arrhythmias result from different mechanisms, and that class III anti‐arrhythmic agents are more effective in suppressing induced ventricular tachycardia due to reentry than spontaneous arrhythmias which result from nonreentrant mechanisms. © 1993 wiley‐Liss, Inc.
Effects of combinations of methylxanthines and adenosine analogs on locomotor activity in control and chronic caffeine‐treated mice
Authors: Nikodijević Olga , Jacobson Kenneth A. , Daly John W. 
Published: January 2005

AbstractChronic caffeine ingestion (CCI) by male NIH Swiss strain mice results in a prolonged reduction in locomotor activity and alterations in response to caffeine, other xanthines, and adenosine analogs. Caffeine, the A1 selective 8‐cyclopentyltheophylline (CPT), and the A2‐selective 3,7‐dimethyl‐1‐propargylxanthine (DMPX) remain stimulatory and the bell‐shaped locomotor dose‐response curves are left‐shifted after CCI. The depressant effects of methylxanthines that are potent phosphodiesterase inhibitors remain after CCI. After CCI, mice became more sensitive to depressant effects of A1, mixed A1/A2, and A2 agonists. In the presence of caffeine the A1‐selective agonist N6‐cyclohexyladenosine (CHA), the mixed A1/A2 agonist 5′‐N‐ethylcarboxamidoadenosine and the A2‐selective agonist 2‐[(2‐aminoethylamino)‐carbonylethylphenylethylamino]‐5′‐N‐ethylcarboxamidoadenosine (APEC) all have dose‐response curves, appearing to consist of initial depressant effects, then stimulatory effects, and finally pronounced depressant effects. The phasic character is reduced or absent after CCI. Synergistic depressant effects of combinations of CHA and APEC also appear reduced after CCI. © 1993 wiley‐Liss, Inc.
L‐368,899, a potent orally active oxytocin antagonist for potential use in preterm labor
Authors: Pettibone D. J. , Clineschmidt B. V. , Guidotti M. T. , Lis E. V. , Reiss D. R. , Woyden C. J. , Bock M. G. , Evans B. E. , Freidinger R. M. , Hobbs D. W. , Veber D. F. , Williams P. D. , Chiu S.‐H. L. , Thompson K. L. , Schorn T. W. , Siegl P. K. S. , Kaufman M. J. , Cukierski M. A. , Haluska G. J. , Cook M. J. , Novy M. J. 
Published: January 2005

AbstractL‐368,899 [1S‐(‐7,7‐dimethyl‐2‐endo‐(2S‐amino‐4‐(methylsulfonyl)butyramido)‐bicyclo(2.2.1)‐heptan‐1‐yl)methanesulfonyl)‐4‐(2‐methylphenyl)piperazine] was characterized in vitro and in vivo as a potent and selective, orally bioavailable oxytocin (OT) antagonist. L‐368,899 exhibits high affinity for rat (Ki, 3.6 nM) and human (Ki, 13 nM) uterine OT receptors with selectivity versus liver arginine‐vasopressin (AVP)‐V1 and kidney AVP‐V2 receptors in both species. In vitro, L‐368,899 is a potent and competitive OT antagonist in the rat isolated uterus (pA2, 8.9) and mouse anococcygeus muscle (pA2, 8.3) and is inactive against a number of different contractile agents in these preparations. L‐368,899 also inhibits OT‐stimulated phosphatidylinositol turnover in rat uterine slices and exhibits no agonist‐like activity in any of the in vitro assays. In vivo, L‐368,899 selectively antagonizes the uterine contractile effects of OT in the anesthetized rat given both i.v. and intraduodenally (i.d.) (AD50; 350 μg/kg i.v., 7 mg/kg i.d.) with a moderate duration of action. In near‐term pregnant rhesus macaques, L‐368,899 is a potent inhibitor of OT‐stimulated uterine activity (AD50, 27 μg/kg i.v.) and OT‐mediated spontaneous, nocturnal uterine contractions. L‐368,899 is orally bioavailable in several species and, combined with adequate aqueous solubility, represents a potential new tocolytic agent for both oral and i.v. use. © 1993 wiley‐Liss, Inc.
Structure, synthesis, and antitumor activity of the hydrolysis product of the antitumor agent carmethizole
Authors: Anderson Wayne K. , Houston D. Michael , Jarosinski Mark A. , Kinder Frederick R. , Kode Rao N. , Van Roey Patrick , Salerno Jeffrey M. 
Published: January 2005

AbstractThe two isomeric monocarbamates, 2b and 2c, related to the antitumor drug carmethizole (1) were synthesized and the structure of the carmethizole hydrolysis product, 2b, was established by X‐ray crystallography. The chemical reactivity, toxicity, and antitumor activity of the two monocarbamates, 2b and 2c, were compared with 1. © 1993 wiley‐Liss, Inc.
Nicotine and tetrahydroaminoacradine: Evidence for improved attention in patients with dementia of the Alzheimer type
Authors: Sahakian Barbara J. , Coull Jennifer T. 
Published: January 2005

AbstractA placebo‐controlled, single‐blind study investigated the effects of administering three acute doses of nicotine (0.4, 0.6, and 0.8 mg) to a group of patients suffering from dementia of the Alzheimer type (DAT), and to young and aged normal controls. Performance on objective computerised tests provided evidence for improvements in attentional function rather than memory, in patients with mild to moderate DAT. Despite the lack of drug effect on mnemonic ability, these results demonstrate that DAT patients have significant attentional deficits which can be remediated by nicotine administration. They add to the growing body of evidence that the cholinergic system is involved in the control of attentional processes; and are substantiated by the findings of a second study examining the use of a chronic dose of the cholinesterase inhibitor THA, as a treatment for DAT. In this study, effects on both subjective clinical rating scales and objective computerised tests were assessed. In regard to the former, analysis of the three main clinical outcome measures showed statistically significant effects of the drug on the Mini‐Mental State Examination (MMSE) and the Abbreviated Mental Test Score (AMTS), but not on the Activities of Daily Living scale (ADL). Using objective computerised CANTAB tests, sensitive to specific aspects of memory and attention, evidence was found for improvements in attentional function rather than memory, in patients with mild to moderate DAT. These data will clearly provide important comparative data for future investigations of putative cognitive enhancing drugs in DAT sufferers. © 1994 Wiley‐Liss, Inc.
Comparison of the ability of direct‐ and indirect‐acting nicotinic agonists to induce nicotinic receptor up‐regulation in rat cerebral cortex
Authors: Yang Xiao‐Hong , Buccafusco Jerry J. 
Published: January 2005

AbstractChronic twice daily systemic administration of nicotine (1 mg [2 μmol]/kg, sc) over 10 days to rats produced a significant increase in the apparent Bmax for cortical nicotinic receptors. Similar results were obtained whether the labeled ligand employed was [3H]methylcarbamylcholine ([3H]MCC) or [3H]cytisine: Rats were treated twice daily for 10 days with the cholinesterase inhibitor physostigmine (25 μg [64 nmol]/kg, sc) to indirectly activate nicotinic receptors. This regimen inhibited cortical cholinesterase activity by about 51%. Binding analysis of physostigmine‐treated rat cortical tissue indicated that while the Bmax for muscarinic receptors was significantly reduced, there was no change in the binding parameters for neuronal nicotinic receptors. In the next series of experiments, chronic twice daily intracerebroventricular (icv) injection of 30 μg [108 nmol] of MCC, like nicotine, also produced a significant increase in the Bmax for cortical nicotinic receptors. MCC treatment also produced a small but significant increase in the apparent Kd. Twice daily icv injection of 6 μg [23 nmol] of the competitive nicotinic antagonist dihydro‐β‐erythroidine hydrobromide (DHBE) for 10 days did not itself alter the apparent Bmax for cortical nicotinic receptors. In a separate group of rats 6 μg [23 nmol] icv of DHBE preceded by 15 min the icv injection of 30 μg [108 nmol] of MCC. This regimen was administered twice daily for 10 days. Under these conditions the DHBE produced a significant 44% inhibition of the MCC‐induced increase in Bmax. Antagonist pretreatment also blocked the small MCC‐induced increase in Kd. Thus, direct activation of the agonist binding site of the neuronal nicotinic receptor following chronic administration of nicotine or the acetycholine‐like MCC leads to receptor up‐regulation. Indirect activation through cholinesterase inhibition was not effective in this regard. © 1994 Wiley‐Liss, Inc.
Nicotinic potentiation of glutamatergic synapses in the prefrontal cortex: New insight into the analysis of the role of nicotinic receptors in cognitive functions
Authors: Vidal Catherine 
Published: January 2005

AbstractIn contrast with the now well‐recognized effects of nicotine in promoting learning and memory, little is known about the functional and pharmacological properties of putative nicotinic acetylcholine receptors located in neocortical areas involved in cognitive functions. Recent electrophysiological experiments using intracellular recordings in the rat prefrontal cortex in vitro have revealed that nicotine selectively enhances the amplitude of excitatory postsynaptic potentials mediated by glutamate in pyramidal cells. The effect was blocked by the specific nicotinic antagonists neuronal bungarotoxin and dihydro‐β‐erythroidine. Several arguments suggest that the potentiation of excitatory potentials by nicotine is due to the activation of presynaptic nicotinic receptors located on glutamatergic afferent terminals. Thus the control by nicotinic receptors of the effectiveness of excitatory inputs to the prefrontal cortex might influence significantly the processing of information in this area. The possibility of a functional cooperation between nicotinic and glutamatergic systems in the neocortex provides an integrative mechanism for the involvement of both neurotransmitter systems in synaptic plasticity underlying memory processes. © 1994 Wiley‐Liss, Inc.
Structure activity relationships for derivatives of adenosine‐5′‐triphosphate as agonists at P2 purinoceptors: Heterogeneity within P2x and P2y subtypes
Authors: Burnstock Geoffrey , Fischer Bilha , Hoyle Charles H. V. , Maillard Michel , Ziganshin Airat U. , Brizzolara Antonia L. , von Isakovics Amy , Boyer José L. , Harden T. Kendall , Jacobson Kenneth A. 
Published: January 2005

AbstractThe structure‐activity relationships for a variety of adenine nucleotide analogues at P2X and P2Y‐purinoceptors were investigated. Compounds formed by structural modifications of the ATP molecule including substitutions of the purine ring (C2, C8, N1, and N6‐substituents, and a uridine base instead of adenine), the ribose moiety (2′ and 3′‐positions), and the triphosphate group (lower phosphates, bridging oxygen substitution, and cyclization) were prepared. Pharmacological activity at P2Y‐purinoceptors was assayed in the guinea pig taenia coli, endothelial cells of the rabbit aorta, smooth muscle of the rabbit mesenteric artery, and turkey erythrocyte membranes. Activity at P2X‐purinoceptors was assayed in the rabbit saphenous artery and the guinea‐pig vas deferens and urinary bladder. Some of the analogues displayed selectivity, or even specificity, for either the P2X‐ or the P2Y‐purinoceptors. Certain analogues displayed selectivity or specificity within the P2X‐ or P2Y‐purinoceptor superfamilies, giving hints about possible subclasses. For example, 8‐(6‐aminohexylamino)ATP and 2′,3′‐isopropylidene‐AMP were selective for endothelial P2Y‐purinoceptors over P2Y‐purinoceptors in the guinea pig taenia coli, rabbit aorta, and turkey erythrocytes. These compounds were both inactive at P2X‐purinoceptors. The potent agonist N6‐methyl ATP and the somewhat less potent agonist 2′‐deoxy‐ATP were selective for P2Y‐purinoceptors in the guinea pig taenia coli, but were inactive at P2X‐purinoceptors and the vascular P2Y‐purinoceptors. 3′‐Benzylamino‐3′‐deoxyATP was very potent at the P2X‐purinoceptors in the guinea pig vas deferens and bladder, but not in the rabbit saphenous artery and was inactive at P2Y receptors. These data suggest that specific compounds can be developed that can be utilized to activate putative subtypes of the P2X‐ and P2Y‐purinoceptor classes. © 1994 Wiley‐Liss, Inc.
Cardiovascular effects of nicorandil and nitroprusside in furosemide plus digoxin pretreated dogs
Authors: Humphrey Stephen J. 
Published: January 2005

AbstractIn support of human congestive heart failure (CHF) trials, the cardiovascular effects of the vasodilators nicorandil (NIC) and nitroprusside (NP) were examined in anesthetized and conscious dogs pretreated with the diuretic furosemide (FURO) and the cardiac glycoside digoxin (DIG). In anesthetized control dogs, iv NP (2–19 μg/kg/min) and NIC (24–105 μg/kg/min) maximally reduced mean arterial pressure (MAP) by 43 and 40 mmHg, respectively, with moderate increases in heart rate (HR). These hypotensive responses to NP and NIC were unmodified by iv FURO (2.65 mg/kg) + DIG (0.075 mg/kg) pretreatment (PT). FURO + DIG reduced central venous pressure (CVP) BY 3 mmHg, masking the separate effects of NP and NIC. In a third group, FURO's fluid volume depletion and DIG's plasma concentrations were unaffected by adjunctive NIC infused for 2.5 h at a mean 17 μg/kg/min iv. No untoward interactions were seen with any combination. In conscious dogs, the hypotension and tachycardia seen with iv NP (2–20 μg/kg/min) and NIC (20–160 μg/kg/min) were also unchanged after 5 days of oral FURO (5 mg/kg/day) and DIG (0.0125 mg/kg/day), with no intolerance. Repeated oral NIC (7.5 mg/kg/day × 3 days) in these chronic FURO + DIG dogs ws consistently hypotensive but steadily more tachycardiac. This study offers a prototype of 3‐way CHF drug interaction, demonstrates that NIC and NP can be safely combined with acute and chronic FURO and DIG, and shows that these CHF agents minimally affect the cardiovascular responses to NIC and NP in dogs.