bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological diversity between native human 5‐HT1B and 5‐HT1D receptors sited on different neurons and involved in different functions
Authors: Marcoli Manuela , Maura Guido , Munari Claudio , Ruelle Antonio , Raiteri Maurizio 
Published: January 2005

The releases of [3H]5‐hydroxytryptamine ([3H]5‐HT) and of endogenous glutamic acid and their modulation through presynaptic h5‐HT1B autoreceptors and h5‐HT1D heteroreceptors have been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery.
The inhibition by 5‐HT of the K+ (15 mM)‐evoked overflow of [3H]5‐HT was antagonized by the 5‐HT1B/5‐HT1D receptor ligand GR 127935, which was ineffective on its own; this drug was previously found to behave as a full agonist at the h5‐HT1D heteroreceptor regulating glutamate release.
The recently proposed selective h5‐HT1B receptor ligand SB‐224289 also prevented the effect of 5‐HT at the autoreceptor, being inactive on its own; in contrast, SB‐224289, at 1 μM, was unable to interact with the h5‐HT1D heteroreceptor.
The inhibitory effect of 5‐HT on the K+‐evoked overflow of glutamate was antagonized by the h5‐HT1D receptor ligand BRL‐15572; added in the absence of 5‐HT the compound was without effect. BRL‐15572 (1 μM) was unable to modify the effect of 5‐HT at the autoreceptor regulating [3H]5‐HT release.
The selective 5‐HT1A receptor antagonist (+)‐WAY 100135, previously found to be an agonist at the h5‐HT1D heteroreceptor regulating glutamate release, could not interact with the h5‐HT1B autoreceptor when added at 1 μM.
It is concluded that native h5‐HT1B and h5‐HT1D receptors exhibit a hitherto unexpected pharmacological diversity.

British Journal of Pharmacology (1999) 126, 607–612; doi:10.1038/sj.bjp.0702336
Effects of a new C5a receptor antagonist on C5a‐ and endotoxin‐ induced neutropenia in the rat
Authors: Short Anna , Wong Allan K , Finch Angela M , Haaima Gerald , Shiels Ian A , Fairlie David P , Taylor Stephen M 
Published: January 2005

A new C5a receptor antagonist, the cyclic peptide Phe‐[Orn‐Pro‐D‐cyclohexylalanine‐Trp‐Arg], (F‐[OPdChaWR]), was tested for its ability to antagonize the neutropenic effects of both C5a and endotoxin in rats. Human recombinant C5a (2 μg kg−1 i.v.) caused rapid neutropenia, characterized by an 83% decrease in circulating polymorphonuclear leukocytes (PMNs) at 5 min. Administration of F‐[OPdChaWR] (0.3–3 mg kg−1 i.v.), did not affect the levels of circulating PMNs but, when given 10 min prior to C5a, it inhibited the C5a‐induced neutropenia by up to 70%. Administration of E. Coli lipopolysaccharide (LPS, 1 mg kg−1 i.v.) also caused neutropenia with an 88% decrease in circulating PMNs after 30 min. When rats were pretreated with F‐[OPdChaWR] (0.3–10 mg kg−1 i.v.) 10 min prior to LPS, there was a dose‐dependent antagonism of the neutropenia caused by LPS, with up to 69% reversal of neutropenia observed 30 min after LPS administration. These findings suggest that C5a receptor antagonists may have therapeutic potential in the many diseases known to involve either endotoxin or C5a.British Journal of Pharmacology (1999) 126, 551–554; doi:10.1038/sj.bjp.0702338
Inhibition of inducible nitric oxide synthase by β‐lapachone in rat alveolar macrophages and aorta
Authors: Liu Shing‐Hwa , Tzeng Huei‐Ping , Kuo Min‐Liang , Lin‐Shiau Shoei‐Yn 
Published: January 2005

β‐Lapachone, a plant product, has been shown to be a novel inhibitor of DNA topoisomerase. In this study, we performed experiments to examine the effects of β‐lapachone on lipopolysaccharide (LPS)‐induced inducible nitric oxide (NO) synthase (iNOS) in rat alveolar macrophages and aortic rings.
In alveolar macrophages, incubation with LPS (10 μg ml−1) for various time intervals resulted in a significant increase in nitrite production and iNOS protein synthesis, that was inhibited by co‐incubation with β‐lapachone (1–4.5 μM) without any cytotoxic effects. However, addition of β‐lapachone after induction of NO synthase by LPS failed to affect the nitrite production.
Treatment with LPS (10 μg ml−1) for 6 h resulted in significant expression of mRNA for iNOS which was significantly inhibited in the presence of β‐lapachone (3 μM) in alveolar macrophages.
In endothelium‐intact rings of thoracic aorta, β‐lapachone (1 and 3 μM) markedly inhibited the hypocontractility to phenylephrine in aortic rings treated with LPS (10 μg ml−1) for 4 h. When β‐lapachone was added 3 h after LPS into the medium, the contractions evoked by phenylephrine were not significantly different in the presence or absence of β‐lapachone.
Treatment with LPS (10 μg ml−1) for 4 h resulted in a significant increase in iNOS protein synthesis which was inhibited in the presence of β‐lapachone (3 μM), but did not affect the constitutive (endothelial and neuronal) NOS forms in aortic rings.
These results indicate that β‐lapachone is capable of inhibiting expression and function of iNOS in rat alveolar macrophages and aortic rings. It is considered that β‐lapachone can be developed as a potential anti‐inflammatory agent in the future.

British Journal of Pharmacology (1999) 126, 746–750; doi:10.1038/sj.bjp.0702341
Assessment of the effects of endothelin‐1 and magnesium sulphate on regional blood flows in conscious rats, by the coloured microsphere reference technique
Authors: Kemp P A , Gardiner S M , March J E , Rubin P C , Bennett T 
Published: January 2005

There is evidence to suggest that magnesium (Mg2+) is beneficial in the treatment of a number of conditions, including pre‐eclampsia and acute myocardial infarction. The mode of action of Mg2+ in these conditions is not clear, although the vasodilator properties of Mg2+ are well documented both in vitro and in vivo.
Previously, we demonstrated that i.v. infusion of magnesium sulphate (MgSO4) alone, or in the presence of vasoconstrictors, caused increases in flow and conductance in the common carotid, internal carotid and hindquarters vascular beds, in conscious rats. Therefore, the objective of the present study was to investigate the regional and subregional changes in haemodynamics in response to the vasoconstrictor peptide endothelin‐1 (ET‐1) and MgSO4 in more detail, using the coloured microsphere reference technique.
Infusion of ET‐1 and MgSO4 had similar effects on heart rate and mean arterial pressure as in our previous study. Infusion of ET‐1 caused a rise in mean arterial pressure and a fall in heart rate, and infusion of MgSO4 returned mean arterial pressure to control levels with no effect on heart rate.
The responses to MgSO4 in the presence of ET‐1 showed considerable regional heterogeneity with blood flow increasing (e.g. skeletal muscle), decreasing (e.g. stomach) or not changing (e.g. kidney). Of particular interest was the finding that MgSO4 caused increases in flow in the cerebral and coronary vascular beds.
This, and our previous studies, have shown that MgSO4 can reverse vasoconstriction in a number of vascular beds, and indicate that this compound may have therapeutic benefit in conditions associated with vasospasm.

British Journal of Pharmacology (1999) 126, 621–626; doi:10.1038/sj.bjp.0702342
Attenuation of haloperidol‐induced catalepsy by a 5‐HT2C receptor antagonist
Authors: Reavill C , Kettle A , Holland V , Riley G , Blackburn T P 
Published: January 2005

Atypical neuroleptics produce fewer extrapyramidal side‐effects (EPS) than typical neuroleptics. The pharmacological profile of atypical neuroleptics is that they have equivalent or higher antagonist affinity for 5‐HT2 than for dopamine D2 receptors. Our aim was to identify which 5‐HT2 receptor contributed to the atypical profile. Catalepsy was defined as rats remaining immobile over a horizontal metal bar for at least 30 s, 90 min after dosing. Radioligand binding assays were carried out with homogenates of human recombinant 5‐HT2A, 5‐HT2B and 5‐HT2C receptors expressed in Human Embryo Kidney (HEK293) cells. Haloperidol (1.13 mg kg−1 i.p.) induced catalepsy in all experiments. The selective 5‐HT2C/2B receptor antagonist, SB‐228357 (0.32–10 mg kg−1 p.o.) significantly reversed haloperidol‐induced catalepsy whereas the 5‐HT2A and 5‐HT2B receptor antagonists, MDL‐100907 (0.003–0.1 mg kg−1 p.o.) and SB‐215505 (0.1–3.2 mg kg−1 p.o.) respectively did not reverse haloperidol‐induced catalepsy. The data suggest a role for 5‐HT2C receptors in the anticataleptic action of SB‐228357.British Journal of Pharmacology (1999) 126, 572–574; doi:10.1038/sj.bjp.0702350
Roles of oxygen radicals and elastase in citric acid‐induced airway constriction of guinea‐pigs
Authors: Lai Y ‐L , Chiou W ‐Y , Lu F J , Chiang L Y 
Published: January 2005

Antioxidants attenuate noncholinergic airway constriction. To further investigate the relationship between tachykinin‐mediated airway constriction and oxygen radicals, we explored citric acid‐induced bronchial constriction in 48 young Hartley strain guinea‐pigs, divided into six groups: control; citric acid; hexa(sulphobutyl)fullerenes+citric acid; hexa(sulphobutyl)fullerenes+phosphoramidon+citric acid; dimethylthiourea (DMTU)+citric acid; and DMTU+phosphoramidon+citric acid. Hexa(sulphobutyl)fullerenes and DMTU are scavengers of oxygen radicals while phosphoramidon is an inhibitor of the major degradation enzyme for tachykinins.
Animals were anaesthetized, paralyzed, and artificially ventilated. Each animal was given 50 breaths of 4 ml saline or citric acid aerosol. We measured dynamic respiratory compliance (Crs), forced expiratory volume in 0.1 (FEV0.1), and maximal expiratory flow at 30% total lung capacity (V[dot above]max30) to evaluate the degree of airway constriction.
Citric acid, but not saline, aerosol inhalation caused marked decreases in Crs, FEV0.1 and V[dot above]max30, indicating marked airway constriction. This constriction was significantly attenuated by either hexa(sulphobutyl)fullerenes or by DMTU. In addition, phosphoramidon significantly reversed the attenuating action of hexa(sulphobutyl)fullerenes, but not that of DMTU.
Citric acid aerosol inhalation caused increases in both lucigenin‐ and t‐butyl hydroperoxide‐initiated chemiluminescence counts, indicating citric acid‐induced increase in oxygen radicals and decrease in antioxidants in bronchoalveolar lavage fluid. These alterations were significantly suppressed by either hexa(sulphobutyl)fullerenes or DMTU.
An elastase inhibitor eglin‐c also significantly attenuated citric acid‐induced airway constriction, indicating the contributing role of elastase in this type of constriction.
We conclude that both oxygen radicals and elastase play an important role in tachykinin‐mediated, citric acid‐induced airway constriction.

British Journal of Pharmacology (1999) 126, 778–784; doi:10.1038/sj.bjp.0702352
Dual coupling of heterologously‐expressed rat P2Y6 nucleotide receptors to N‐type Ca2+ and M‐type K+ currents in rat sympathetic neurones
Authors: Filippov Alexander K , Webb Tania E , Barnard Eric A , Brown David A 
Published: January 2005

The P2Y6 receptor is a uridine nucleotide‐specific G protein‐linked receptor previously reported to stimulate the phosphoinositide (PI) pathway. We have investigated its effect in neurones, by micro‐injecting its cRNA into dissociated rat sympathetic neurones and recording responses of N‐type Ca2+ (ICa(N)) and M‐type K+ (IK(M)) currents.
In P2Y6 cRNA‐injected neurones, UDP or UTP produced a voltage‐dependent inhibition of ICa(N) by ∼53% in whole‐cell (disrupted‐patch) mode and by ∼73% in perforated‐patch mode; no inhibition occurred in control cells. Mean IC50 values (whole‐cell) were: UDP, 5.9±0.3 nM; UTP, 20±1 nM. ATP and ADP (1 μM) had no significant effect. Pertussis toxin (PTX) substantially (∼60%) reduced UTP‐mediated inhibition in disrupted patch mode but not in perforated‐patch mode.
Uridine nucleotides also inhibited IK(M) in P2Y6 cRNA‐injected cells (by up to 71% at 10 μM UTP; perforated‐patch). Mean IC50 values were: UDP, 30±3 nM; UTP, 115±12 nM. ATP (10 μM) again had no effect. No significant inhibition occurred in control cells. Inhibition was PTX‐resistant.
Thus, the P2Y6 receptor, like the P2Y2 subtype studied in this system, couples to both of these two neuronal ion channels through at least two different G proteins. However, the P2Y6 receptor displays a much higher sensitivity to its agonists than the P2Y2 receptor in this expression system and higher than previously reported using other expression methods. The very high sensitivity to both UDP and UTP suggests that it might be preferentially activated by any locally released uridine nucleotides.

British Journal of Pharmacology (1999) 126, 1009–1017; doi:10.1038/sj.bjp.0702356
An in vitro electrophysiological study on the effects of phenytoin, lamotrigine and gabapentin on striatal neurons
Authors: Calabresi P , Centonze D , Marfia G A , Pisani A , Bernardi G 
Published: January 2005

We performed intracellular recordings from a rat corticostriatal slice preparation in order to compare the electrophysiological effects of the classical antiepileptic drug (AED) phenytoin (PHT) and the new AEDs lamotrigine (LTG) and gabapentin (GBP) on striatal neurons.
PHT, LTG and GBP affected neither the resting membrane potential nor the input resistance/membrane conductance of the recorded cells. In contrast, these agents depressed in a dose‐dependent and reversible manner the current‐evoked repetitive firing discharge.
These AEDs also reduced the amplitude of glutamatergic excitatory postsynaptic potentials (EPSPs) evoked by cortical stimulation. However, substantial pharmacological differences between these drugs were found. PHT was the most effective and potent agent in reducing sustained repetitive firing of action potentials, whereas LTG and GBP preferentially inhibited corticostriatal excitatory transmission. Concentrations of LTG and GBP effective in reducing EPSPs, in fact, produced only a slight inhibition of the firing activity of these cells.
LTG, but not PHT and GBP, depressed cortically‐evoked EPSPs increasing paired‐pulse facilitation (PPF) of synaptic transmission, suggesting that a presynaptic site of action was implicated in the effect of this drug. Accordingly, PHT and GBP, but not LTG reduced the membrane depolarizations induced by exogenously‐applied glutamate, suggesting that these drugs preferentially reduce postsynaptic sensitivity to glutamate released from corticostriatal terminals.
These data indicate that in the striatum PHT, LTG and GBP decrease neuronal excitability by modulating multiple sites of action. The preferential modulation of excitatory synaptic transmission may represent the cellular substrate for the therapeutic effects of new AEDs whose use may be potentially extended to the therapy of neurodegenerative diseases involving the basal ganglia.

British Journal of Pharmacology (1999) 126, 689–696; doi:10.1038/sj.bjp.0702361
Aryl propanolamines: comparison of activity at human β3 receptors, rat β3 receptors and rat atrial receptors mediating tachycardia
Authors: Cohen Marlene L , Bloomquist William , Kriauciunas Aidas , Shuker Anthony , Calligaro David 
Published: January 2005

The in vitro activity of four aryl propanolamines was compared to two prototypic β3 receptor agonists, CGP 12177 and CL316243 at the human β3 receptor, the rat β3 receptor in the stomach fundus and receptors mediating atrial tachycardia.
L‐739,574 was the most potent (EC50=9 nM) and selective agonist at the human β3 receptor with high maximal response (74% of the maximal response to isoproterenol).
A phenol‐biaryl ether analogue possessed modest affinity for the human β3 receptor (EC50=246 nM), but was highly efficacious with a maximal response 82% of the maximal response to isoproterenol. The other derivatives were intermediate in potency with low maximal responses.
These agonists at the human β3 receptor did not activate the rat β3 receptor in the rat stomach fundus. In fact, the aryl propanolamines (10−6 M) inhibited CL316243‐induced activation of the rat β3 receptor. Thus, agonist activity at the human β3 receptor translated into antagonist activity at the rat β3 receptor.
L739,574 and the phenol biaryl ether increased heart rate via β1 receptors.
Although CGP12177 produced atrial tachycardia, neither the indole sulphonamide nor biphenyl biaryl ether did, although both had high affinity for the human β3 receptor. Thus, the atrial tachycardic receptor was not identical to the human β3 receptor.
These studies (a) characterized four aryl propanolamines with high affinity at the human β3 receptor, (b) found that they were antagonists at the rat β3 receptor, an observation with profound implications for in vivo rat data, and (c) established that the rodent atrial non‐β1, β2 or β3 tachycardic receptor was also unrelated to the human β3 receptor.

British Journal of Pharmacology (1999) 126, 1018–1024; doi:10.1038/sj.bjp.0702364
Studies on the role of dopamine in the degeneration of 5‐HT nerve endings in the brain of Dark Agouti rats following 3,4‐methylenedioxymethamphetamine (MDMA or ‘ecstasy’) administration
Authors: Colado M I , O'Shea E , Granados R , Esteban B , Martín A B , Green A R 
Published: January 2005

We investigated whether dopamine plays a role in the neurodegeneration of 5‐hydroxytryptamine (5‐HT) nerve endings occurring in Dark Agouti rat brain after 3,4‐methylenedioxymethamphetamine (MDMA or ‘ecstasy’) administration.
Haloperidol (2 mg kg−1 i.p.) injected 5 min prior and 55 min post MDMA (15 mg kg−1 i.p.) abolished the acute MDMA‐induced hyperthermia and attenuated the neurotoxic loss of 5‐HT 7 days later. When the rectal temperature of MDMA+haloperidol treated rats was kept elevated, this protective effect was marginal.
MDMA (15 mg kg−1) increased the dopamine concentration in the dialysate from a striatal microdialysis probe by 800%. L‐DOPA (25 mg kg−1 i.p., plus benserazide, 6.25 mg kg−1 i.p.) injected 2 h after MDMA (15 mg kg−1) enhanced the increase in dopamine in the dialysate, but subsequent neurodegeneration was unaltered. L‐DOPA (25 mg kg−1) injected before a sub‐toxic dose of MDMA (5 mg kg−1) failed to induce neurodegeneration.
The MDMA‐induced increase in free radical formation in the hippocampus (indicated by increased 2,3‐ and 2,5‐dihydroxybenzoic acid in a microdialysis probe perfused with salicylic acid) was unaltered by L‐DOPA.
The neuroprotective drug clomethiazole (50 mg kg−1 i.p.) did not influence the MDMA‐induced increase in extracellular dopamine.
These data suggest that previous observations on the protective effect of haloperidol and potentiating effect of L‐DOPA on MDMA‐induced neurodegeneration may have resulted from effects on MDMA‐induced hyperthermia.
The increased extracellular dopamine concentration following MDMA may result from effects of MDMA on dopamine re‐uptake, monoamine oxidase and 5‐HT release rather than an ‘amphetamine‐like’ action on dopamine release, thus explaining why the drug does not induce degeneration of dopamine nerve endings.

British Journal of Pharmacology (1999) 126, 911–924; doi:10.1038/sj.bjp.0702373
Investigation of the inhibitory effects of homocysteine and copper on nitric oxide‐mediated relaxation of rat isolated aorta
Authors: Emsley Alison M , Jeremy Jamie Y , Gomes Guiomar N , Angelini Gianni D , Plane Frances 
Published: January 2005

Elevated plasma levels of homocysteine (HC) and copper have both been associated with the development of inflammatory vascular diseases, such as atherosclerosis. In this study, the effects of a combination of HC and copper on nitric oxide (NO)‐mediated relaxation of isolated rat aortic rings were investigated.
Exposure to HC (10–100 μM; 30 min) had no effect on relaxation to acetylcholine (ACh; 0.01–10 μM, n=4). Pre‐incubation of aortic rings with a higher concentration of HC for an extended period (1 mM; 180 min) significantly inhibited endothelium‐dependent relaxation (n=4), but this inhibition was prevented by the presence of the copper chelator bathocuprione (10 μM, 180 min, n=6).
Exposure to HC (100 μM) and copper (10–100 μM; 30 min) caused a copper concentration‐dependent inhibition of endothelium‐dependent relaxation (n=4). This inhibitory effect was reduced in the presence of either superoxide dismutase (SOD; 100 u ml−1; n=4) or catalase (100 u ml−1; n=4), and further reduced by the presence of both enzymes (n=5).
HC and copper (100 μM; 30 min) significantly inhibited endothelium‐independent relaxation to glyceryl trinitrate (0.01–10 μM; n=8). In contrast, HC (1 mM), alone or in combination with copper (100 μM), did not inhibit relaxation to the endothelium‐independent relaxant sodium nitroprusside (0.01–10 μM; n=4).
These data indicate that the presence of copper greatly enhances the inhibitory actions of HC on NO‐mediated relaxation of isolated aortic rings. The reduction of inhibition by catalase and SOD indicates a possible role for copper‐catalyzed generation of superoxide and hydrogen peroxide leading to an increased inactivation or decreased production of endothelium‐derived NO.

British Journal of Pharmacology (1999) 126, 1034–1040; doi:10.1038/sj.bjp.0702374
G‐protein activation by putative antagonists at mutant Thr373Lys α2A adrenergic receptors
Authors: Wurch T , Colpaert F C , Pauwels P J 
Published: January 2005

Replacement of a threonine by a lysine at position 373 in the C‐terminal portion of the third intracellular loop of the human α2A‐adrenergic receptor (α2A AR) has been reported to generate a constitutively active mutant receptor in analogy with similar mutations in the α1B and β2 AR (Ren et al., 1993). In the present study, the mutant Thr373Lys α2A AR receptor was investigated by measuring the formation of inositol phosphates in either the absence or presence of mouse Gα15 protein in Cos‐7 cells.
Increased affinity, potency and/or efficacy for the agonists [(−)‐adrenaline, UK 14304, clonidine, guanabenz and oxymetazoline] was observed, consistent with a precoupled mutant α2A AR: G‐protein state. The basal inositol phosphates response was similar at the wild‐type (wt) and mutant α2A AR, but was enhanced at the mutant α2A AR upon co‐expression with the mouse Gα15 protein. This enhanced response could not be attenuated in the presence of any of the tested α2 AR antagonists (10 μM), suggesting that inverse agonist activity did not occur at the mutant α2A AR.
Ligands that so far have been identified as antagonists at the wt α2A AR demonstrated either no intrinsic activity (MK 912, WB 4101, RS 15385, RX 811059 and RX 821002) or positive efficacy [Emax, % vs. 1 μM UK 14304: dexefaroxan (27±7), idazoxan (34±9), atipamezole (27±4), BRL 44408 (59±5) and SKF 86466 (54±9)] at the mutant α2A AR, but only in the presence of the mouse Gα15 protein. The ligand potencies corresponded with their respective pKi values at the mutant α2A AR receptor.
The partial agonist effect of SKF 86466 was resistant to pertussis toxin treatment (100 ng ml−1) and not affected by co‐expression of the rat Gαi1 protein. It was virtually absent in the presence of 10 μM RS 15385. SKF 86466 was without intrinsic activity upon co‐expression of the mouse Gαq protein.
Some putative α2 AR antagonists exerted a partial agonist activity that was highly dependent on the presence of specific G‐protein α‐subunits, suggesting that these ligands cause selective G‐protein activation at the mutant α2A AR.

British Journal of Pharmacology (1999) 126, 939–948; doi:10.1038/sj.bjp.0702379