bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison of the effects on central 5‐HT function of sibutramine hydrochloride and other weight‐modifying agents
Authors: Heal D J , Cheetham S C , Prow M R , Martin K F , Buckett W R 
Published: January 2005

Effects on 5‐HT function of sibutramine and its active metabolites, BTS 54 354 and BTS 54 505, were compared with fluoxetine, (+)‐fenfluramine and (+)‐amphetamine.
In vitro sibutramine weakly inhibited [3H]‐5‐HT uptake into brain synaptosomes. BTS 54 354, BTS 54 505 and fluoxetine were powerful [3H]‐5‐HT uptake inhibitors, whereas (+)‐fenfluramine and (+)‐amphetamine were very much weaker. Conversely, whilst sibutramine, its metabolites and fluoxetine did not release [3H]‐5‐HT from brain slices at 10−5M, (+)‐fenfluramine and (+)‐amphetamine concentration‐dependently increased [3H]‐5‐HT release.
Sibutramine and fluoxetine had no effect on 5‐hydroxytryptophan (5‐HTP) accumulation in either frontal cortex or hypothalamus at doses <10 mg kg−1. In contrast, (+)‐amphetamine (3 mg kg−1) reduced 5‐HTP in hypothalamus, whilst (+)‐fenfluramine (1 mg kg−1) decreased 5‐HTP in both regions.
Sibutramine (10 mg kg−1 i.p.) and fluoxetine (10 mg kg−1 i.p.) produced slow, prolonged increases of extracellular 5‐HT in the anterior hypothalamus. In contrast, (+)‐fenfluramine (3 mg kg−1 i.p.) and (+)‐amphetamine (4 mg kg−1 i.p.) induced rapid, short‐lasting increases in extracellular 5‐HT.
Only (+)‐fenfluramine (10 mg kg−1) altered 5‐HT2A receptors in rat frontal cortex when given for 14 days, producing a 61% reduction in receptor number and a 18% decrease in radioligand affinity.
These results show that sibutramine powerfully enhances central 5‐HT function via its secondary and primary amine metabolites; this effect, like that of fluoxetine, is almost certainly mediated through 5‐HT uptake inhibition. By contrast, (+)‐fenfluramine enhances 5‐HT function predominantly by increasing 5‐HT release. (+)‐Amphetamine, though weaker than (+)‐fenfluramine, also enhances 5‐HT function by release.

British Journal of Pharmacology (1998) 125, 301–308; doi:10.1038/sj.bjp.0702067
Actions of general anaesthetics and arachidonic acid pathway inhibitors on K+ currents activated by volatile anaesthetics and FMRFamide in molluscan neurones
Authors: Lopes C M B , Franks N P , Lieb W R 
Published: January 2005

K+ currents activated by volatile general anaesthetics (IK(An)) and by the neuropeptide FMRFamide (IK(FMRFa)) were studied under voltage clamp in isolated identified neurones from the pond snail Lymnaea stagnalis.
IK(An) was activated by all the volatile anaesthetics studied. The maximal responses varied from agent to agent, with halothane≈sevoflurane>isoflurane>enflurane≈chloroform.
IK(An) was inhibited rather than activated by the n‐alcohols from hexanol to dodecanol and by the 6‐ and 8‐carbon cycloalcohols. The n‐alcohols exhibited a cutoff effect, with dodecanol being unable to half‐inhibit IK(An).
Unlike IK(An) which did not desensitize at reasonable halothane concentrations, IK(FMRFa) desensitized at most FMRFamide concentrations studied. This desensitization could be substantially removed by halothane. Nonetheless, both IK(An) and IK(FMRFa) had similar sensitivities to the potassium channel blockers tetraethylammonium and 4‐aminopyridine, consistent with both currents flowing through the same channels. Responses to low concentrations of halothane and FMRFamide showed synergy.
The phospholipase A2 inhibitor aristolochic acid inhibited IK(An), consistent with a role for arachidonic acid (AA). The lipoxygenase and cyclooxygenase inhibitor nordihydroguaiaretic acid blocked IK(FMRFa) but did not affect IK(An). IK(An) and IK(FMRFa) were little affected by the cyclooxygenase inhibitor indomethacin. These findings suggest that neither lipoxygenase nor cyclooxygenase pathways of AA metabolism are involved in the anaesthetic activation of IK(An).
Inhibitors of a third, cytochrome P450‐mediated, pathway of AA metabolism (clotrimazole and econazole) potently blocked IK(An), suggesting possible roles for certain cytochrome P450 isoforms in the activation of IK(An).

British Journal of Pharmacology (1998) 125, 309–318; doi:10.1038/sj.bjp.0702069
Blockade of 5‐Hydroxytryptamine and noradrenaline uptake by venlafaxine: a comparative study with paroxetine and desipramine
Authors: Béïque Jean‐Claude , de Montigny Claude , Blier Pierre , Debonnel Guy 
Published: January 2005

Venlafaxine is an antidepressant agent which blocks in vitro the reuptake of both 5‐HT and NA. The present in vivo electrophysiological studies were undertaken, in the rat, to compare the effects of venlafaxine on 5‐HT and NA reuptake to those of the selective 5‐HT reuptake inhibitor paroxetine and the selective NA reuptake inhibitor desipramine.
Administered acutely, venlafaxine dose‐dependently prolonged the time required for a 50% recovery (RT50) of the firing activity of dorsal hippocampus CA3 pyramidal neurons from the suppression induced by microiontophoretic applications of 5‐HT and NA. Venlafaxine and paroxetine increased with a similar potency the RT50 values for 5‐HT, while desipramine was more potent than venlafaxine at increasing the RT50 values for NA. Moreover, venlafaxine demonstrated a greater potency at increasing the RT50 values for 5‐HT compared to that of NA.
A two‐day treatment with venlafaxine (delivered s.c. by osmotic minipumps) increased the RT50 values for both 5‐HT and NA applications. The RT50 values for 5‐HT were significantly increased at a dose of 10 mg kg−1 day−1, whereas those for NA were increased at a dose of 20 mg kg−1 day−1, consistent with the data obtained following the acute administration of venlafaxine.
Taken together, these results indicate that, in vivo, venlafaxine blocks both reuptake processes, with a potency greater for the 5‐HT than for the NA reuptake process. This dual action, combined with the differential potency of venlafaxine, might constitute the biological substratum responsible for its apparent unique clinical efficacy in major depression.

British Journal of Pharmacology (1998) 125, 526–532; doi:10.1038/sj.bjp.0702074
Interactions between inducible isoforms of nitric oxide synthase and cyclo‐oxygenase in vivo: investigations using the selective inhibitors, 1400W and celecoxib
Authors: Hamilton Lorna C , Warner Timothy D 
Published: January 2005

Exposure of tissues to endotoxin (LPS) and/or cytokines leads to the induction of both inducible nitric oxide synthase (iNOS) and cyclo‐oxygenase‐2 (COX‐2). It has previously been reported that there is ‘cross‐talk’ between these two systems. However, such previous studies have been limited by the availability of highly selective inhibitors. Here we have investigated the interactions between iNOS and COX‐2 in vivo using 1400W, an iNOS‐selective inhibitor, and celecoxib, a COX‐2‐selective inhibitor.
Infusion of LPS to rats for 6 h caused a time‐dependent increase in the plasma concentrations of 6 keto‐prostaglandin F1α (6 keto‐PGF1α) and nitrite/nitrate (NO2/NO3), consistent with the induction of iNOS and COX‐2. Bolus injection of arachidonic acid (AA) at t=6 h resulted in a further increase of circulating levels of 6 keto‐PGF1α in LPS‐treated animals.
Treatment of rats with 1400W or the non‐selective NOS inhibitor NG‐monomethyl‐L‐arginine (L‐NMMA) inhibited the increase in plasma NO2/NO3 but were both without effect on the plasma concentration of 6 keto‐PGF1α before or after AA.
Treatment with the non‐steroidal anti‐inflammatory drugs (NSAIDs), A771726 or diclofenac, or with celecoxib significantly reduced the increase in circulating 6 keto‐PGF1α caused by LPS, and the large increase in 6 keto‐PGF1α following injection of AA. None of the COX inhibitors affected the increase in plasma NO2/NO3. Dexamethasone, however, significantly inhibited both the increase in 6 keto‐PGF1α and the increase in NO2/NO3.
In conclusion, the use of selective inhibitors does not support the concept of cross talk in vivo between iNOS and COX‐2.

British Journal of Pharmacology (1998) 125, 335–340; doi:10.1038/sj.bjp.0702077
P2X receptor‐mediated excitation of nociceptive afferents in the normal and arthritic rat knee joint
Authors: Dowd E , McQueen D S , Chessell I P , Humphrey P P A 
Published: January 2005

We tested the hypothesis that functional P2X receptors are present on peripheral terminals of primary afferent articular nociceptors in the rat knee joint. Neural activity was recorded extracellularly from the medial articular nerve innervating the knee joint in rats anaesthetized with pentobarbitone.
The selective P2X receptor agonist, αβ methylene ATP (αβmeATP), and the endogenous ligand, ATP, caused a rapid short‐lasting excitation of a sub‐population of C and Aδ nociceptive afferent nerves innervating normal knee joints when injected intra‐arterially or intra‐articularly, and this effect was antagonized by the non‐selective P2 receptor antagonist PPADS.
Induction of a chronic (14–21 days) unilateral inflammatory arthritis of the knee joint using locally injected Freund's adjuvant neither increased or decreased responsiveness of joint nociceptors to αβmeATP or ATP.
Our results support the hypothesis that αβmeATP‐sensitive P2X receptors are expressed on peripheral nociceptive afferents in the rat knee joint suggesting that they may be involved in the initiation of nociception and pain.

British Journal of Pharmacology (1998) 125, 341–346; doi:10.1038/sj.bjp.0702080
Adaptive changes in the pharmacodynamics of midazolam in different experimental models of epilepsy: kindling, cortical stimulation and genetic absence epilepsy
Authors: Cleton A , Voskuyl R A , Danhof M 
Published: January 2005

The objective of this investigation was to determine quantitatively whether experimental epilepsy is associated with a change in the pharmacodynamics of benzodiazepines in vivo. For that purpose the pharmacodynamics of midazolam were quantified by an integrated pharmacokinetic‐pharmacodynamic approach in three different models of experimental epilepsy: amygdala kindling, cortical stimulation and genetic absence epilepsy.
The time course of the EEG effect was determined in conjunction with the decline of drug concentrations after intravenous administration of 10 mg kg−1 midazolam. The pharmacokinetics of midazolam were most adequately described by a bi‐exponential equation. No influence of epilepsy on the pharmacokinetics of midazolam was observed.
The increase in β activity (11.5–30 Hz) of the EEG as derived by Fast Fourier Transformation analysis was used as pharmacodynamic endpoint. For each individual rat the increase in β activity was directly related to the concentration in blood on the basis of the sigmoidal Emax pharmacodynamic model. In all three models a significant reduction in the maximal effect was observed, in amygdala kindling 28%, in the cortical stimulation model 49% and in genetic absence epilepsy 37%. No differences in the other pharmacodynamic parameters, E0, EC50,u and Hill factor, were observed.
It is inferred that in three different models of epilepsy there is a similar change in GABAergic functioning which is associated with a significant reduction in the intrinsic activity of midazolam in vivo. These models provide therefore a useful basis for further studies on the mechanism of epilepsy‐induced changes in pharmacodynamics of anti‐epileptic drugs.

British Journal of Pharmacology (1998) 125, 615–620; doi:10.1038/sj.bjp.0702088
Mechanism of voltage‐ and use‐dependent block of class A Ca2+ channels by mibefradil
Authors: Aczél S , Kurka B , Hering S 
Published: January 2005

The action of mibefradil was studied on wild type class A calcium (Ca2+) channels and various class A/L‐type channel chimaeras expressed in Xenopus oocytes. The mechanism of Ca2+ channel block by mibefradil was evaluated with two microelectrode voltage clamp.
Resting‐state dependent block (or initial block) of barium currents (IBa) through class A Ca2+ channels was concentration dependent with an IC50 value of 208±23 μM.
Mibefradil (50 μM) did not significantly affect the midpoint voltage of the steady‐state inactivation curve suggesting that inactivation does not promote Ca2+ channel block. Chimaeric class A/L‐type Ca2+ channels inactivating with faster or slower kinetics than wild type class A channels were equally well inhibited by mibefradil as wild type class A channels.
Frequent Ca2+ channel activation facilitated IBa inhibition by mibefradil (use‐dependent block). Recovery from use‐dependent block was voltage‐dependent, being slower at depolarized membrane potentials (τ=75±15 s at −70 mV, (n=6) vs τ=20±2 s at −100 mV, (n=6), P<0.05).
We suggest that use‐dependent block of class A Ca2+ channels by mibefradil occurs because of slow recovery from open channel block (SROB) and not because of drug binding to inactivated channels.
Voltage‐dependent slow recovery from open state‐dependent block provides a molecular basis for understanding the cardiovascular profile of mibefradil such as selectivity for vasculature and relative lack of negative inotropic effects.

British Journal of Pharmacology (1998) 125, 447–454; doi:10.1038/sj.bjp.0702092
Uncoupling of bradykinin‐induced phosphoinositide hydrolysis and Ca2+ mobilization by phorbol ester in canine cultured tracheal epithelial cells
Authors: Yang Chuen‐Mao , Luo Shue‐Fen , Wu Wen‐Bin , Pan Shiow‐Lin , Tsai Yih‐Jeng , Chiu Chi‐Tso , Wang Chuan‐Chwan 
Published: January 2005

Regulation of the increase in inositol phosphates (IPs) production and intracellular Ca2+ concentration ([Ca2+]i by protein kinase C (PKC) was investigated in canine cultured tracheal epithelial cells (TECs). Stimulation of TECs by bradykinin (BK) led to IPs formation and caused an initial transient [Ca2+]i peak in a concentration‐dependent manner.
Pretreatment of TECs with phorbol 12‐myristate 13‐acetate (PMA, 1 μM) for 30 min attenuated the BK‐induced IPs formation and Ca2+ mobilization. The maximal inhibition occurred after incubating the cells with PMA for 2 h.
The concentrations of PMA that gave half‐maximal (pEC50) inhibition of BK‐induced IPs accumulation and an increase in [Ca2+]i were 7.07 M and 7.11 M, respectively. Inactive phorbol ester, 4α‐phorbol 12,13‐didecanoate at 1 μM, did not inhibit these responses. Prior treatment of TECs with staurosporine (1 μM), a PKC inhibitor, inhibited the ability of PMA to attenuate BK‐induced responses, suggesting that the inhibitory effect of PMA is mediated through the activation of PKC.
In parallel with the effect of PMA on the BK‐induced IPs formation and Ca2+ mobilization, the translocation and down‐regulation of PKC isozymes were determined. Analysis of cell extracts by Western blotting with antibodies against different PKC isozymes revealed that TECs expressed PKC‐α, βI, βII, γ, δ, ε, Θ and ζ. With PMA treatment of the cells for various times, translocation of PKC‐α, βI, βII, γ, δ, ε and Θ from cytosol to the membrane was seen after 5 min, 30 min, 2 h, and 4 h treatment. However, 6 h treatment caused a partial down‐regulation of these PKC isozymes. PKC‐ζ was not significantly translocated and down‐regulated at any of the times tested.
Treatment of TECs with 1 μM PMA for either 30 min or 6 h did not significantly change the KD and Bmax receptor for BK binding (control: KD=1.7±0.3 nM; Bmax=50.5±4.9 fmol/mg protein), indicating that BK receptors are not a site for the inhibitory effect of PMA on BK‐induced responses.
In conclusion, these results suggest that activation of PKC may inhibit the phosphoinositide hydrolysis and consequently attenuate the [Ca2+]i increase or inhibit independently both responses to BK. The translocation of pKC‐α, βI, βII, δ, ε, γ, and Θ induced by PMA caused an attenuation of BK‐induced IPs accumulation and Ca2+ mobilization in TECs.

British Journal of Pharmacology (1998) 125, 627–636; doi:10.1038/sj.bjp.0702094
Frequency‐dependent inhibition of neuronal activity by topiramate in rat hippocampal slices
Authors: Wu Shang‐Peng , Tsai Jing‐Jane , Gean Po‐Wu 
Published: January 2005

Topiramate is a structurally novel anticonvulsant which was recently approved for adjunctive therapy in partial and secondarily generalized seizures. The present study was aimed at elucidating the mechanisms underlying the anticonvulsant efficacy of topiramate using intra‐ and extracellular recording techniques in the in vitro hippocampal slices.
When stimuli were delivered every 20 s, topiramate had no measurable effect on both field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs). However, increasing the stimulation frequency from 0.05–0.2 Hz, topiramate significantly decreased the slope of fEPSP and the amplitude of PS in a concentration‐dependent manner. The amplitude of presynaptic fiber volley was also reduced.
Topiramate did not affect the magnitude of paired‐pulse inhibition and monosynaptically evoked inhibitory postsynaptic potentials (IPSPs).
Sustained repetitive firing was elicited by injection of long duration (500 ms) depolarizing current pulses (500–800 pA). Superfusion with topiramate significantly reduced the number of action potentials evoked by a given current pulse.
After blockade of GABA receptors by bicuculline, burst firing which consisted of a train of several spikes riding on a large depolarizing wave termed paroxysmal depolarizing shift (PDS) was recorded. Application of topiramate reduced the duration of PDS and later spikes with less effect on the initial action potential.
These results suggest that frequency‐dependent inhibition of neuronal activity due to blockade of Na+ channels may account largely for the anticonvulsant efficacy of topiramate.

British Journal of Pharmacology (1998) 125, 826–832; doi:10.1038/sj.bjp.0702096
Enhanced acetylcholine induced relaxation in small mesenteric arteries from pregnant rats: an important role for endothelium‐derived hyperpolarizing factor (EDHF)
Authors: Gerber R T , Anwar M A , Poston L 
Published: January 2005

Small mesenteric arteries from pregnant rats demonstrated greater sensitivity (pEC50 : P<0.001) and maximum relaxation (P<0.01) to acetylcholine (ACh) than those of control non‐pregnant animals.
Maximum relaxation, but not sensitivity, to ACh remained greater (P<0.01) in pregnant animals when evaluated in 25 mM KCl, which prevents relaxation dependent upon hyperpolarization. ACh induced relaxation in the presence of 25 mM KCl was completely inhibited in pregnant and non‐pregnant groups by Nω‐nitro L‐arginine methyl ester (L‐NAME, 100 μM), indomethacin (INDO, 10 μM) and oxadiazole quinoxalin (ODQ, 1 μM), suggesting pregnancy associated enhancement of dilator prostanoid and/or nitric oxide (NO) synthesis.
ACh induced relaxation in 5 mM KCl was only partially inhibited by a combination of Nω‐nitro L‐arginine methyl ester (L‐NAME, 100 μM), indomethacin (INDO, 10 μM) and oxadiazole quinoxalin (ODQ, 1 μM). The residual relaxation, which was greater in arteries from pregnant rats (maximum relaxation: P<0.01), was prevented by 25 mM KCl, indicating pregnancy associated enhanced synthesis/reduced degradation of a hyperpolarizing factor. Residual relaxation to ACh in 5 mM KCl was inhibited by the cytochrome P450 inhibitor, proadifen (1 μM) in the pregnant group (P<0.001).
Relaxation to spermine NONOate was similar in pregnant and non‐pregnant groups and totally inhibited by ODQ (in the presence of L‐NAME).
This study suggests that, in addition to enhanced endothelium dependent NO/dilator prostanoid synthesis, a hyperpolarizing factor may contribute to the vascular adaptation to pregnancy.

British Journal of Pharmacology (1998) 125, 455–460; doi:10.1038/sj.bjp.0702099
Effects of the Aconitum alkaloid songorine on synaptic transmission and paired‐pulse facilitation of CA1 pyramidal cells in rat hippocampal slices
Authors: Ameri Angela 
Published: January 2005

The present study investigated the electrophysiological effects of songorine (1–100 μM), an alkaloid occurring in plants of the Aconitum genus, in rat hippocampal slices.
Songorine (10–100 μM) evoked a concentration‐dependent increase in the amplitude of the orthodromic population spike and in the slope of the field e.p.s.p. The enhancement was long‐lasting and was not reversed by up to 90 min of washout. Songorine failed to affect size and shape of the presynaptic fiber spike which represents the compound action potential of the Schaffer collaterals. This indicates that enhancement of the synaptic response is no consequence of an increased afferent excitability.
The antidromically evoked population spike was not affected by songorine at concentrations up to 100 μM suggesting that the enhancement of the orthodromic population spike and of the field e.p.s.p. was not due to an increase in pyramidal cell excitability.
The input‐output curve for the postsynaptic population spike was shifted to the left implying that a presynaptic fiber spike of the same size elicited a larger postsynaptic response, indicating a decrease in threshold for generation of the population spike.
The songorine‐evoked increase in excitability was not affected by the NMDA receptor antagonist, D‐AP5. However, the effect of songorine was completely abolished by the selective dopamine D2 receptor antagonist sulpiride (0.1 μM) as well as by haloperidol (10 μM) and was mimicked by application of the dopamine releaser, amantadine (100 mM). In contrast, the selective D1 receptor antagonist, SCH23390, did not block the action of songorine.
The results indicate that the plant alkaloid songorine enhances excitatory synaptic transmission which may be due to an agonistic action at D2 receptors.

British Journal of Pharmacology (1998) 125, 461–468; doi:10.1038/sj.bjp.0702100
Haemodynamic effects of a selective adenosine A2A receptor agonist, CGS 21680, in chronic heart failure in anaesthetized rats
Authors: Nekooeian Ali A , Tabrizchi Reza 
Published: January 2005

Recently we demonstrated that the administration of an A2A adenosine receptor agonist, CGS 21680, to anaesthetized rats with acute heart failure (1 h post‐coronary artery ligation) resulted in an increase in cardiac output. In the present investigation, the effects of CGS 21680 on cardiac output, vascular resistance, heart rate, blood pressure and mean circulatory filling pressure (Pmcf) were investigated in anaesthetized rats with chronic heart failure (8 weeks post‐coronary artery ligation).
Experiments were conducted in five groups (n=6) of animals: sham‐operated vehicle‐treated (0.9% NaCl; 0.037 mL kg−1 min−1) animals in which the occluder was placed but not pulled to ligate the coronary artery; coronary artery‐ligated vehicle‐treated animals; and coronary artery‐ligated CGS 21680‐treated (0.1, 0.3 or 1.0 μg kg−1 min−1) animals.
Baseline blood pressure, cardiac output and rate of rise in left ventricular pressure (+dP/dt) were significantly reduced in animals with coronary artery ligation when compared to sham‐operated animals. Coronary artery ligation resulted in a significant increase in left ventricular end‐diastolic pressure, Pmcf and venous resistance when compared to sham‐operated animals.
Administration of CGS 21680 at 0.3 and 1.0 μg kg−1 min−1 significantly (n=6; P<0.05) increased cardiac output by 19±4% and 39±5%, and heart rate by 14±2% and 15±1%, respectively, when compared to vehicle treatment in coronary artery‐ligated animals. Administration of CGS 21680 also significantly reduced blood pressure and arterial resistance when compared to coronary artery‐ligated vehicle‐treated animals. Infusion of CGS 21680 also significantly reduced venous resistance when compared to vehicle‐treated coronary artery‐ligated animals.
The results show that heart failure is characterized by reduced cardiac output, and increased left ventricular end‐diastolic pressure, venous resistance and Pmcf. Acute treatment with CGS 21680 in animals with chronic heart failure decreased left ventricular end‐diastolic pressure and increased cardiac output. This increase in cardiac output was the result of reduced arterial and venous resistances and increased heart rate.

British Journal of Pharmacology (1998) 125, 651–658; doi:10.1038/sj.bjp.0702105