bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of bradykinin on K+ currents in NG108–15 cells treated with U73122, a phospholipase C inhibitor, or neomycin
Authors: Hildebrandt Jan‐Peter , Plant Timothy D , Meves Hans 
Published: August 2006

Bradykinin has multiple effects on differentiated NG108–15 neuroblastoma×glioma cells: it increases Ins(1,4,5)P3 production and intracellular Ca2+ concentration [Ca2+]i, evokes a Ca2+ activated K+ current (IK(Ca)) and inhibits M current (IM). We studied the effect of the aminosteroid U73122 and the antibiotic neomycin, both putative blockers of phospholipase C (PLC), on these four bradykinin effects.
Preincubation with 1 or 5 μm U73122 for 15 min partly suppressed Ins(1,4,5)P3 generation and the increase in [Ca2+]i induced by 1 μm bradykinin. U73122 10 μm caused total and irreversible inhibition. The inactive analogue U73343 was without effect.
Resting levels of Ins(1,4,5)P3 were not affected. However, resting [Ca2+]i was increased by 10 μm U73122, but not by U73343. Individual cells responded to 10 μm U73122 with a small increase in [Ca2+]i, followed in some cells by a large further rise.
Pretreatment of whole‐cell clamped cells with 1 μm U73122 for 30 min reduced the bradykinin‐induced IK(Ca) to a fifth of its normal size. To suppress it totally, a 7–12 min pretreatment with 5 μm U73122 was required. Again, U73343 was without effect.
U73122 and U73343 at concentrations of 5–10 μm irreversibly decreased the holding current (Ih) which at a holding potential of −30 or −20 mV mainly flows through open M channels. The decrease was often preceded by a transient increase.
M current (IM) measured with 1 s pulses, was also decreased by 5–10 μm U73122 and U73343, but short applications of U73122 could cause a small increase. The bradykinin‐induced inhibition of IM was not affected by U73122.
Preincubation with 1 or 3 mm neomycin for 15 min did not affect Ins(1,4,5)P3 generation and the increase in [Ca2+]i induced by bradykinin. Pretreatment with 3 mm neomycin for about 20 min diminished the bradykinin‐induced IK(Ca) to a fifth of its normal size.
The four main conclusions drawn from the results are: (a) U73122 suppresses bradykinin‐induced PLC activation and IK(Ca), but not IM inhibition. (b) This indicates that the transient outward current IK(Ca), but not the decrease of IM in response to bradykinin, is mediated by PLC. (c) U73122 itself inhibits IM and mobilizes Ca2+ from intracellular stores. (d) Externally applied neomycin is not an effective inhibitor of PLC‐mediated signalling pathways in NG108–15 cells.

British Journal of Pharmacology (1997) 120, 841–850; doi:10.1038/sj.bjp.0700991
Evidence for the involvement of 5‐HT4 receptors in the 5‐hydroxytryptamine‐induced pattern of migrating myoelectric complex in sheep
Authors: Plaza Miguel‐Angel , Arruebo María‐Pilar , Murillo María‐Divina 
Published: August 2006

The effects induced by 5‐hydroxytryptamine (5‐HT) on gastrointestinal myoelectric activity in conscious sheep were recorded through electrodes chronically implanted and analysed by computer. The 5‐HT receptors and the cholinergic neuronal pathways involved in these actions were investigated.
The intravenous (i.v.) administration of 5‐HT (2, 4 and 8 μg kg−1 min−1, 5 min) induced an antral inhibition concomitant with a duodenal activity front that migrated to the jejunum, followed by a period of intestinal inactivity. This myoelectric pattern closely resembled that observed in the phases III and I of the migrating myoelectric complex (MMC) in sheep. The 0.5 μg kg−1 min−1 dose evoked the same pattern in only two out of the six animals used. Likewise, the 1 μg kg−1 min−1 dose similarly affected four of the six animals. In addition, a transient stimulation was observed in the antrum and jejunum when the two highest doses were used.
The 5‐HT1 antagonist, methiothepin (0.1 mg kg−1), the 5‐HT2 antagonists, ritanserin (0.1 mg kg−1) and ketanserin (0.3 mg kg−1), the 5‐HT3 antagonists, granisetron (0.2 mg kg−1) and ondansetron (0.5 mg kg−1), as well as the 5‐HT4 antagonist, GR113808 (0.2 mg kg−1), did not modify the spontaneous gastrointestinal myoelectric activity. However, the cholinoceptor antagonists, atropine (0.2 mg kg−1) and hexamethonium (2 mg kg−1), inhibited gastrointestinal activity.
When these antagonists were injected i.v. 10 min before 5‐HT (2 or 4 μg kg−1 min−1, 5 min), only GR113808, atropine and hexamethonium were able to modify the 5‐HT‐induced actions, all of them being completely blocked by the three antagonists.
Our data show that 5‐HT initiates a MMC‐like pattern in the gastrointestinal area in sheep through 5‐HT4 receptors. Furthermore, these actions are mediated by cholinergic neural pathways involving muscarinic and nicotinic receptors. However, our results do not indicate a role for either 5‐HT1, 5‐HT2 or 5‐HT3 receptors in the 5‐HT‐induced effects.

British Journal of Pharmacology (1997) 120, 1144–1150; doi:10.1038/sj.bjp.0700997
The site of general anaesthesia and cytochrome P450 oxygenases: similarities defined by straight chain and cyclic alcohols
Authors: LaBella F S , Chen Q ‐M , Stein D , Queen G 
Published: August 2006

General anaesthetics disrupt normal cell receptivity and responsiveness while sparing vital respiratory processes. Ultimate elucidation of the molecular basis of general anaesthesia presumes the identification of one or more subcellular components with appropriate sensitivity to the entire array of anaesthetics.
Previously, we showed the universal cellular enzymes, cytochrome P450 mono‐oxygenases, to be sensitive at relevant concentrations to all anaesthetics tested. The potential significance of P450 inhibition by anaesthetics resides in the contribution of this enzyme family, in conjunction with that of cyclo‐oxygenases and lipoxygenases, to the generation from arachidonic acid of lipid second messengers, the eicosanoids.
We have shown that P450 enzymes model the site of general anaesthesia in the tadpole with respect to (a) an absolute sensitivity to increasing chain‐length series of flexible, straight chain primary and secondary alcohols and straight chain diols, (b) an absolute sensitivity to increasing molecular weight series of rigid cyclic alkanols and cyclic alkanemethanols, (c) the points of abrupt change and of reversal (cut‐off) in the linear relationship between increasing anaesthetic potency with increasing carbon chain length, and (d) non‐differentiation between secondary alkanol enantiomers. These findings reveal the P450 enzyme family as the most relevant biomolecular counterpart of the site of general anaesthesia, thus far identified.

British Journal of Pharmacology (1997) 120, 1158–1164; doi:10.1038/sj.bjp.0701006
Attenuation of diet‐induced atherosclerosis in rabbits with a highly selective 15‐lipoxygenase inhibitor lacking significant antioxidant properties
Authors: Sendobry Sandra M. , Cornicelli Joseph A. , Welch Kathryn , Bocan Thomas , Tait Bradley , Trivedi Bharat K. , Colbry Norman , Dyer Richard D. , Feinmark Steven J. , Daugherty Alan 
Published: August 2006

15‐Lipoxygenase (15‐LO) has been implicated in the pathogenesis of atherosclerosis because of its localization in lesions and the many biological activities exhibited by its products. To provide further evidence for a role of 15‐LO, the effects of PD 146176 on the development of atherosclerosis in cholesterol‐fed rabbits were assessed. This novel drug is a specific inhibitor of the enzyme in vitro and lacks significant non specific antioxidant properties.
PD 146176 inhibited rabbit reticulocyte 15‐LO through a mixed noncompetitive mode with a Ki of 197 nm. The drug had minimal effects on either copper or 2,2′‐azobis(2‐amidinopropane)hydrochloride (ABAP) induced oxidation of LDL except at concentrations 2 orders higher than the Ki.
Control New Zealand rabbits were fed a high‐fat diet containing 0.25% wt./wt. cholesterol; treated animals received inhibitor in this diet (175 mg kg−1, b.i.d.). Plasma concentrations of inhibitor were similar to the estimated Ki (197 nm). During the 12 week study, there were no significant differences in weight gain, haematocrit, plasma total cholesterol concentrations, or distribution of lipoprotein cholesterol.
The drug plasma concentrations achieved in vivo did not inhibit low‐density lipoprotein (LDL) oxidation in vitro. Furthermore, LDL isolated from PD 146176‐treated animals was as susceptible as that from controls to oxidation ex vivo by either copper or ABAP.
PD 146176 was very effective in suppressing atherogenesis, especially in the aortic arch where lesion coverage diminished from 15±4 to 0% (P<0.02); esterified cholesterol content was reduced from 2.1±0.7 to 0 μg mg−1 (P<0.02) in this region. Immunostainable lipid‐laden macrophages present in aortic intima of control animals were totally absent in the drug‐treated group.
Results of these studies are consistent with a role for 15‐LO in atherogenesis.

British Journal of Pharmacology (1997) 120, 1199–1206; doi:10.1038/sj.bjp.0701007
Nitric oxide production and endothelium‐dependent vasorelaxation induced by wine polyphenols in rat aorta
Authors: Andriambeloson Emile , Kleschyov Andrei L , Muller Bernard , Beretz Alain , Stoclet Jean Claude , Andriantsitohaina Ramaroson 
Published: August 2006

The aim of this work was to investigate the mechanism of vasorelaxation induced by red wine polyphenolic compounds (RWPC) and two defined polyphenols contained in wine, leucocyanidol and catechin. The role of the endothelium, especially endothelium‐derived nitric oxide (NO), was also investigated.
Relaxation produced by polyphenols was studied in rat aortic rings with and without functional endothelium, pre‐contracted to the same extent with noradrenaline (0.3 and 0.1 μm, respectively). RWPC and leucocyanidol, but not catechin, produced complete relaxation of vessels with and without endothelium. However, 1000 fold higher concentrations were needed to relax endothelium‐denuded rings compared to those with functional endothelium.
High concentrations of catechin (in the range of 10−1 g l−1) only produced partial relaxation (maximum 30%) and had the same potency in rings with and without endothelium.
The NO synthase inhibitor, Nω‐nitro‐l‐arginine‐methyl‐ester (l‐NAME, 300 μm) completely abolished the endothelium‐dependent but not the endothelium‐independent relaxations produced by all of the polyphenolic compounds.
In contrast to superoxide dismutase (SOD, 100 u ml−1), neither RWPC nor leucocyanidol affected the concentration‐response curve for the NO donor, SIN‐1 (3‐morpholino‐sydnonimine) which also produces superoxide anion (O2−).
In aortic rings with endothelium, RWPC (10−2 g l−1) produced a 7 fold increase in the basal production of guanosine 3′: 5′‐cyclic monophosphate (cyclic GMP) which was prevented by l‐NAME (300 μm).
Electron paramagnetic resonance (e.p.r.) spectroscopy studies with Fe2+‐diethyldithiocarbamate as an NO spin trap demonstrated that RWPC and leucocyanidol increased NO levels in rat thoracic aorta about 2 fold. This NO production was entirely dependent on the presence of the endothelium and was abolished by l‐NAME (300 μm).
These results show that RWPC and leucocyanidol, but not the structurally closely related polyphenol catechin, induced endothelium‐dependent relaxation in the rat aorta. They indicate that this effect results from enhanced synthesis of NO rather than enhanced biological activity of NO or protection against breakdown by O2−. It is concluded that some polyphenols, with specific structure, contained in wine possess potent endothelium‐dependent vasorelaxing activity.

British Journal of Pharmacology (1997) 120, 1053–1058; doi:10.1038/sj.bjp.0701011
The effects of recombinant rat μ‐opioid receptor activation in CHO cells on phospholipase C, [Ca2+]i and adenylyl cyclase
Authors: Smart D , Hirst R A , Hirota K , Grandy D K , Lambert D G 
Published: August 2006

The rat μ‐opioid receptor has recently been cloned, yet its second messenger coupling remains unclear. The endogenous μ‐opioid receptor in SH‐SY5Y cells couples to phospholipase C (PLC), increases [Ca2+]i and inhibits adenylyl cyclase (AC). We have examined the effects of μ‐opioid agonists on inositol(1,4,5)trisphosphate (Ins(1,4,5)P3), [Ca2+]i and adenosine 3′: 5′‐cyclic monophosphate (cyclic AMP) formation in Chinese hamster ovarian (CHO) cells transfected with the cloned μ‐opioid receptor.
Opioid receptor binding was assessed with [3H]‐diprenorphine ([3H]‐DPN) as a radiolabel. Ins(1,4,5)P3 and cyclic AMP were measured by specific radioreceptor assays. [Ca2+]i was measured fluorimetrically with Fura‐2.
Scatchard analysis of [3H]‐DPN binding revealed that the Bmax varied between passages. Fentanyl (10 pm–1 μm) dose‐dependently displaced [3H]‐DPN, yielding a curve which had a Hill slope of less than unity (0.6±0.1), and was best fit to a two site model, with pKi values (% of sites) of 9.97±0.4 (27±4.8%) and 7.68±0.07 (73±4.8%). In the presence of GppNHp (100 μm) and Na+ (100 mm), the curve was shifted to the right and became steeper (Hill slope=0.9±0.1) with a pKi value of 6.76±0.04.
Fentanyl (0.1 nm–1 μm) had no effect on basal, but dose‐dependently inhibited forskolin (1 μm)‐stimulated, cyclic AMP formation (pIC50=7.42±0.23), in a pertussis toxin (PTX; 100 ng ml−1 for 24 h)‐sensitive and naloxone‐reversible manner (Ki=1.7 nm). Morphine (1 μm) and [d‐Ala2, MePhe4, gly(ol)5]‐enkephalin (DAMGO, 1 μm) also inhibited forskolin (1 μm)‐stimulated cyclic AMP formation, whilst [d‐Pen2, d‐Pen5], enkephalin (DPDPE, 1 μm) did not.
Fentanyl (0.1 nm–10 μm) caused a naloxone (1 μm)‐reversible, dose‐dependent stimulation of Ins(1,4,5)P3 formation, with a pEC50 of 7.95±0.15 (n=5). PTX (100 ng ml−1 for 24 h) abolished, whilst Ni2+ (2.5 mm) inhibited (by 52%), the fentanyl‐induced Ins(1,4,5)P3 response. Morphine (1 μm) and DAMGO (1 μm), but not DPDPE (1 μm), also stimulated Ins(1,4,5)P3 formation. Fentanyl (1 μm) also caused an increase in [Ca2+]i (80±16.4 nm, n=6), reaching a maximum at 26.8±2.5 s. The increase in [Ca2+]i remained elevated until sampling ended (200 s) and was essentially abolished by the addition of naloxone (1 μm). Pre‐incubation with naloxone (1 μm, 3 min) completely abolished fentanyl‐induced increases in [Ca2+]i.
In conclusion, the cloned μ‐opioid receptor when expressed in CHO cells stimulates PLC and inhibits AC, both effects being mediated by a PTX‐sensitive G‐protein. In addition, the receptor couples to an increase in [Ca2+]i. These findings are consistent with the previously described effector‐second messenger coupling of the endogenous μ‐opioid receptor.

British Journal of Pharmacology (1997) 120, 1165–1171; doi:10.1038/sj.bjp.0701012
Naloxone‐insensitive inhibition of acetylcholine release from parasympathetic nerves innervating guinea‐pig trachea by the novel opioid, nociceptin
Authors: Patel Hema J , Giembycz Mark A , Spicuzza Lucia , Barnes Peter J , Belvisi Maria G 
Published: August 2006

The novel peptide, nociceptin and the μ‐opioid agonist [d‐Ala2, N‐Me‐Phe4, Gly5‐ol]‐enkephalin (DAMGO) produced a concentration‐dependent inhibition of electrical field stimulation (EFS)‐evoked release of acetylcholine (ACh) from cholinergic nerves innervating guinea‐pig trachea. The non‐selective opioid receptor antagonist, naloxone, did not antagonize the inhibitory action of nociceptin under conditions where the inhibition of ACh release evoked by DAMGO was completely reversed. It is suggested that DAMGO and nociceptin can inhibit cholinergic, parasympathetic neurotransmission to the airways via the activation of classical (naloxone‐sensitive) and novel (naloxone‐insensitive) opioid receptors, respectively.British Journal of Pharmacology (1997) 120, 735–736; doi:10.1038/sj.bjp.0701013
The ability of a new hypoglycaemic agent, A‐4166, compared to sulphonylureas, to increase cytosolic Ca2+ in pancreatic β‐cells under metabolic inhibition
Authors: Fujitani Shoji , Okazaki Kyoko , Yada Toshihiko 
Published: August 2006

N‐(trans‐4‐isopropylcyclohexanecarbonyl)‐d‐phenylalanine (A‐4166) is a new non‐sulphonylurea oral hypoglycaemic agent which stimulates insulin release by increasing cytosolic Ca2+ concentration ([Ca2+]i) in β‐cells.
We studied comparative effects of A‐4166 and sulphonylureas on [Ca2+]i, measured by dual‐wavelength fura‐2 microfluorometry, in single rat pancreatic β‐cells under normal conditions and conditions where glucose metabolism was inhibited.
A glucokinase inhibitor, mannoheptulose (10 mm), a mitochondrial respiratory inhibitor, KCN (100 μm), and uncouplers, dinitrophenol (DNP, 50 μm) and carbonyl cyanide p‐trifluoromethoxyphenylhydrazone (FCCP, 0.3 μm), were used to abolish glucose‐induced increases in [Ca2+]i in a reversible manner.
Under control conditions, A‐4166 was one order more potent than tolbutamide in increasing [Ca2+]i, and maximal responses were evoked by 30 μm A‐4166 and 300 μm tolbutamide. These equipotent concentrations were employed for the comparative study where glucose metabolism was inhibited.
In the presence of mannoheptulose, [Ca2+]i responses to tolbutamide, but not those to A‐4166, were attenuated in a reversible manner.
KCN, DNP and FCCP inhibited [Ca2+]i responses to tolbutamide to a much greater extent than those to A‐4166. Responses to tolbutamide even at 3.3 times the equipotent concentration (1000 μm) were also markedly attenuated by these inhibitors. Responses evoked by another sulphonylurea, gliclazide, were inhibited by DNP to a larger extent than A‐4166‐induced responses.
The results indicate that A‐4166 acts more effectively than sulphonylureas to increase [Ca2+]i in β‐cells during metabolic inhibition.

British Journal of Pharmacology (1997) 120, 1191–1198; doi:10.1038/sj.bjp.0701017
Evaluation of BTS 67 582, a novel antidiabetic agent, in normal and diabetic rats
Authors: Jones R B , Dickinson K , Anthony D M , Marita A R , Kaul C L , Buckett W R 
Published: August 2006

The effect of BTS 67 582, a novel antidiabetic agent, has been evaluated on plasma glucose and plasma insulin in normal and streptozotocin‐induced diabetic rats.
BTS 67 582 (3 to 300 mg kg−1, p.o.) caused a dose‐ and time‐ dependent reduction in plasma glucose and an increase in plasma insulin in both fasted and glucose‐loaded normal rats. The ED50 for the glucose lowering effect of BTS 67 582 in fasted rats was 37.6, 18.4 and 18.5 mg kg−1 at 1, 2 and 4 h after administration respectively.
In streptozotocin‐induced (50 mg kg−1, i.v.) diabetic rats, BTS 67 582 (37–147 mg kg−1, p.o.) caused significant reductions of plasma glucose following a glucose load, whereas glibenclamide (100 mg kg−1, p.o.) was ineffective. BTS 67 582 significantly increased plasma insulin compared to controls whereas glibenclamide did not.
BTS 67 582 did not displace [3H]‐glibenclamide from its binding sites in rat brain, guinea‐pig ventricle or the HIT‐T15 insulinoma β‐cell line. BTS 67 582 does not therefore appear to modulate its action via an effect on the ‘sulphonylurea’ receptor.
In fasted rats, the glucose lowering effect of BTS 67 582 (100 mg kg−1 p.o.) and glibenclamide (1 mg kg−1, p.o.) were antagonized by diazoxide (30 mg kg−1, i.p.). In addition BTS 67 582, like glibenclamide, caused a dose‐dependent rightward shift of cromakalim‐induced relaxation of noradrenaline precontracted rat aortic strips, suggesting the involvement of KATP channels.
In summary, BTS 67 582 produces a blood glucose‐lowering effect in normal and streptozotocin‐induced diabetic rats associated with increased insulin concentrations. This effect appears to be due to a blockade of ATP‐sensitive potassium channel activity via a different binding site to that of glibenclamide.

British Journal of Pharmacology (1997) 120, 1135–1143; doi:10.1038/sj.bjp.0701019
Induction by staurosporine of nitric oxide synthase expression in vascular smooth muscle cells: role of NF‐κB, CREB and C/EBPβ
Authors: Hecker Markus , Preiß Christiane , Schini‐Kerth Valérie B 
Published: August 2006

The effect of different protein kinase inhibitors on the expression of the inducible isoform of nitric oxide (NO) synthase (iNOS) was investigated in cultured vascular smooth muscle cells (VSMC) isolated from the rat aorta.
The non‐selective protein kinase C (PKC) inhibitor, staurosporine, but not the more selective PKC inhibitors, calphostin C and Ro 31‐8220, or the tyrosine kinase inhibitors, genistein and erbstatin analogue (erbstatin A), elicited a distinct (up to six fold) up‐regulation of iNOS gene expression in these cells, as demonstrated by a parallel increase in iNOS mRNA and protein abundance as well as an accumulation of nitrite (NO2−) in the conditioned medium. Actinomycin D and cycloheximide inhibited the effect of staurosporine, suggesting an involvement of both DNA transcription and de novo protein synthesis.
Staurosporine also synergistically potentiated the stimulating effect of interleukin‐1β (IL‐1β), but not that of the adenylyl cyclase activator, forskolin, on NO2− production and iNOS protein abundance. Staurosporine, on the other hand, had no effect on the IL‐1β‐mediated increase in iNOS mRNA abundance. The effect of staurosporine on both basal and IL‐1β‐stimulated NO2− production was concentration‐dependent with an apparent maximum at 3 nm. Among the other protein kinase inhibitors tested, only calphostin C also enhanced the stimulant effect of IL‐1β approximately two fold, while genistein, erbstatin A and Ro 31‐8220 inhibited rather than potentiated it.
Staurosporine did not influence basal activity of the transcription factors CREB and nuclear factor κB (NF‐κB), but increased that of C/EBP. Moreover, staurosporine significantly augmented the activation of C/EBP by IL‐1β and forskolin.
These findings suggest that in cultured VSMC a staurosporine‐sensitive protein kinase exists, which is unlikely to be related to PKC, that prevents iNOS gene expression presumably by suppressing basal C/EBP activity. They also indicate that NF‐κB and a member of the C/EBP family of transcription factors, presumably C/EBPβ, act synergistically under basal conditions and possibly also following exposure to IL‐1β in the up‐regulation of iNOS gene expression in these cells. Targeting of the activation of C/EBPβ may thus represent an interesting approach to interfere selectively with the cytokine‐induced over‐production of NO in acute and chronic inflammatory conditions.

British Journal of Pharmacology (1997) 120, 1067–1074; doi:10.1038/sj.bjp.0701026
A comparative study on the rat aorta and mesenteric arterial bed of the possible role of nitric oxide in the desensitization of the vasoconstrictor response to an α1‐adrenoceptor agonist
Authors: Kamata Katsuo , Makino Ayako 
Published: August 2006

In thoracic aortic strips with intact endothelium, the first and second (1 h later) dose‐response curves obtained with methoxamine were almost the same.
Methoxamine caused a dose‐dependent increase in perfusion pressure in the rat isolated mesenteric arterial bed, but the second (1 h later) dose‐response curve for methoxamine showed a significant attenuation of the response in comparison with the first.
The attenuation shown by the second dose‐response curve for methoxamine was significantly reduced, but not abolished, in mesenteric arterial beds without endothelium. Incubating endothelium‐intact mesenteric arterial beds with NG‐nitro‐l‐arginine (l‐NOARG) caused a significant, but not complete, reversal of the attenuation shown in the second dose‐response curve.
Incubating the mesenteric arterial bed with capsaicin, tetrodotoxin, indomethacin or with isotonic high k+ (60 mm) plus nicardipine did not affect the above attenuation seen in the second dose‐response curve.
The guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) level in the effluent from the perfused mesenteric arterial bed was significantly increased after the second exposure to methoxamine. This effect was significantly smaller after removal of the endothelium or pretreatment with l‐NOARG.
These results suggest that a desensitization to methoxamine develops rapidly in the mesenteric arterial bed, but not in the aorta, and that release of nitric oxide from the endothelium plays a major role in this desensitization.

British Journal of Pharmacology (1997) 120, 1221–1228; doi:10.1038/sj.bjp.0701031