bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lack of interaction between nitric oxide and the redox modulatory site of the NMDA receptor
Authors: Aizenman Elias , Potthoff William K 
Published: January 2005

The inhibitory effects of nitric oxide (NO) on N‐methyl‐D‐aspartate (NMDA) receptor function have been proposed to be mediated via the interaction of this gas with a redox‐sensitive thiol moiety on the receptor. Here, we evaluated this suggested mechanism by examining the actions of various NO donors on native neuronal receptors as well as in wild‐type and cysteine‐mutated recombinant NMDA receptors expressed in Chinese hamster ovary (CHO) cells.
The NO donor N‐ethyl‐2‐(1‐ethyl‐2‐hydroxy‐2‐nitrosohydraxino)ethanamine (NOC‐12; 100 μM) produced a rapid and readily reversible inhibition of whole‐cell currents induced by NMDA (30 μM) in cultured cortical neurons. The inhibition was apparent at all holding potentials, though a more pronounced block was observed at negative voltages. The effects of NOC‐12 disappeared when the donor was allowed to expire. A similar receptor block was observed with another NO‐releasing agent, S‐nitroso‐N‐acetylpenicillamine (SNAP; 1 mM).
The blocking effects of NO released by SNAP, 3‐morpholinosydnonimine (SIN‐1; 1 mM), and 3‐[2‐hydroxy‐1‐(1‐methylethyl)‐2‐nitrosohydrazino]‐1‐propanamine (NOC‐5; 100 μM) on currents mediated by recombinant NR1/NR2B receptors were virtually indistinguishable from those observed on native receptors. Furthermore, mutating cysteines 744 and 798 of NR1, which constitute the principal redox modulatory site of the NR1/NR2B receptor configuration, did not affect the inhibition produced by NO.
The NR2A subunit may contribute its own redox‐sensitive site. However, the effects of NO on NR1/NR2A receptors were very similar to those seen for all other receptor configurations evaluated. Hence, we conclude that NO does not exert its inhibition of NMDA‐induced responses via a modification of any of the previously described redox‐sensitive sites on the receptor.

British Journal of Pharmacology (1999) 126, 296–300; doi:10.1038/sj.bjp.0702295
Selective effects of a 4‐oxystilbene derivative on wild and mutant neuronal chick α7 nicotinic receptor
Authors: Maggi L , Palma E , Eusebi F , Moretti M , Balestra B , Clementi F , Gotti C 
Published: January 2005

We assessed the pharmacological activity of triethyl‐(β‐4‐stilbenoxy‐ethyl) ammonium (MG624), a drug that is active on neuronal nicotinic receptors (nicotinic AChR). Experiments on the major nicotinic AChR subtypes present in chick brain, showed that it inhibits the binding of [125I]‐αBungarotoxin (αBgtx) to the α7 subtype, and that of [3H]‐epibatidine (Epi) to the α4β2 subtype, with Ki values of respectively 106 nM and 84 μM.
MG624 also inhibited ACh elicited currents (IACh) in the oocyte‐expressed α7 and α4β2 chick subtypes with half‐inhibitory concentrations (IC50) of respectively 109 nM and 3.2 μM.
When tested on muscle‐type AChR, it inhibited [125I]‐αBgtx binding with a Ki of 32 μM and ACh elicited currents (IACh) in the oocyte‐expressed α1β1γδ chick subtype with an IC50 of 2.9 μM.
The interaction of MG624 with the α7 subtype was investigated using an α7 homomeric mutant receptor with a threonine‐for‐leucine 247 substitution (L247T α7). MG624 did not induce any current in oocytes expressing the wild type α7 receptor, but did induce large currents in the oocyte‐expressed L247T α7 receptor. The MG624 elicited current (IMG624) has an EC50 of 0.2 nM and a Hill coefficient nH of 1.9, and is blocked by the nicotinic receptor antagonist methyllycaconitine (MLA).
These binding and electrophysiological studies show that MG624 is a potent antagonist of neuronal chick α7 nicotinic AChR, and becomes a competitive agonist following the mutation of the highly conserved leucine residue 247 located in the M2 channel domain.

British Journal of Pharmacology (1999) 126, 285–295; doi:10.1038/sj.bjp.0702299
Growth‐inhibitory effect of cyclic GMP‐ and cyclic AMP‐dependent vasodilators on rat vascular smooth muscle cells: effect on cell cycle and cyclin expression
Authors: Kronemann Nicola , Nockher Wolfgang A , Busse Rudi , Schini‐Kerth Valérie B 
Published: January 2005

The possibility that the antiproliferative effect of cyclic GMP‐ and cyclic AMP‐dependent vasodilators involves an impaired progression of vascular smooth muscle cells (VSMC) through the cell cycle and expression of cyclins, which in association with the cyclin‐dependent kinases control the transition between the distinct phases of the cell cycle, was examined.
FCS (10%) stimulated the transition of quiescent VSMC from the G0/G1 to the S phase (maximum within 18–24 h and then to the G2/M phase (maximum within 22–28 h). Sodium nitroprusside and 8‐Br‐cyclic GMP, as well as forskolin and 8‐Br‐cyclic AMP markedly reduced the percentage of cells in the S phase after FCS stimulation.
FCS stimulated the low basal protein expression of cyclin D1 (maximum within 8–24 h) and E (maximum within 8–38 h) and of cyclin A (maximum within 14–30 h). The stimulatory effect of FCS on cyclin D1 and A expression was inhibited, but that of cyclin E was only minimally affected by the vasodilators.
FCS increased the low basal level of cyclin D1 mRNA after a lag phase of 2 h and that of cyclin A after 12 h. The vasodilators significantly reduced the FCS‐stimulated expression of cyclin D1 and A mRNA.
These findings indicate that cyclic GMP‐ and cyclic AMP‐dependent vasodilators inhibit the proliferation of VSMC by preventing the progression of the cell cycle from the G0/G1 into the S phase, an effect which can be attributed to the impaired expression of cyclin D1 and A.

British Journal of Pharmacology (1999) 126, 349–357; doi:10.1038/sj.bjp.0702305
Effects of heptanol on the neurogenic and myogenic contractions of the guinea‐pig vas deferens
Authors: Venkateswarlu K , Dange Sumedha Y , Manchanda Rohit 
Published: January 2005

The effects of the putative gap junction uncoupler, 1‐heptanol, on the neurogenic and myogenic contractile responses of guinea‐pig vas deferens were studied in vitro.
Superfusion of 2.0 mM heptanol for 20–30 min produced the following reversible changes in the biphasic neurogenic contractile response (8 trials): (i) suppression of both phases; (ii) delayed development of both the first as well as the second phase, accompanied by complete temporal separation of the two phases; (iii) prominent oscillations of force during the second (noradrenergic) phase only.
To eliminate prejunctional effects of heptanol, myogenic contractions were evoked by field stimulation of the vas in the presence of suramin (200 μM) and prazosin (1 μM). Heptanol (2.0 mM) abolished these contractions reversibly.
These results show that (i) heptanol inhibits both excitatory junction potential (EJP)‐dependent and non EJP‐dependent contractions of the vas; (ii) a postjunctional site of action of heptanol, probably intercellular uncoupling of smooth muscle cells, contributes to the inhibition of contraction.

British Journal of Pharmacology (1999) 126, 227–234; doi:10.1038/sj.bjp.0702307
Acute troglitazone action in isolated perfused rat liver
Authors: Preininger Kurt , Stingl Harald , Englisch Rainer , Fürnsinn Clemens , Graf Jürg , Waldhäusl Werner , Roden Michael 
Published: January 2005

The thiazolidinedione compound, troglitazone, enhances insulin action and reduces plasma glucose concentrations when administered chronically to type 2 diabetic patients.
To analyse to what extent thiazolidinediones interfere with liver function, we examined the acute actions of troglitazone (0.61 and 3.15 μM) on hepatic glucose and lactate fluxes, bile secretion, and portal pressure under basal, insulin‐ and/or glucagon‐stimulated conditions in isolated perfused rat livers.
During BSA‐free perfusion, high dose troglitazone increased basal (P<0.01), but inhibited glucagon‐stimulated incremental glucose production by ∼75% (10.0±2.5 vs control: 40.0±7.2 μmol g liver−1, P<0.01). In parallel, incremental lactate release rose ∼6 fold (13.1±5.9 vs control: 2.2±0.8 mmol g liver−1, P<0.05), while bile secretion declined by ∼67% [0.23±0.02 vs control: 0.70±0.05 mg g liver−1 min−1), P<0.001]. Low dose troglitazone infusion did not enhance the inhibitory effect of insulin on glucagon‐stimulated glucose production, but rapidly increased lactate release (P<0.0005) and portal venous pressure (+0.17±0.07 vs +0.54±0.07 cm buffer height, P<0.0001).
These results indicate that troglitazone exerts both insulin‐like and non‐insulin‐like hepatic effects, which are blunted by addition of albumin, possibly due to troglitazone binding.

British Journal of Pharmacology (1999) 126, 372–378; doi:10.1038/sj.bjp.0702318
Mibefradil (Ro 40‐5967) inhibits several Ca2+ and K+ currents in human fusion‐competent myoblasts
Authors: Liu Jian‐Hui , Bijlenga Philippe , Occhiodoro Teresa , Fischer‐Lougheed Jacqueline , Bader Charles R , Bernheim Laurent 
Published: January 2005

The effect of mibefradil (Ro 40–5967), an inhibitor of T‐type Ca2+ current (ICa(T)), on myoblast fusion and on several voltage‐gated currents expressed by fusion‐competent myoblasts was examined.
At a concentration of 5 μM, mibefradil decreases myoblast fusion by 57%. At this concentration, the peak amplitudes of ICa(T) and L‐type Ca2+ current (ICa(L)) measured in fusion‐competent myoblasts are reduced by 95 and 80%, respectively. The IC50 of mibefradil for ICa(T) and ICa(L) are 0.7 and 2 μM, respectively.
At low concentrations, mibefradil increased the amplitude of ICa(L) with respect to control.
Mibefradil blocked three voltage‐gated K+ currents expressed by human fusion‐competent myoblasts: a delayed rectifier K+ current, an ether‐à‐go‐go K+ current, and an inward rectifier K+ current, with a respective IC50 of 0.3, 0.7 and 5.6 μM.
It is concluded that mibefradil can interfere with myoblast fusion, a mechanism fundamental to muscle growth and repair, and that the interpretation of the effect of mibefradil in a given system should take into account the action of this drug on ionic currents other than Ca2+ currents.

British Journal of Pharmacology (1999) 126, 245–250; doi:10.1038/sj.bjp.0702321
Modulation of ATP‐responses at recombinant rP2X4 receptors by extracellular pH and zinc
Authors: Wildman S S , King B F , Burnstock G 
Published: January 2005

The modulatory effects of extracellular H+ and Zn2+ were tested against ATP‐responses at rat P2X4 (rP2X4) receptors expressed in Xenopus oocytes under voltage‐clamp conditions.
ATP (0.1–100 μM, at pH 7.5), evoked inward currents via rP2X4 receptors (EC50 value, 4.1±0.98 μM; nH, 1.2±0.1). ATP potency was reduced 2 fold, at pH 6.5, without altering maximal activity. ATP potency was reduced by a further 4 fold, at pH 5.5, and the maximal activity of ATP was also reduced. Alkaline conditions (pH 8.0) had no effect on ATP‐responses.
Zn2+ (100 nM–10 μM) potentiated ATP‐responses at the rP2X4 receptor by 2 fold, whereas higher concentrations (30 μM–1 mM) inhibited ATP‐responses. Zn2+ potentiation was due to an increase in ATP potency, whereas its inhibitory action was due to a reduction in ATP efficacy.
Zn2+ modulation of ATP‐responses was pH‐dependent. At pH 6.5, the bell‐shaped curve for Zn2+ was shifted to the right by 1 log unit. At pH 5.5, Zn2+ potentiation was abolished and its inhibitory effect reduced considerably.
Suramin (50 μM) also potentiated ATP‐responses at rP2X4 receptors. Neither H+ (pH 6.5 and 5.5), Zn2+ (10–100 μM) or a combination of both failed to reveal an inhibitory action of suramin at rP2X4 receptors.
In conclusion, H+ and Zn2+ exerted opposite effects on the rP2X4 receptor by lowering and raising agonist potency, respectively. H+ (3 μM) and Zn2+ (30 μM) also reduces agonist efficacy by lowering the number of rP2X4 receptors available for activation. The striking differences between the modulatory actions of H+ and Zn2+ at rP2X4 and rP2X2 receptors are discussed.

British Journal of Pharmacology (1999) 126, 762–768; doi:10.1038/sj.bjp.0702325
Endothelin receptor expression and pharmacology in human saphenous vein graft
Authors: Maguire Janet J , Davenport Anthony P 
Published: January 2005

We have investigated the expression and pharmacology of endothelin (ET) receptors in human aortocoronary saphenous vein grafts.
Subtype‐selective ligands were used to autoradiographically identify ETA ([125I]‐PD151242) and ETB ([125I]‐BQ3020) receptors. In graft saphenous vein ETA receptors predominated in the media, with few ETB receptors identified. Neither subtype was detected in the thickened neointima.
The ratio of medial ETA:ETB receptors was 75% : 25% in both graft and control saphenous vein.
ET‐1 contracted control (EC50 2.9 nM) and graft (EC50 4.5 nM) saphenous vein more potently than diseased coronary artery (EC50 25.5 nM).
In all three blood vessels ET‐1 was 100 times more potent than ET‐3 and three times more potent than sarafotoxin 6b (S6b). Little or no response was obtained in any vessel with the ETB agonist sarafotoxin 6c (S6c).
The ETA antagonist PD156707 (100 nM) blocked ET‐1 responses in all three vessels with pKb values of approximately 8.0.
For individual graft veins the EC50 value for ET‐1 and ‘age’ of graft in years showed a significant negative correlation.
In conclusion there is no alteration in ET receptor expression in the media of saphenous veins grafted into the coronary circulation compared to control veins. ETA receptors predominantly mediate the vasoconstrictor response to ET‐1 in graft vein, with no apparent up‐regulation of ETB receptors. The sensitivity of the graft vein to ET‐1 increased with graft ‘age’, suggesting that these vessels may be particularly vulnerable to the increased plasma ET levels that are detected in patients with cardiovascular disease.

British Journal of Pharmacology (1999) 126, 443–450; doi:10.1038/sj.bjp.0702326
Signalling by CXC‐chemokine receptors 1 and 2 expressed in CHO cells: a comparison of calcium mobilization, inhibition of adenylyl cyclase and stimulation of GTPγS binding induced by IL‐8 and GROα
Authors: Hall David A , Beresford Isabel J M , Browning Christopher , Giles Heather 
Published: January 2005

The effect of interleukin‐8 (IL‐8) and growth‐related oncogene α (GROα) on [35S]‐guanosine 5′‐O‐(3‐thiotriphosphate) ([35S]GTPγS) binding, forskolin‐stimulated cyclic AMP accumulation and cytosolic calcium concentration were determined in recombinant CHO cells expressing HA‐tagged CXC‐chemokine receptors 1 and 2 (CXCR1 and CXCR2).
Radioligand binding assays confirmed that the binding profiles of the recombinant receptors were similar to those of the native proteins. IL‐8 displaced [125I]‐IL‐8 binding to CXCR1 and CXCR2 with pKi values of 8.89±0.05 and 9.27±0.03, respectively. GROα, a selective CXCR2 ligand, had a pKi value of 9.66±0.39 at CXCR2 but a pKi>8 at CXCR1. Calcium mobilization experiments were also consistent with previous reports on native receptors.
Activation of both receptors resulted in stimulation of [35S]GTPγS binding and inhibition of adenylyl cyclase.
A comparison of the functional data at CXCR1 showed that a similar potency order (IL‐8>>GROα) was obtained in all three assays. However, at CXCR2 whilst the potency orders for calcium mobilization and inhibition of adenylyl cyclase were similar (IL‐8GROα), the order was reversed for stimulation of [35S]GTPγS binding (GROα>IL‐8).
All of the functional responses at both receptors were inhibited by pertussis toxin (PTX), suggesting coupling to a Gi/Go protein. However, the calcium mobilization induced by IL‐8 at CXCR1 was not fully inhibited by PTX, suggesting an interaction with a G‐protein of the Gq family. Our results with pertussis toxin also suggested that, in the [35S]GTPγS binding assay, CXCR1 displays some constitutive activity.
Thus, we have characterized the binding and several functional responses at HA‐tagged CXCRs 1 and 2 and have shown that their pharmacology agrees well with that of the native receptors. We also have preliminary evidence that CXCR1 displays constitutive activity in our cell line and that CXCR2 may traffic between different PTX sensitive G‐proteins.

British Journal of Pharmacology (1999) 126, 810–818; doi:10.1038/sj.bjp.0702329
Absence of G‐protein activation by μ‐opioid receptor agonists in the spinal cord of μ‐opioid receptor knockout mice
Authors: Narita Minoru , Mizoguchi Hirokazu , Narita Michiko , Sora Ichiro , Uhl George R , Tseng Leon F 
Published: January 2005

The ability of μ‐opioid receptor agonists to activate G‐proteins in the spinal cord of μ‐opioid receptor knockout mice was examined by monitoring the binding to membranes of the non‐hydrolyzable analogue of GTP, guanosine‐5′‐O‐(3‐[35S]thio)triphosphate ([35S]GTPγS).
In the receptor binding study, Scatchard analysis of [3H][D‐Ala2,NHPhe4,Gly‐ol]enkephalin ([3H]DAMGO; μ‐opioid receptor ligand) binding revealed that the heterozygous μ‐knockout mice displayed approximately 40% reduction in the number of μ‐receptors as compared to the wild‐type mice. The homozygous μ‐knockout mice showed no detectable μ‐binding sites.
The newly isolated μ‐opioid peptides endomorphin‐1 and ‐2, the synthetic selective μ‐opioid receptor agonist DAMGO and the prototype of μ‐opioid receptor agonist morphine each produced concentration‐dependent increases in [35S]GTPγS binding in wild‐type mice. This stimulation was reduced by 55–70% of the wild‐type level in heterozygous, and virtually eliminated in homozygous knockout mice.
No differences in the [35S]GTPγS binding stimulated by specific δ1‐ ([D‐Pen2,5]enkephalin), δ2‐ ([D‐Ala2]deltorphin II) or κ1‐ (U50,488H) opioid receptor agonists were noted in mice of any of the three genotypes.
The data clearly indicate that μ‐opioid receptor gene products play a key role in G‐protein activation by endomorphins, DAMGO and morphine in the mouse spinal cord. They support the idea that μ‐opioid receptor densities could be rate‐limiting steps in the G‐protein activation by μ‐opioid receptor agonists in the spinal cord. These thus indicate a limited physiological μ‐receptor reserve. Furthermore, little change in δ1‐, δ2‐ or κ1‐opioid receptor‐G‐protein complex appears to accompany μ‐opioid receptor gene deletions in this region.

British Journal of Pharmacology (1999) 126, 451–456; doi:10.1038/sj.bjp.0702330
Effects of vitamin C and of a cell permeable superoxide dismutase mimetic on acute lipoprotein induced endothelial dysfunction in rabbit aortic rings
Authors: Fontana L , McNeill K L , Ritter J M , Chowienczyk P J 
Published: January 2005

Low density lipoprotein (LDL) inhibits endothelium‐dependent relaxation. The mechanism is uncertain, but increased production of superoxide anion O2− with inactivation of endothelium‐derived NO and formation of toxic free radical species have been implicated. We investigated effects of the cell permeable superoxide dismutase mimetic manganese (III) tetrakis (1‐methyl‐4‐pyridyl) porphyrin (MnTMPyP), the free radical scavenger vitamin C and arginine (which may reduce O2− formation) on acute LDL‐induced endothelial dysfunction in rabbit aortic rings, using LDL prepared by ultracentrifugation of plasma from healthy men and aortic rings from New Zealand white rabbits.
LDL (150 μg protein ml−1 for 20 min) markedly inhibited relaxation of aortic rings (in Krebs' solution at 37°C and pre‐constricted to 80% maximum tension with noradrenaline) to acetylcholine 82±10% (mean percentage difference between sum of relaxations after each concentration of acetylcholine in the presence and absence of LDL, ±s.e.mean, n=26, P<0.001) but not to the endothelium‐independent agonist nitroprusside.
MnTMPyP (10 μM) reduced inhibitory effects of LDL from 124±27 to 56±17% (n=6, P<0.05).
Vitamin C (1  mM) reduced inhibitory effects of LDL from 59±8 to 22±5% (n=6, P<0.05).
Inhibitory effects of LDL were similar in the absence or presence of arginine (84±12 vs 79±16%, n=14, P=0.55). Effects of L‐arginine (10 mM) did not differ significantly from those of D‐arginine (10 mM).
Acute (20 min) exposure of aortic rings to LDL impairs endothelium‐dependent relaxation which can be partially restored by MnTMPyP and vitamin C. This is consistent with LDL causing increased O2− generation.

British Journal of Pharmacology (1999) 126, 730–734; doi:10.1038/sj.bjp.0702331
Inhibition of poly(ADP‐ribose) synthetase (PARS) and protection against peroxynitrite‐induced cytotoxicity by zinc chelation
Authors: Virág László , Szabó Csaba 
Published: January 2005

Peroxynitrite, a potent oxidant formed by the reaction of nitric oxide and superoxide causes thymocyte necrosis, in part, via activation of the nuclear enzyme poly(ADP‐ribose) synthetase (PARS). The cytotoxic PARS pathway initiated by DNA strand breaks and excessive PARS activation has been shown to deplete cellular energy pools, leading to cell necrosis. Here we have investigated the effect of tetrakis‐(2‐pyridylmethyl)‐ethylenediamine (TPEN) a heavy metal chelator on peroxynitrite‐induced cytotoxicity.
TPEN (10 μM) abolished cell death induced by authentic peroxynitrite (25 μM) and the peroxynitrite generating agent 3‐morpholinosidnonimine (SIN‐1, 250 μM). Preincubation of TPEN with equimolar Zn2+ but not Ca2+ or Mg2+ blocked the cytoprotective effect of the chelator.
TPEN (10 μM) markedly reduced the peroxynitrite‐induced decrease of mitochondrial transmembrane potential, secondary superoxide production and mitochondrial membrane damage, indicating that it acts proximal to mitochondrial alterations.
Although TPEN (1–300 μM) did not scavenge peroxynitrite, it inhibited PARS activation in a dose‐dependent manner.
The cytoprotective effect of TPEN is only partly mediated via PARS inhibition, as the chelator also protected PARS‐deficient thymocytes from peroxynitrite‐induced death.
While being cytoprotective against peroxynitrite‐induced necrotic death, TPEN (10 μM), similar to other agents that inhibit PARS, enhanced apoptosis (at 5–6 h after exposure), as characterized by phosphatydilserine exposure, caspase activation and DNA fragmentation.
In conclusion, the current data demonstrate that TPEN, most likely by zinc chelation, exerts protective effects against peroxynitrite‐induced necrosis. Its effects are, in part, mediated by inhibition of PARS.

British Journal of Pharmacology (1999) 126, 769–777; doi:10.1038/sj.bjp.0702332
Non‐specific action of methoxamine on Ito, and the cloned channels hKv 1.5 and Kv 4.2
Authors: Parker Chris , Li Qi , Fedida David 
Published: January 2005

The α1‐adrenoceptor agonist methoxamine acted independently of receptor activation to reduce Ito and the sustained outward current in rat ventricular myocytes, and hKv 1.5 and Kv 4.2 cloned K+ channel currents. Two hundred μM methoxamine reduced Ito by 36% in the presence of 2 μM prazosin, and by 37 and 38% after preincubation of myocytes with either N‐ethylmaleimide or phenoxybenzamine (n=6). The EC50 values at +60 mV for direct reduction of Ito, hKv 1.5, and Kv 4.2 by methoxamine were 239, 276, and 363 μM, respectively, with Hill coefficients of 0.87–1.5.
Methoxamine accelerated Ito and Kv 4.2 current inactivation in a concentration‐ and voltage‐dependent manner. Apparent rate constants for methoxamine binding and unbinding gave Kd values in agreement with EC50 values measured from dose‐response relations. The voltage‐dependence of block supported charged methoxamine binding to a putative intracellular site that sensed ∼20% of the transmembrane electrical field.
In the presence of methoxamine, deactivating Kv 4.2 tail currents displayed a distinct rising phase, and were slowed relative to control, such that tail current crossover was observed. These observations support a dominant mechanism of open channel block, although closed channel block could not be ruled out.
Single‐channel data from hKv 1.5 patches revealed increased closed times with blank sweeps and decreased burst duration in the presence of drug, and a reduction of mean channel open time from 1.8 ms in control to 0.4 ms in 500 μM methoxamine. For this channel, therefore, both open and closed channel block appeared to be important mechanisms for the action of methoxamine.

British Journal of Pharmacology (1999) 126, 595–606; doi:10.1038/sj.bjp.0702335