bluuebunny/crossref_metadata_2025_split huggingface dataset:
HMG‐CoA reductase inhibitors and P‐glycoprotein modulation
Authors: Bogman Katrijn , Peyer Anne‐Kathrin , Török Michael , Küsters Ernst , Drewe Jürgen 
Published: January 2005

Five 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitors (statins), (e.g. atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin), were investigated for their ability to reverse P‐glycoprotein (P‐gp) mediated rhodamine 123 (R123) transport in a murine monocytic leukaemia cell line that over‐expresses the multi‐drug resistance protein 1a/b (mdr1a/1b).
P‐gp modulation was studied by a fluorimetric assay and confocal microscopy by means of R123 efflux and uptake experiments, respectively.
Atorvastatin acid, methyl ester and lactone, lovastatin lactone and simvastatin lactone inhibited R123 transport in a concentration‐dependent manner. Lovastatin acid, simvastatin acid, fluvastatin and pravastatin did not show a significant inhibition of the R123 transport in our cell system. Atorvastatin methyl ester and lactone showed the highest affinities for P‐gp and results were comparable for both methods.
In conclusion, monitoring of R123 transport in living cells by confocal microscopy in addition to fluorimetric assay is a sensitive tool to study P‐gp affinity in drug screening that is especially useful for early phases of drug development.

British Journal of Pharmacology (2001) 132, 1183–1192; doi:10.1038/sj.bjp.0703920
Inhibitory effect of 2,3‐butanedione monoxime (BDM) on Na+/Ca2+exchange current in guinea‐pig cardiac ventricular myocytes
Authors: Watanabe Yasuhide , Iwamoto Takahiro , Matsuoka Isao , Ohkubo Satoko , Ono Tomoyuki , Watano Tomokazu , Shigekawa Munekazu , Kimura Junko 
Published: January 2005

The effect of 2,3‐butanedione monoxime (BDM), a ‘chemical phosphatase’, on Na+/Ca2+exchange current (INCX) was investigated using the whole‐cell voltage‐clamp technique in single guinea‐pig cardiac ventricular myocytes and in CCL39 fibroblast cells expressing canine NCX1.INCXwas identified as a current sensitive to KB‐R7943, a relatively selective NCX inhibitor, at 140 mMNa+and 2 mMCa2+in the external solution and 20 mMNa+and 433 nMfree Ca2+in the pipette solution.In guinea‐pig ventricular cells, BDM inhibitedINCXin a concentration‐dependent manner. The IC50value was 2.4 mMwith a Hill coefficients of 1. The average time for 50% inhibition by 10 mMBDM was 124±31 s (n=5).The effect of BDM was not affected by 1 μMokadaic acid in the pipette solution, indicating that the inhibition was notviaactivation of okadaic acid‐sensitive protein phosphatases.Intracellular trypsin treatmentviathe pipette solution significantly suppressed the inhibitory effect of BDM, implicating an intracellular site of action of BDM.PAM (pralidoxime), another oxime compound, also inhibitedINCXin a manner similar to BDM.Isoprenaline at 50 μMand phorbol 12‐myristate 13‐acetate (PMA) at 8 μMdid not reverse the inhibition ofINCXby BDM.BDM inhibitedINCXin CCL39 cells expressing NCX1 and in its mutant in which its three major phosphorylatable serine residues were replaced with alanines.We conclude that BDM inhibitsINCXbut the mechanism of inhibition is not by dephosphorylation of the Na+/Ca2+exchanger as a ‘chemical phosphatase’.British Journal of Pharmacology(2001)132, 1317–1325; doi:10.1038/sj.bjp.0703926
Inhibition of aggregation of rabbit and human platelets induced by adrenaline and 5‐hydroxytryptamine by KB‐R7943, a Na+/Ca2+ exchange inhibitor
Authors: Takano Shizuko , Kimura Junko , Ono Tomoyuki 
Published: January 2005

We investigated the effect of KB‐R7943, a Na+/Ca2+ exchange inhibitor, on the aggregation response induced by adrenaline and 5‐hydroxytryptamine (5‐HT), alone or in combination in human and rabbit platelets in the presence or absence of ouabain.
KB‐R7943 inhibited aggregation induced by the combination of adrenaline and 5‐HT in a concentration‐dependent manner. The IC50 values of KB‐R7943 were 4.2±2.0 or 3.0±0.7 μM with washed rabbit platelets with or without ouabain pretreatment, respectively.
In platelet‐rich human plasma, the aggregation was biphasic. The IC50 value of KB‐R7943 was 17.2±4.4 μM for the first phase aggregation.
KB‐R7943 did not inhibit the first phase of aggregation induced by adrenaline alone, or the monophasic aggregation induced by 5‐HT alone.
The aggregation of rabbit platelets depended on the presence of K+ in the medium, and K+‐dependent and K+‐independent Ca2+ influx were observed in resting platelets. Ouabain treatment increased only the K+‐dependent but not the K+‐independent Ca2+ influx.
KB‐R7943 inhibited K+‐dependent Ca2+ influx with or without ouabain pretreatment, but not K+‐independent Ca2+ influx.
From these results, we conclude that KB‐R7943 inhibits the adrenaline plus 5‐HT induced aggregation of rabbit and human platelets by inhibiting K+‐dependent Na+/Ca2+ exchange (NCKX). Our results suggest that NCKX plays an important role in platelet aggregation.

British Journal of Pharmacology (2001) 132, 1383–1388; doi:10.1038/sj.bjp.0703928
Investigation of mechanisms that mediate reactive hyperaemia in guinea‐pig hearts: role of KATP channels, adenosine, nitric oxide and prostaglandins
Authors: Kingsbury M P , Robinson H , Flores N A , Sheridan D J 
Published: January 2005

Reactive hyperaemia is a transient vasodilatation following a brief ischaemic period. ATP‐dependent K+ (KATP) channels may be important in mediating this response, however it is unclear whether mitochondrial KATP channels contribute to this in the heart.
We examined the involvement of KATP channels and the relative role of mitochondrial channels as mediators of coronary reactive hyperaemia and compared them to mechanisms involving NO, prostaglandins and adenosine in the guinea‐pig isolated heart.
Reactive hyperaemic vasodilatation (peak vasodilator response and flow debt repayment) were assessed after global zero‐flow ischaemia (5 – 120 s) in the presence of nitro‐L‐arginine methyl ester (L‐NAME, 10−5 M, n=9), 8‐phenyltheophylline (8‐PT, 10−6 M, n=12) and indomethacin (10−5 M, n=12). Glibenclamide (10−6 M, n=12) a non‐selective KATP channel inhibitor and 5‐hydroxy‐decanoic acid (5‐HD, 10−4 M, n=10) a selective mitochondrial KATP channel inhibitor were also used. The specificity of the effects of glibenclamide and 5‐HD (n=6 each) were confirmed using pinacidil (38 nmol – 10 μmol) and diazoxide (42 nmol – 2 μmol).
Glibenclamide was most effective in blocking the hyperaemic response (by 87%, P<0.001) although 5‐HD and 8‐PT also had a marked effect (40% inhibition, P<0.001 and 32%, P<0.001, respectively). L‐NAME and indomethacin had little effect.
Perfusion with L‐NAME and glibenclamide significantly reduced baseline coronary flow (22%, P<0.01 and 33%, P<0.01) while 8‐PT, indomethacin and 5‐HD had no effect.
KATP channels are the major mediators of the coronary reactive hyperaemic response in the guinea‐pig. Although mitochondrial KATP channels contribute, they appear less important than sarcolemmal channels.

British Journal of Pharmacology (2001) 132, 1209–1216; doi:10.1038/sj.bjp.0703929
Gα14 links a variety of Gi‐ and Gs‐coupled receptors to the stimulation of phospholipase C
Authors: Ho Maurice K C , Yung Lisa Y , Chan Joy S C , Chan Jasmine H P , Wong Cecilia S S , Wong Yung H 
Published: January 2005

The bovine Gα14 is a member of the Gq subfamily of G proteins that can regulate phospholipase Cβ isoforms but the extent to which Gα14 recognizes different receptor classes is not known.
Gα14 was cotransfected with a variety of receptors in COS‐7 cells, and agonist‐induced stimulation of phospholipase C was then measured.
Activation of the type 2 but not type 1 somatostatin receptor in cells coexpressing Gα14 stimulated the accumulation of inositol phosphates; functional expression of both subtypes of somatostatin receptors was determined by the ability of somatostatin to inhibit cyclic AMP accumulation.
Among the three opioid receptors (μ, δ, and κ), only the δ receptor was capable of stimulating IP formation when coexpressed with Gα14 in COS‐7 cells.
A panel of Gi‐ and Gs‐linked receptors was screened for their ability to stimulate IP accumulation via Gα14. The adenosine A1, complement C5a, dopamine D1, D2 and D5, formyl peptide, luteinizing hormone, secretin, and the three subtypes of melatonin (mt1, MT2, and Xenopus) receptors were all incapable of activating Gα14, while the α2‐ and β2‐adrenoceptors were able to do so.
Gα14‐mediated stimulation of phospholipase Cβ was agonist dose‐dependent. These data demonstrate that although Gα14 can interact with different classes of receptors, it is much less promiscuous than Gα15 or Gα16.

British Journal of Pharmacology (2001) 132, 1431–1440; doi:10.1038/sj.bjp.0703933
Protective effect of a PAR2‐activating peptide on histamine‐induced bronchoconstriction in guinea‐pig
Authors: Cicala C , Spina D , Keir S D , Severino B , Meli R , Page C P , Cirino G 
Published: January 2005

Protease activated receptor‐2 (PAR2) is a seven transmembrane domain G protein coupled receptor proteolytically activated. PAR2, together with other PARs, can be also activated by peptides mimicking the sequence of the receptor tethered ligand. We have evaluated the effect of systemic administration of a peptide activating PAR2 (PAR2‐AP, SLIGRL) on histamine‐induced increase in lung resistances in the guinea‐pig.
Intravenous administration of PAR2‐AP (1 mg kg−1) significantly inhibited histamine‐induced increase in lung resistance in a time‐dependent fashion that was not abolished by indomethacin or vagotomy.
Bronchoprotective effect of PAR2‐AP was not reversed by the cyclo‐oxygenase inhibitor, indomethacin, the nitric oxide synthetase inhibitor, L‐NAME, nor by the non‐selective beta‐antagonist, propranolol.
Indomethacin augmented the bronchoconstriction to histamine which was inhibited by PAR2‐AP. Furthermore, in vagotomized animals, the bronchial hyper‐responsiveness to histamine was significantly reduced, and in these circumstances, PAR2‐AP still retained the capacity to provide bronchoprotection against histamine.
PAR2‐AP also produced a modest reduction in histamine‐induced protein leakage in trachea and upper bronchi.
Our results indicated that PAR2 might have a bronchoprotective role in the guinea‐pig in vivo independent of prostaglandin or nitric oxide release.

British Journal of Pharmacology (2001) 132, 1229–1234; doi:10.1038/sj.bjp.0703934
Mechanism of CGRP‐induced relaxation in rat intramural coronary arteries
Authors: Sheykhzade Majid , Berg Nyborg Niels C 
Published: January 2005

This study investigates the mechanism of CGRP‐induced relaxation in intramural coronary arteries by determining the effect of CGRP on cytosolic Ca2+ concentration ([Ca2+]i) using FURA‐2 technique.
CGRP concentration‐dependently (10 pM – 100 nM) decreased the [Ca2+]i and tension of coronary arteries precontracted with either U46619 or BAY K 8644, and also of resting coronary arteries in PSS. In 36 mM K+‐depolarized arteries, CGRP reduced only the tension without affecting the [Ca2+]i.
In 300 nM U46619‐ precontracted arteries, pretreatment with 10 μM thapsigargin significantly (P<0.05) attenuated the CGRP‐induced reduction in the tension (but not [Ca2+]i).
In 300 nM U46619‐precontracted arteries, pretreatment with either 100 nM charybdotoxin or 100 nM iberiotoxin or 10 nM felodipine significantly (P<0.05) attenuated the CGRP‐induced reduction in both [Ca2+]i and tension. In contrast, 1 μM glibenclamide did not affect the CGRP‐induced responses in these coronary arteries.
In resting coronary arteries, only pretreatment with the combination of 1 μM glibenclamide and 100 nM charybdotoxin attenuated the CGRP‐induced decrease in the [Ca2+]i and tension, suggesting a different mechanism of action for CGRP in resting coronary arteries.
We conclude that CGRP relaxes precontracted rat coronary arteries via three mechanisms: (1) a decrease in [Ca2+]i by inhibiting the Ca2+ influx through membrane hyperpolarization mediated partly by activation of the large conductance Ca2+‐activated potassium channels, (2) a decrease in [Ca2+]i presumably by sequestrating cytosolic Ca2+ into thapsigargin‐sensitive Ca2+ storage sites and (3) a decrease in the Ca2+‐sensitivity of the contractile apparatus. In resting coronary arteries, however, there seems to be an interplay between different types of K+ channels.

British Journal of Pharmacology (2001) 132, 1235–1246; doi:10.1038/sj.bjp.0703936
GLC‐3: a novel fipronil and BIDN‐sensitive, but picrotoxinin‐insensitive, L‐glutamate‐gated chloride channel subunit from Caenorhabditis elegans
Authors: Horoszok Lucy , Raymond Valérie , Sattelle David B , Wolstenholme Adrian J 
Published: January 2005

We report the cloning and expression of a novel Caenorhabditis elegans polypeptide, GLC‐3, with high sequence identity to previously cloned L‐glutamate‐gated chloride channel subunits from nematodes and insects.
Expression of glc‐3 cRNA in Xenopus oocytes resulted in the formation of homo‐oligomeric L‐glutamate‐gated chloride channels with robust and rapidly desensitizing currents, an EC50 of 1.9±0.03 mM and a Hill coefficient of 1.5±0.1. GABA, glycine, histamine and NMDA all failed to activate the GLC‐3 homo‐oligomer at concentrations of 1 mM. The anthelminthic, ivermectin, directly and irreversibly activated the L‐glutamate‐gated channel with an EC50 of 0.4±0.02 μM.
The GLC‐3 channels were selective for chloride ions, as shown by the shift in the reversal potential for L‐glutamate‐gated currents after the reduction of external Cl− from 107.6 to 62.5 mM.
Picrotoxinin failed to inhibit L‐glutamate agonist responses at concentrations up to 1 mM. The polycyclic dinitrile, 3,3‐bis‐trifluoromethyl‐bicyclo[2,2,1]heptane‐2,2‐dicarbonitrile (BIDN), completely blocked L‐glutamate‐induced chloride currents recorded from oocytes expressing GLC‐3 with an IC50 of 0.2±0.07 μM. The phenylpyrazole insecticide, fipronil, reversibly inhibited L‐glutamate‐gated currents recorded from the GLC‐3 receptor with an IC50 of 11.5±0.11 μM.
In this study, we detail the unusual antagonist pharmacology of a new GluCl subunit from C. elegans. Unlike all other native and recombinant nematode GluCl reported to date, the GLC‐3 receptor is insensitive to picrotoxinin, but is sensitive to two other channel blockers, BIDN and fipronil. Further study of this receptor may provide insights into the molecular basis of non‐competitive antagonism by these compounds.

British Journal of Pharmacology (2001) 132, 1247–1254; doi:10.1038/sj.bjp.0703937
Disturbance of peristalsis in the guinea‐pig isolated small intestine by indomethacin, but not cyclo‐oxygenase isoform‐selective inhibitors
Authors: Shahbazian Anaid , Schuligoi Rufina , Heinemann Akos , Peskar Bernhard A , Holzer Peter 
Published: January 2005

Since the cyclo‐oxygenase (COX) isoform‐nonselective inhibitor indomethacin is known to modify intestinal motility, we analysed the effects of COX‐1 and COX‐2 inhibition on intestinal peristalsis.
Peristalsis in isolated segments of the guinea‐pig small intestine was triggered by a rise of the intraluminal pressure and recorded via the pressure changes associated with peristalsis.
The COX‐1 inhibitor SC‐560, the COX‐2 inhibitor NS‐398 (both at 0.1  – 1 μM) and the isoform‐nonselective inhibitors flurbiprofen (0.01 – 10 μM) and piroxicam (0.1 – 50 μM) were without major influence on peristalsis, whereas indomethacin and etodolac (0.1 – 10 μM) disturbed the regularity of peristalsis by causing nonpropulsive circular muscle contractions.
Radioimmunoassay measurements showed that SC‐560, NS‐398, indomethacin and etodolac (each at 1 μM) suppressed the release of 6‐keto‐prostaglandin F1α (6‐keto‐PGF1α) from the intestinal segments.
Reverse transcription – polymerase chain reaction tests revealed that, relative to glyceraldehyde‐3 phosphate dehydrogenase ribonucleic acid, the expression of COX‐1 mRNA increased by a factor of 2.0 whereas that of COX‐2 mRNA rose by a factor of 7.9 during the 2 h experimental period.
Pharmacological experiments indicated that the action of indomethacin to disturb intestinal peristalsis was unrelated to inhibition of L‐type calcium channels, adenosine triphosphate‐sensitive potassium channels or phosphodiesterase type IV.
These results show that selective inhibition of COX‐1 and COX‐2 does not grossly alter peristaltic motor activity in the guinea‐pig isolated small intestine and that the effect of indomethacin to disturb the regular pattern of propulsive motility in this species is unrelated to COX inhibition.

British Journal of Pharmacology (2001) 132, 1299–1309; doi:10.1038/sj.bjp.0703940
Platelet GPIIb/IIIa binding characteristics of small molecule RGD mimetic: distinct binding profile for Roxifiban
Authors: Mousa Shaker A , Bozarth Jeffrey M , Naik Ulhas P , Slee Andrew 
Published: January 2005

A number of non‐peptide orally active RGD mimetic prodrug such as Orbofiban, Sibrafiban, SR121566, Roxifiban and others entered into the clinical evaluation stage. Some of these agents were terminated and some are still in clinical trials.
The present study examined the platelet GPIIb/IIIa binding profiles for the active form of Roxifiban, Sibrafiban, SR121566 and Orbofiban using 3H‐Roxifiban active form (XV459), 3H‐DMP728, 125I‐Echistatin, and 125I‐Fibrinogen.
Either DMP728, Orbofiban, Sibrafiban, SR121566 or Roxifiban active form as well as other RGD mimetic bind to the same binding site (s) on human platelets as evident from the competitive inhibition of binding of each other to human platelet. Additionally, Roxifiban active form competed with FITC labeled GPIIb/IIIa antagonist cyclic RGD peptidomimetic (XL086) as demonstrated using confocal microscopy technique.
Roxifiban active form (XV459) demonstrated the highest potency in inhibiting 3H‐XV459, 3H‐DMP728, 125I‐Echistatin, and 125I‐Fibrinogen binding to human platelets as compared to the others.
Structure activity relationship within the isoxazoline Roxifiban series showed that substituent at the α‐carbon next to the carboxy terminal represents an exosite for the affinity binding to human platelets leading to slow platelet dissociation rate.
These data indicated a distinct binding profile for Roxifiban (high affinity to both activated and resting platelets associated with a relatively slow Koff) as compared to others. These differences might determine the pharmacodynamics and pharmackokinetics of the different GPIIb/IIIa antagonists.

British Journal of Pharmacology (2001) 133, 331–336; doi:10.1038/sj.bjp.0703943
Chronic systemic administration of salmeterol to rats promotes pulmonary β2‐adrenoceptor desensitization and down‐regulation of Gsα
Authors: Finney Paul A , Donnelly Louise E , Belvisi Maria G , Chuang Tsu‐Tshen , Birrell Mark , Harris Andrew , Mak Judith C W , Scorer Carol , Barnes Peter J , Adcock Ian M , Giembycz Mark A 
Published: January 2005

The aim of the present study was to examine the effects of chronic infusion of the long‐acting agonist salmeterol on pulmonary β2‐adrenoceptor function in Sprague‐Dawley rats in vivo and to elucidate the molecular basis of any altered state.
Systemic administration of rats with salmeterol for 7 days compromised the ability of salmeterol and prostaglandin E2 (PGE2), given acutely by the intravenous route, to protect against ACh‐induced bronchoconstriction when compared to rats treated identically with vehicle.
β1‐ and β2‐adrenoceptor density was significantly reduced in lung membranes harvested from salmeterol‐treated animals, which was associated with impaired salmeterol‐ and PGE2‐induced cyclic AMP accumulation ex vivo.
Three variants of Gsα that migrated as 42, 44 and 52 kDa peptides on SDS polyacrylamide gels were detected in lung membranes prepared from both groups of rats but the intensity of each isoform was markedly reduced in rats that received salmeterol.
The activity of cytosolic, but not membrane‐associated, G‐protein receptor‐coupled kinase was elevated in the lung of salmeterol‐treated rats when compared to vehicle‐treated animals.
The ability of salmeterol, administered systemically, to protect the airways of untreated rats against ACh‐induced bronchoconstriction was short‐acting (toff ∼45 min), which contrasts with its long‐acting nature when given to asthmatic subjects by inhalation.
These results indicate that chronic treatment of rats with salmeterol results in heterologous desensitization of pulmonary Gs‐coupled receptors. In light of previous data obtained in rats treated chronically with salbutamol, we propose that a primary mechanism responsible for this effect is a reduction in membrane‐associated Gsα. The short‐acting nature of salmeterol, when administered systemically, and the reduction in β‐adrenoceptor number may be due to metabolism to a biologically‐active, short‐acting and non‐selective β‐adrenoceptor agonist.

British Journal of Pharmacology (2001) 132, 1261–1270; doi:10.1038/sj.bjp.0703946
Evidence for a non‐adrenoceptor, imidazoline‐mediated contractile response to oxymetazoline in the porcine isolated rectal artery
Authors: Minyan Wang , Dunn W R , Blaylock N A , Chan S L F , Wilson V G 
Published: January 2005

Imidazoline derivatives are known to elicit responses through both α2‐adrenoceptor and non‐adrenoceptor, imidazoline sites, though as yet there are no examples of the latter on vascular smooth muscle. In the presence of 0.3 μM prazosin, neither UK‐14304 (0.01 – 3 μM) nor oxymetazoline (0.01 – 30 μM) caused a significant contraction of the porcine isolated rectal artery, a preparation with a low density of α2‐adrenoceptors. In the presence of a combination of U46619 and forskolin, however, both agonists produced concentration‐dependent contractions. Pretreatment with phenoxybenzamine (3 μM) abolished responses to UK‐14304, but left those elicited by oxymetazoline largely unaffected. The putative I3 imidazoline antagonist 2‐(2,3 dihydro‐2‐benzofuranyl)‐2‐imidazole (KU‐14R, 10 μM) caused a 6 fold rightward displacement of the phenoxybenzamine‐insensitive concentration – response curve to oxymetazoline. Our data indicates that non‐adrenoceptor, imidazoline sites, pharmacologically similar to the I3 imidazoline site on islet cells, mediate vasoconstriction in the porcine isolated rectal artery.British Journal of Pharmacology (2001) 132, 1359–1363; doi:10.1038/sj.bjp.0703949
Thrombin‐induced p38 mitogen‐activated protein kinase activation is mediated by epidermal growth factor receptor transactivation pathway
Authors: Kanda Yasunari , Mizuno Katsushige , Kuroki Yasutomi , Watanabe Yasuhiro 
Published: January 2005

Thrombin is a potent mitogen for vascular smooth muscle cells (VSMC) and has been implicated its pathogenic role in vascular remodelling. However, the signalling pathways by which thrombin mediates its mitogenic response are not fully understood.
We have previously reported that thrombin activates p38 mitogen‐activated protein kinase (p38 MAPK) by a tyrosine kinase‐dependent mechanism, and that p38 MAPK has a role in thrombin‐induced mitogenic response in rat VSMC.
In the present study, we examine the involvement of epidermal growth factor (EGF) receptor in thrombin‐induced p38 MAPK activation. We found that thrombin induced EGF receptor tyrosine phosphorylation (transactivation) in A10 cells, a clonal VSMC cell line. A selective inhibitor of EGF receptor kinase (AG1478) inhibited the p38 MAPK activation in a dose‐dependent manner, whereas it had no effect on the response to platelet‐derived growth factor (PDGF). EGF receptor phosphorylation induced by thrombin was inhibited by BAPTA‐AM and GF109203X, which suggest a requirement for intracellular Ca2+ increase and protein kinase C.
We next examined the effect of AG1478 on thrombin‐induced DNA synthesis. AG1478 inhibited thrombin‐induced DNA synthesis in a dose‐dependent manner. In contrast, PDGF‐induced DNA synthesis was not affected by AG1478.
In conclusion, these data suggest that the EGF receptor transactivation and subsequent p38 MAPK activation is required for thrombin‐induced proliferation of VSMC.

British Journal of Pharmacology (2001) 132, 1657–1664; doi:10.1038/sj.bjp.0703952