bluuebunny/crossref_metadata_2025 huggingface dataset:
Resolution of P‐glycoprotein and non‐P‐glycoprotein effects on drug permeability using intestinal tissues from mdr1a (−/−) mice
Authors: Stephens R H , O'Neill C A , Bennett J , Humphrey M , Henry B , Rowland M , Warhurst G
Published: January 2005

Intestinal xenobiotic transporters are a significant barrier to the absorption of many orally administered drugs. P‐glycoprotein (PGP) is the best known, but several others, including members of the multidrug resistance‐associated protein (MRP) family, are also expressed. Definitive information on their precise effect on intestinal drug permeability is scarce due to a lack of specific inhibitors and the difficulty of studying non‐PGP activity in the presence of high PGP expression.

We have investigated the in vitro use of intestinal tissues from PGP knockout (mdr1a (−/−)) mice as a tool for dissecting the mechanisms of intestinal drug efflux. The permeability characteristics of digoxin (DIG), paclitaxel (TAX) and etoposide (ETOP) were measured in ileum from mdr1a (−/−) and wild‐type (FVB) mice mounted in Ussing chambers.

DIG and TAX exhibited marked efflux across FVB tissues (B‐A : A‐B apparent permeability (Papp) ratio 10 and 17 respectively) which was absent in mdr1a (−/−) tissues, confirming that PGP is the sole route of intestinal efflux for these compounds. The A‐B Papp of both compounds was 3 – 5 fold higher in mdr1a (−/−) than in FVB.

Polarized transport of ETOP in FVB tissues was reduced but not abolished in mdr1a (−/−) tissues. Residual ETOP efflux in mdr1a (−/−) tissues was abolished by the MRP inhibitor MK571, indicating involvement of both PGP and MRP.

MK571 abolished calcein efflux in mdr1a (−/−) tissues, while quinidine had no parallel effect in FVB tissues, suggesting involvement of MRP but not PGP.

Tissues from mdr1a (−/−) mice provide a novel approach for investigating the influence of PGP ablation on intestinal permeability and for resolving PGP and non‐PGP mechanisms that modulate drug permeability.

British Journal of Pharmacology (2002) 135, 2038–2046; doi:10.1038/sj.bjp.0704668
Bretylium or 6‐OHDA‐resistant, action potential‐evoked Ca2+ transients in varicosities of the mouse vas deferens
Authors: Jackson V Margaret , Cunnane Tom C
Published: January 2005

Action potential‐evoked calcium transients in varicosities in mouse vas deferens were monitored using laser scanning confocal microscopy. Their significance was examined by comparison with excitatory junction potentials (EJPs) and neurogenic contractions, both indirect measurements of transmitter release. Bretylium abolished EJPs, as well as the ATP and NA‐mediated phases of contraction. However, bretylium revealed a prominent late component of contraction that was atropine‐sensitive. Bretylium abolished calcium transients in 21%, enhanced in 16% and had no effect in 63% of varicosities examined. Pre‐treatment with 6‐OHDA reduced NA levels to below detectable levels but many strings of varicosities still responded to nerve impulses with ‘normal’ calcium transients. Varicosities in which calcium transients were abolished by these agents were sympathetic. The identity of those varicosities in which calcium transients were resistant to bretylium (sympathetic but no uptake‐1 sites, parasympathetic, sensory) remains to be established.

British Journal of Pharmacology (2002) 135, 1845–1850; doi:10.1038/sj.bjp.0704677
BIBN4096BS is a potent competitive antagonist of the relaxant effects of α‐CGRP on human temporal artery: comparison with CGRP(8‐37)
Authors: Verheggen Raphaela , Bumann Katja , Kaumann Alberto J.
Published: January 2005

Release of CGRP during migraine may produce harmful dilatation of cranial arteries, thereby possibly causing pain. We have compared the antagonism by BIBN4096BS and CGRP(8‐37) of the relaxant effects of α‐CGRP on rings of human temporal artery.

α‐CGRP relaxed the arteries precontracted with 9 – 24 mM KCl (−logEC50=9.4) nearly as efficaciously as sodium nitroprusside (10 μM).

BIBN4096BS (0.1 – 100 nM) antagonized the effects of α‐CGRP in surmountable manner with slopes of Schild‐plots not different from unity. −LogKB values of 10.1 and 10.4 were estimated for BIBN4096BS when administered before or during the KCl‐contracture respectively.

BIBN4096BS (1 μM) did not modify the relaxant effects of papaverine and sodium nitroprusside.

CGRP(8‐37) (1 – 10 μM) antagonized the effects of α‐CGRP in a surmountable manner with slopes of Schild‐plots not different from unity. −LogKB values of 6.6 and 6.7 were estimated for CGRP(8‐37) administered before or during the KCl‐contracture respectively.

The high affinity of BIBN4096BS for CGRP receptors of human temporal artery makes it an excellent tool to explore the hypothesis of CGRP‐evoked cerebral vasodilation in migraine.

British Journal of Pharmacology (2002) 136, 120–126; doi:10.1038/sj.bjp.0704682
Cellular basis of endothelial dysfunction in small mesenteric arteries from spontaneously diabetic (db/db−/−) mice: role of decreased tetrahydrobiopterin bioavailability
Authors: Pannirselvam Malarvannan , Verma Subodh , Anderson Todd J , Triggle Chris R
Published: January 2005

Endothelium‐dependent and ‐independent regulation of vascular tone in small mesenteric arteries (SMA) from control (db/db +/?) and diabetic (db/db −/−) mice was compared.

Phenylephrine‐induced maximum contraction, but not sensitivity, of SMA in db/db −/− compared to db/db +/? was enhanced.

Acetylcholine (ACh), but not sodium nitroprusside (SNP), ‐induced relaxation was reduced in SMA from db/db −/− compared to db/db +/?.

ACh‐induced relaxation of SMA was inhibited by a combination of Nω‐nitro‐L‐arginine and indomethacin in db/db +/?, but not in db/db −/−.

Acute incubation of SMA with tetrahydrobiopterin (BH4, 10 μM) and sepiapterin (100 μM) enhanced ACh‐induced relaxation in SMA from db/db −/−, but not from db/db +/? 2,4‐diamino‐6‐hydroxypyrimidine, an inhibitor of GTP cyclohydrolase I, (10 mM), impaired the sensitivity of SMA from db/db +/? to ACh, which was restored by co‐incubation with BH4 (10 μM).

BH4 and superoxide dismutase (SOD, 150 u ml−1), either alone or in combination, had no effect on either ACh or SNP‐induced relaxation in SMA from eNOS −/− mice.

Incubation of SMA with SOD (150 iu ml−1), catalase (200 iu ml−1) and L‐arginine (1 mM) had no effect on ACh‐induced relaxation of SMA. However, the combination of polyethylene glycol‐SOD (200 iu ml−1) and catalase (80 u ml−1) improved the sensitivity of ACh‐induced relaxation in db/db −/−, but not in db/db +/?.

These data suggest that increased production of superoxide anions and decreased availability of BH4 result in an ‘uncoupling’ of nitric oxide synthase and endothelial dysfunction in SMA from db/db −/− mice.

British Journal of Pharmacology (2002) 136, 255–263; doi:10.1038/sj.bjp.0704683
Dissociation of the PAF‐receptor from NADPH oxidase and adenylate cyclase in human neutrophils results in accelerated influx and delayed clearance of cytosolic calcium
Authors: Steel H C. , Anderson R
Published: January 2005

The magnitude and duration of the abruptly occurring increases in cytosolic Ca2+ in human neutrophils following activation with PAF (20 and 200 nM) and FMLP (1 μM), have been compared and related to alterations in NADPH oxidase activity, membrane potential and intracellular cyclic AMP.

Cytosolic Ca2+ and membrane potential were measured by spectrofluorimetry, transmembrane fluxes of Ca2+ by radiometric procedures, and NADPH oxidase activity and cyclic AMP by chemiluminescence and radioimmunoassay respectively.

Activation of neutrophils with both PAF (200 nM) and FMLP (1 μM) was accompanied by an abrupt increase in cytosolic Ca2+, which was of similar magnitude for each activator (393±9 and 378±17 nM respectively). Unlike FMLP‐activated cells in which Ca2+ was rapidly removed from the cytosol, peak levels of cytosolic Ca2+ were sustained for longer (0.14±0.02 vs 1.16±0.04 min, P0.0001) and declined at a slower rate in PAF‐treated neutrophils.

The prolonged elevation of cytosolic Ca2+ in PAF‐treated cells was due to accelerated store‐operated influx of extracellular cation and was attenuated by dibutyryl cyclic AMP (4 mM), the Ca2+‐chelator, EGTA (5 mM), and SKF 96365 (10 μM). In contrast to FMLP, basal levels of superoxide production and cyclic AMP were unaltered in PAF‐activated neutrophils, while only moderate membrane depolarization was detected.

These observations demonstrate that mechanisms which restore Ca2+ homeostasis to FMLP‐activated neutrophils, viz. activation of NADPH oxidase and adenylate cyclase, are not operative in PAF‐treated cells, presenting the potential hazard of Ca2+ overload and hyperactivity.

British Journal of Pharmacology (2002) 136, 81–89; doi:10.1038/sj.bjp.0704685
Release inhibitory receptors activation favours the A2A‐adenosine receptor‐mediated facilitation of noradrenaline release in isolated rat tail artery
Authors: Fresco Paula , Diniz Carmen , Queiroz Glória , Gonçalves Jorge
Published: January 2005

Interactions between A2A‐adenosine receptors and α2‐, A1‐ and P2‐ release‐inhibitory receptors, on the modulation of noradrenaline release were studied in isolated rat tail artery. Preparations were labelled with [3H]‐noradrenaline, superfused with desipramine‐containing medium, and stimulated electrically (100 pulses at 5 Hz or 20 pulses at 50 Hz).

Blockade of α2‐autoreceptors with yohimbine (1 μM) increased tritium overflow elicited by 100 pulses at 5 Hz but not by 20 pulses at 50 Hz.

The selective A2A‐receptor agonist 2‐p‐(2‐carboxyethyl)phenethylamino‐5′‐N‐ethylcarboxamidoadenosine (CGS 21680; 1 – 100 nM) enhanced tritium overflow elicited by 100 pulses at 5 Hz. Yohimbine prevented the effect of CGS 21680, which was restored by the A1‐receptor agonist N6‐cyclopentyladenosine (CPA; 100 nM) or by the P2‐receptor agonist 2‐methylthioadenosine triphosphate (2‐MeSATP; 80 μM).

CGS 21680 (100 nM) failed to increase tritium overflow elicited by 20 pulses at 50 Hz. The α2‐adrenoceptor agonist 5‐bromo‐6‐(2‐imidazolin‐2‐ylamino)‐quinoxaline (UK 14304; 30 nM), the A1‐receptor agonist CPA (100 nM) or the P2‐receptor agonist 2‐MeSATP (80 μM) reduced tritium overflow. In the presence of these agonists CGS 21680 elicited a facilitation of tritium overflow.

Blockade of potassium channels with tetraethylammonium (TEA; 5 mM) increased tritium overflow elicited by 100 pulses at 5 Hz to values similar to those obtained in the presence of yohimbine but did not prevent the effect of CGS 21680 (100 nM) on tritium overflow.

It is concluded that, in isolated rat tail artery, the facilitation of noradrenaline release mediated by A2A‐adenosine receptors is favoured by activation of release inhibitory receptors.

British Journal of Pharmacology (2002) 136, 230–236; doi:10.1038/sj.bjp.0704686
Airway hyperresponsiveness to adenosine induced by lipopolysaccharide in Brown Norway rats
Authors: Tigani B , Hannon J. P. , Rondeau C. , Mazzoni L. , Fozard J. R.
Published: January 2005

We have explored the effects of bacterial endotoxin (lipopolysaccharide; LPS) on the response of the airways of Brown Norway (BN) rats to adenosine. Comparisons have been drawn with the effects on responses to methacholine and 5‐hydroxytryptamine.

In vehicle‐challenged animals, adenosine, given i.v. was only a weak bronchoconstrictor. In contrast, 1 h following intratracheal administration of LPS, 0.3 mg kg−1, bronchoconstrictor responses to adenosine were markedly and selectively enhanced. At this time point, there were no significant changes in leukocyte numbers, eosinophil peroxidase and myeloperoxidase activities or protein concentrations in bronchoalveolar lavage (BAL) fluid. Twenty‐four hours after challenge, the sensitivity of the airways to both adenosine and methacholine was reduced relative to the earlier time point and there were substantial increases in each marker of inflammation in BAL fluid.

The bronchoconstrictor response to adenosine was blocked selectively by methysergide, disodium cromoglycate and the broad‐spectrum adenosine receptor antagonist, 8‐SPT, but not by DPCPX or ZM 243185, selective antagonists for the A1 and A2A receptors, respectively.

Thus, the response to adenosine augmented following LPS is mast cell mediated and involves a receptor which can be blocked by 8‐SPT but not by selective A1 or A2A receptor antagonists. It thus bears similarity to the augmented response to adenosine induced by allergen challenge in actively sensitized BN rats. Exposure to LPS could be a factor along with allergen in determining the increased sensitivity of the airways of asthmatics to adenosine.

British Journal of Pharmacology (2002) 136, 111–119; doi:10.1038/sj.bjp.0704688
Effect of sodium nitroprusside and 8‐bromo cyclic GMP on nerve‐mediated and acetylcholine‐evoked secretory responses in the rat pancreas
Authors: Yago Maria D. , Tapia Jose A. , Salido Gines M. , Adeghate Ernest , Juma Lubna M. O. , Martinez‐Victoria Emilio , Mañas Mariano , Singh Jaipaul
Published: January 2005

The effects of sodium nitroprusside (SNP) and 8‐bromo‐guanosine 3′5′ cyclic monophosphate (8‐Br‐cyclic GMP) on nerve‐mediated and acetylcholine (ACh)‐evoked amylase secretion, tritiated choline ([3H]‐choline) release and on intracellular free calcium concentration ([Ca2+]i) in the isolated rat pancreas were investigated.

Electrical field stimulation (EFS; 10 Hz) and ACh (1×10−5 M) caused large increases in amylase output from pancreatic segments. The response to ACh was blocked by atropine (1×10−5 M) whereas the EFS‐evoked response was markedly reduced but not abolished. In contrast, pretreatment with tetrodotoxin (1×10−6 M) abolished the secretory effect of EFS.

Either SNP (1×10−3 M) or 8‐Br‐cyclic GMP (1×10−4 M) inhibited amylase secretion compared to basal. Combining either SNP or 8‐Br‐cyclic GMP with EFS resulted in a marked decrease in amylase output compared to EFS alone. In contrast, either SNP or 8‐Br‐cyclic GMP had no significant effect on the amylase response to ACh. When extracellular Ca2+ concentration ([Ca2+]o) was elevated from 2.56 mM to 5.12 mM, SNP failed to inhibit the response to EFS.

EFS stimulated the release of 3H from pancreatic segments preloaded with [3H]‐choline. Either SNP or 8‐Br‐cyclic GMP had no effect on basal 3H release but significantly reduced the EFS‐evoked response.

In fura‐2 loaded acinar cells, SNP elicited a small decrease in [Ca2+]i compared to basal and had no effect on the ACh‐induced [Ca2+]i peak response.

Nitric oxide may modulate the release of endogenous neural ACh in response to EFS in the rat pancreas.

British Journal of Pharmacology (2002) 136, 49–56; doi:10.1038/sj.bjp.0704693
Modulation of 5‐HT4 receptor function in the rat isolated ileum by fluoxetine: the involvement of endogenous 5‐hydroxytryptamine
Authors: Tuladhar B R. , Costall B , Naylor R J.
Published: January 2005

The effect of the selective serotonin reuptake inhibitor fluoxetine was examined on the 5‐HT4 receptor‐mediated relaxation in the rat isolated ileum.

Fluoxetine unsurmountably antagonized the relaxation to exogenous 5‐HT with abolition of the response at 10 μM. Fluoxetine (10 μM) also caused a gradual loss of the resting tension. These effects of fluoxetine were prevented by a prior addition of the 5‐HT4 receptor selective antagonist GR113808 (100 nM), which itself caused a contraction of the tissues when administered alone.

Fluoxetine (10 μM) also failed to prevent the relaxation due to exogenous 5‐HT and the 5‐HT4 receptor agonist 5‐methoxytryptamine in tissues taken from the rats treated with para‐chlorophenylalanine (300 mg kg−1) for 3 and 6 days, which reduced the 5‐HT level in the mucosa by 88 and 97.5% respectively.

The contraction of the tissues with GR113808 indicates the presence of an endogenous 5‐HT tone at the 5‐HT4 receptor in the rat ileum. It is hypothesized that in the presence of fluoxetine, the concentration of endogenous 5‐HT at the receptor was increased sufficiently to reduce or abolish the relaxation to 5‐HT added exogenously. The inability of fluoxetine to prevent the relaxation to 5‐HT in the presence of GR113808 or after the p‐CPA treatment supports this hypothesis.

British Journal of Pharmacology (2002) 136 150–156; doi:10.1038/sj.bjp.0704694
Effect of low frequency electromagnetic fields on A2A adenosine receptors in human neutrophils
Authors: Varani Katia , Gessi Stefania , Merighi Stefania , Iannotta Valeria , Cattabriga Elena , Spisani Susanna , Cadossi Ruggero , Borea Pier Andrea
Published: January 2005

The present study describes the effect of low frequency, low energy, pulsing electromagnetic fields (PEMFs) on A2A adenosine receptors in human neutrophils.

Saturation experiments performed using a high affinity adenosine antagonist [3H]‐ZM 241385 revealed a single class of binding sites in control and in PEMF‐treated human neutrophils with similar affinity (KD=1.05±0.10 and 1.08±0.12 nM, respectively). Furthermore, after 1 h of exposure to PEMFs the receptor density was statistically increased (P<0.01) (Bmax =126±10 and 215±15 fmol mg−1 protein, respectively).

The effect of PEMFs was specific to the A2A adenosine receptors. This effect was also intensity, time and temperature dependent.

In the adenylyl cyclase assays the A2A receptor agonists, HE‐NECA and NECA, increased cyclic AMP accumulation in untreated human neutrophils with an EC50 value of 43 (40 – 47) and 255 (228 – 284) nM, respectively. The capability of HE‐NECA and NECA to stimulate cyclic AMP levels in human neutrophils was increased (P<0.01) after exposure to PEMFs with an EC50 value of 10(8 – 13) and 61(52 – 71) nM, respectively.

In the superoxide anion (O2−) production assays HE‐NECA and NECA inhibited the generation of O2− in untreated human neutrophils, with an EC50 value of 3.6(3.1 – 4.2) and of 23(20 – 27) nM, respectively. Moreover, in PEMF‐treated human neutrophils, the same compounds show an EC50 value of 1.6(1.2 – 2.1) and of 6.0(4.7 – 7.5) nM respectively.

These results indicate the presence of significant alterations in the expression and in the functionality of adenosine A2A receptors in human neutrophils treated with PEMFs.

British Journal of Pharmacology (2002) 136, 57–66; doi:10.1038/sj.bjp.0704695
Effects of benzothiazepines on human neuronal nicotinic receptors expressed in Xenopus oocytes
Authors: Sala Francisco , Mulet José , Valor Luis Miguel , Criado Manuel , Sala Salvador
Published: January 2005

We have investigated the effect of diltiazem and its newly synthesized derivative (+,−)‐trans‐3‐acetoxy‐8‐chloro‐2,3‐dihydro‐5[2‐diisopropylamine)ethyl]‐2‐(4‐methoxyphenyl)‐1,5‐benzothiazepin‐4‐(5H)‐ona hydrochloride (JAC‐65) on several recombinant human neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes.

At 3 μM, both drugs have little effect on the maximal currents evoked by brief pulses of acetylcholine (ACh) in five subtypes of nAChRs (α7, α3β2, α4β2, α3β4, and α4β4), showing little selectivity among subtypes.

However, both drugs accelerate the decay of the ionic currents evoked upon continuous stimulation of ACh, being this effect larger with JAC‐65, and in β4*‐nAChRs. Such an effect was dependent on the concentrations of both the drug and of the agonist used, and showed the characteristics of a non‐competitive antagonism.

We have further investigated the effect of both drugs when combined with submicromolar concentrations of nicotine, such as those present in plasma of cigarette smokers, and found that JAC‐65, but not diltiazem, is able to greatly enhance the desensitizing effect of these low concentrations of nicotine, specially in β4*‐nAChRs.

Experiments in α4β4‐nAChRs failed to show voltage dependence of the action of JAC‐65. Moreover, recovery from desensitization followed the same time course regardless of the presence of the drug, suggesting that the main mechanism of action of JAC‐65 does not involve open channel block.

In summary, both drugs, diltiazem and JAC‐65, seem to act through a non‐competitive mechanism, accelerating the decay of the ionic currents, being JAC‐65 more effective than diltiazem at the concentrations used in β4*‐nAChRs. Thus, the differences between both benzothiazepines when measuring various parameters suggest that their mechanisms of action could be slightly different. This would require further investigation.

British Journal of Pharmacology (2002) 136, 183–192; doi:10.1038/sj.bjp.0704699
Reduced coronary vasodilator responses to amlodipine in pacing‐induced heart failure in conscious dogs: role of nitric oxide
Authors: Champagne Stéphane , Hittinger Luc , Héloire François , Suto Yukio , Sambin Lucien , Crozatier Bertrand , Su Jin Bo
Published: January 2005

This study examined whether NO is involved in the in‐vivo coronary vasodilator effects of amlodipine (a calcium channel blocker) and whether heart failure (HF) alters the coronary responses to amlodipine.

Nine conscious dogs were chronically instrumented to measure circumflex coronary blood flow (CBF) and coronary diameter (CD). Drugs were administered directly into the circumflex artery through an indwelling catheter to avoid systemic changes. HF was induced by right ventricular pacing (240 b.p.m., 3 weeks).

Compared with control (C), in HF, coronary responses to acetylcholine (1–10 ng kg−1) were reduced while responses to nitroglycerin (0.1–0.5 μg kg−1) were unchanged. In C, amlodipine (30–150 μg kg−1), increased dose‐dependently CBF and CD. After LNA (a NO synthase inhibitor, 2 mg kg−1), amlodipine produced less increases in CBF and CD (+121±26 ml min−1 and +76±35 μm versus +196±40 ml min−1 and +153±39 μm respectively for 150 μg kg−1 amlodipine alone, both P<0.05). In HF, the coronary responses to amlodipine were reduced (150 μg kg−1 of amlodipine increased CBF and CD +121±23 ml min−1 and +77±21 μm respectively, both P<0.05). After LNA, the CBF responses to amlodipine tended to be reduced (+94±19 ml min−1 at 150 μg kg−1) but CD responses were significantly reduced (+41±16 μm, P<0.05). The supplementation with L‐arginine did not enhance the coronary responses to amlodipine.

These results indicate that, in conscious dogs, NO participates in the coronary responses to amlodipine and in HF, the coronary responses to amlodipine are reduced, which is related to a reduced NO production.

British Journal of Pharmacology (2002) 136, 264–270; doi:10.1038/sj.bjp.0704701
Presynaptic adenosine A2A receptors enhance GABAergic synaptic transmission via a cyclic AMP dependent mechanism in the rat globus pallidus
Authors: Shindou Tomomi , Nonaka Hiromi , Richardson Peter J , Mori Akihisa , Kase Hiroshi , Ichimura Michio
Published: January 2005

We previously reported a presynaptic facilitatory action of A2A receptors on GABAergic synaptic transmission in the rat globus pallidus (GP). In the present study we identify the intracellular signalling mechanisms responsible for this facilitatory action of A2A receptors, using biochemical and patch‐clamp methods in rat GP slices.

The adenosine A2A receptor selective agonist CGS21680 (1, 10 μM) and the adenylyl cyclase activator forskolin (1, 10 μM) both significantly increased cyclic AMP accumulation in GP slices. The CGS21680 (1 μM)‐mediated increase in cyclic AMP was inhibited by the A2A receptor selective antagonist KF17837 (10 μM).

In an analysis of miniature inhibitory postsynaptic currents (mIPSCs), forskolin (10 μM) increased the mIPSC frequency without affecting their amplitude distribution, a result similar to that previously reported with CGS21680.

The adenylyl cyclase inhibitor 9‐(tetrahydro‐2‐furanyl)‐9H‐purin‐6‐amine (SQ22,536, 300 μM) abolished the CGS21680‐induced enhancement in the frequency of mIPSCs.

H‐89 (10 μM), a selective inhibitor for cyclic AMP‐dependent protein kinase (PKA), blocked the CGS21680‐induced enhancement of the mIPSC frequency.

The calcium channel blocker CdCl2 (100 μM) did not prevent CGS21680 from increasing the frequency of mIPSCs.

These results indicate that A2A receptor‐mediated potentiation of mIPSCs in the GP involves the sequential activation of the A2A receptor, adenylyl cyclase, and then PKA, and that this facilitatory modulation could occur independently of presynaptic Ca2+ influx.

British Journal of Pharmacology (2002) 136, 296–302; doi:10.1038/sj.bjp.0704702
Inhibitory effects of tramadol on nicotinic acetylcholine receptors in adrenal chromaffin cells and inXenopusoocytes expressing α7 receptors
Authors: Shiraishi Munehiro , Minami Kouichiro , Uezono Yasuhito , Yanagihara Nobuyuki , Shigematsu Akio , Shibuya Izumi
Published: January 2005

Tramadol has been used clinically as an analgesic; however, the mechanism of its analgesic effects is still unknown.

We used bovine adrenal chromaffin cells to investigate effects of tramadol on catecholamine secretion, nicotine‐induced cytosolic Ca2+concentration ([Ca2+]i) increases and membrane current changes. We also investigated effects of tramadol on α7 nicotinic acetylcholine receptors (AChRs) expressed inXenopusoocytes.

Tramadol concentration‐dependently suppressed carbachol‐induced catecholamine secretion to 60% and 27% of the control at the concentration of 10 and 100 μM, respectively, whereas it had little effect on veratridine‐ or high K+‐induced catecholamine secretion.

Tramadol also suppressed nicotine‐induced ([Ca2+]i) increases in a concentration‐dependent manner. Tramadol inhibited nicotine‐induced inward currents, and the inhibition was unaffected by the opioid receptor antagonist naloxone.

Tramadol inhibited nicotinic currents carried by α7 receptors expressed inXenopusoocytes.

Tramadol inhibited both α‐bungarotoxin‐sensitive and ‐insensitive nicotinic currents in bovine adrenal chromaffin cells.

In conclusion, tramadol inhibits catecholamine secretion partly by inhibiting nicotinic AChR functions in a naloxone‐insensitive manner and α7 receptors are one of those inhibited by tramadol.

British Journal of Pharmacology(2002)136, 207–216; doi:10.1038/sj.bjp.0704703
IL‐1β signalling in glial cells in wildtype and IL‐1RI deficient mice
Authors: Parker Lisa C , Luheshi Giamal N , Rothwell Nancy J , Pinteaux Emmanuel
Published: January 2005

Interleukin‐1 (IL‐1) has been implicated in neurodegeneration and in central nervous system (CNS)‐mediated host defence responses to inflammation. All actions of IL‐1 identified to date appear to be mediated through its only known functional type I receptor (IL‐1RI). However, our recent evidence suggests that some actions of IL‐1 in the brain may be IL‐1RI independent, suggesting the involvement of a new, hitherto unknown functional receptor for IL‐1.

The objective of the present study was to determine if primary mixed glial cells express additional functional IL‐1 receptors by studying the signalling mechanisms responsible for the pro‐inflammatory actions of IL‐1β in cultures derived from IL‐1RI−/− and wildtype mice, and to characterize the functional importance of IL‐1 signalling pathways in glia.

IL‐1β induced marked release of IL‐6 and prostaglandin‐E2 (PGE2) in the culture medium, and activated nuclear factor‐kappa B (NFκB) and the mitogen‐activated protein kinases (MAPK) p38, c‐Jun N‐terminal kinase (JNK) and the extracellular signal‐regulated protein kinase (ERK1/2) in cells from wildtype mice. These responses were dependent on IL‐1RI, since cells isolated from IL‐1R1−/− mice did not demonstrate any of these responses.

In wildtype mice, inhibition of p38 or ERK1/2 MAPKs significantly reduced IL‐1β induced IL‐6 release, whilst the NFκB inhibitor caffeic acid phenethyl ester (CAPE) modulated IL‐1 induced IL‐6 release by action on NFκB and MAPKs pathways.

These data demonstrate that IL‐1RI is essential for IL‐1β signalling in cultured mixed glial cells. Thus IL‐1 actions observed in IL‐1RI−/− mice in vivo may occur via an alternative pathway and/or via different CNS cells.

British Journal of Pharmacology (2002) 136, 312–320; doi:10.1038/sj.bjp.0704715
Pharmacological characterization of the 5‐HT receptors mediating contraction and relaxation of canine isolated proximal stomach smooth muscle
Authors: Janssen P , Prins N H , Meulemans A L , Lefebvre R A
Published: January 2005

We aimed to characterize 5‐HT receptors mediating contraction and relaxation to 5‐HT in dog proximal stomach longitudinal muscle (LM) strips.

Of the tryptamine analogues tested, 5‐HT was the most potent contractile agent at basal length, while 5‐CT was the most potent relaxant of PGF2α‐induced contraction. Neither the contractions to 5‐HT, nor the relaxations to 5‐CT were influenced by tetrodotoxin, illustrating that action potential propagation is not involved.

The 5‐HT‐induced contraction was antagonized by mesulergine (0.03 to 0.3 μM) and ketanserin (2–20 nM), but the antagonism was not of a simple competitive nature, indicating multiple receptor involvement. Ketanserin (3 to 30 nM) and mesulergine (30 nM) competitively antagonized the α‐Me‐5‐HT‐induced contraction (pKB: 8.83±0.09 and pA2: 8.25±0.06 respectively). These affinity values are in line with literature affinities of ketanserin and mesulergine at 5‐HT2A receptors in various bioassays.

The 5‐CT‐induced inhibition of PGF2α‐induced contraction was competitively antagonized by mesulergine (pKB estimate: 8.52±0.12) and by the selective 5‐HT7 receptor antagonist SB‐269970 (pKB estimate: 9.36±0.14). Both pKB estimates are in line with literature affinities of these compounds for 5‐HT7 receptors. Mesulergine (30 nM) and SB‐269970 (10 nM) shifted the relaxant curve to 5‐HT parallel to the right in the presence of ketanserin (0.3 μM) (pA2 estimates of 8.08±0.10 and 8.75±0.14 respectively), indicative of 5‐HT7 receptor involvement.

It is concluded that 5‐HT induces dog proximal stomach (LM) contraction via smooth muscle 5‐HT2A receptors and relaxation via smooth muscle 5‐HT7 receptors.

British Journal of Pharmacology (2002) 136, 321–329; doi:10.1038/sj.bjp.0704716
Effects of thymol on calcium and potassium currents in canine and human ventricular cardiomyocytes
Authors: Magyar János , Szentandrássy Norbert , Bányász Tamás , Fülöp László , Varró András , Nánási Péter P
Published: January 2005

Concentration‐dependent effects of thymol (1–1000 μM) was studied on action potential configuration and ionic currents in isolated canine ventricular cardiomyocytes using conventional microelectrode and patch clamp techniques.

Low concentration of thymol (10 μM) removed the notch of the action potential, whereas high concentrations (100 μM or higher) caused an additional shortening of action potential duration accompanied by progressive depression of plateau and reduction of Vmax.

In the canine cells L‐type Ca current (ICa) was decreased by thymol in a concentration‐dependent manner (EC50: 158±7 μM, Hill coeff.: 2.96±0.43). In addition, thymol (50–250 μM) accelerated the inactivation of ICa, increased the time constant of recovery from inactivation, shifted the steady‐state inactivation curve of ICa leftwards, but voltage dependence of activation remained unaltered. Qualitatively similar results were obtained with thymol in ventricular myocytes isolated from healthy human hearts.

Thymol displayed concentration‐dependent suppressive effects on potassium currents: the transient outward current, Ito (EC50: 60.6±11.4 μM, Hill coeff.: 1.03±0.11), the rapid component of the delayed rectifier, IKr (EC50: 63.4±6.1 μM, Hill coeff.: 1.29±0.15), and the slow component of the delayed rectifier, IKs (EC50: 202±11 μM, Hill coeff.: 0.72±0.14), however, K channel kinetics were not much altered by thymol. These effects on Ca and K currents developed rapidly (within 0.5 min) and were readily reversible.

In conclusion, thymol suppressed cardiac ionic channels in a concentration‐dependent manner, however, both drug‐sensitivities as well as the mechanism of action seems to be different when blocking calcium and potassium channels.

British Journal of Pharmacology (2002) 136, 330–338; doi:10.1038/sj.bjp.0704718
Beneficial effects of caffeic acid phenethyl ester in a rat model of vascular injury
Authors: Maffia Pasquale , Ianaro Angela , Pisano Barbara , Borrelli Francesca , Capasso Francesco , Pinto Aldo , Ialenti Armando
Published: January 2005

The aim of this study was to evaluate whether caffeic acid phenethyl ester (CAPE), an active component of propolis, was able to reduce neointimal formation in a model of endothelial injury of rat carotid artery (balloon angioplasty). Furthermore, we investigated the relationship between neointima formation and nuclear factor‐κB (NF‐κB) activation and we correlated NF‐κB activation to the expression of inducible isoform of cyclo‐oxygenase (COX‐2) in injured carotids.

In control group a significant proliferation of neointima was observed 14 days after balloon angioplasty, which was correlated to an increase of NF‐κB/DNA binding activity as well as p50/p65 nuclear levels compared to those observed in the carotids from sham‐operated rats. Furthermore, NF‐κB activation was correlated to increased COX‐2, but not β‐actin, protein expression.

Treatment of rats for 14 days with CAPE (3, 10, 30 mg kg−1) caused a significant inhibition of all the parameters assayed, except β‐actin protein expression.

These results indicate that treatment with CAPE may lead to a reduction of neointima formation by inhibiting NF‐κB activation and suggest that this agent may have therapeutic relevance for the prevention of human restenosis.

British Journal of Pharmacology (2002) 136, 353–360; doi:10.1038/sj.bjp.0704720
E3040 sulphate, a novel thromboxane synthase inhibitor, blocks the Cl− secretion induced by platelet‐activating factor in isolated rat colon
Authors: Sakai Hideki , Suzuki Tomoyuki , Murota Miki , Oketani Kiyoshi , Uchiumi Takaoki , Murakami Manabu , Takeguchi Noriaki
Published: January 2005

E3040 (6‐hydroxy‐5,7‐dimethyl‐2‐methylamino‐4‐(3‐pyridylmethyl)benzothiazole), is a novel dual inhibitor of 5‐lipoxygenase (5‐LOX) and thromboxane synthase (Tx synthase). Here, we examined the effects of E3040 sulphate, a sulphate conjugate of E3040, on these enzyme activities in cell‐free systems and on the thromboxane A2 (TxA2)‐mediated Cl− secretion induced by platelet‐activating factor (PAF) in isolated rat colons.

E3040 sulphate inhibited Tx synthase activity in a concentration‐dependent manner (IC50=0.013 μM), whereas it induced little effects on 5‐LOX and cyclo‐oxygenase activities (IC50>100 μM) with the cell‐free enzyme assay.

With isolated rat colonic mucosa, E3040 sulphate in a concentration‐dependent manner (IC50=1.8 μM) inhibited the Cl− secretion induced by 10 μM PAF. On the other hand, E3040 sulphate (30 μM) induced no effect on the prostaglandin E2 (0.5 μM)‐ and leukotriene D4 (1 μM)‐induced Cl− secretion in the colon.

PAF (10 μM) increased a release of TxB2, a stable metabolite of TxA2, from the colonic mucosa. This increase was significantly inhibited by subsequent addition of E3040 sulphate (30 μM).

Probenecid (100 μM), an inhibitor of organic anion transporter, abolished the inhibitory effect of E3040 sulphate on the PAF‐induced Cl− secretion. Another inhibitor, sulphobromophthalein (30 μM) partially but significantly attenuated the effect of E3040 sulphate. p‐Aminohippuric acid (1 mM) had no effect.

These findings suggest that E3040 sulphate is a novel Tx synthase inhibitor, and that E3040 sulphate taken up into the colonic cells by organic anion transporters inhibits the PAF‐induced Cl− secretion by blocking a release of TxA2.

British Journal of Pharmacology (2002) 136, 383–390; doi:10.1038/sj.bjp.0704723
Increased arginase activity underlies allergen‐induced deficiency of cNOS‐derived nitric oxide and airway hyperresponsiveness
Authors: Meurs Herman , McKay Sue , Maarsingh Harm , Hamer Marco A M , Macic Lejla , Molendijk Niek , Zaagsma Johan
Published: January 2005

A deficiency of constitutive nitric oxide synthase (cNOS)‐derived nitric oxide (NO), due to reduced availability of L‐arginine, importantly contributes to allergen‐induced airway hyperresponsiveness (AHR) after the early asthmatic reaction (EAR). Since cNOS and arginase use L‐arginine as a common substrate, we hypothesized that increased arginase activity is involved in the allergen‐induced NO deficiency and AHR.

Using a guinea‐pig model of allergic asthma, we addressed this hypothesis by examining the effects of the specific arginase inhibitor Nω‐hydroxy‐nor‐L‐arginine (nor‐NOHA) on the responsiveness to methacholine of isolated perfused tracheae from unchallenged control animals and from animals 6 h after ovalbumin challenge. Arginase activity in these preparations was investigated by measuring the conversion of L‐[14C]arginine to [14C]urea.

Airways from allergen‐challenged animals showed a 2 fold (P<0.001) increase in responsiveness to intraluminal (IL) administration of methacholine compared to controls. A similar hyperresponsiveness (1.8 fold, P<0.01) was observed in control airways incubated with the NOS inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME, 0.1 mM, IL), while L‐NAME had no further effect on the airways from challenged animals.

Remarkably, 5 μM nor‐NOHA (IL) normalized the hyperresponsiveness of challenged airways to basal control (P<0.001), and this effect was fully reversed again by 0.1 mM L‐NAME (P<0.05). Moreover, arginase activity in homogenates of the hyperresponsive airways was 3.5 fold (P<0.001) enhanced compared to controls.

The results indicate that enhanced arginase activity contributes to allergen‐induced deficiency of cNOS‐derived NO and AHR after the EAR, presumably by competition with cNOS for the common substrate, L‐arginine. This is the first demonstration that arginase is involved in the pathophysiology of asthma.

British Journal of Pharmacology (2002) 136, 391–398; doi:10.1038/sj.bjp.0704725
AT2 receptor‐dependent vasodilation is mediated by activation of vascular kinin generation under flow conditions
Authors: Katada Jun , Majima Masataka
Published: January 2005

Physiological roles of angiotensin II type 2 receptor (AT2) are not well defined. This study was designed to investigate the mechanisms of AT2‐dependent vascular relaxation by studying vasodilation in pressurized and perfused rat mesenteric arterial segments.

Perfusion of angiotensin II in the presence of AT1 antagonist elicited vascular relaxation, which was completely dependent on AT2 receptors on endothelium. FR173657 (>1 μM), a bradykinin (BK) B2‐specific antagonist, significantly suppressed AT2‐dependent vasodilation (maximum inhibition: 68.5% at 10 μM).

Kininogen‐deficient Brown Norway Katholiek rats showed a significant reduction in AT2‐mediated vasodilatory response compared with normal wild‐type Brown Norway rats.

Indomethacin (>1 μM), aprotinin (10 μM) and soybean trypsin inhibitor (10 μM) also reduced AT2‐dependent vasodilation.

Our results demonstrated that stimulation of AT2 receptors caused a significant vasodilation through local production of BK in resistant arteries of rat mesentery in a flow‐dependent manner. Such vasodilation counterbalances AT1‐dependent vasoconstriction to regulate the vascular tone.

British Journal of Pharmacology (2002) 136, 484–491; doi:10.1038/sj.bjp.0704731
An investigation of the effects of zaprinast, a PDE inhibitor, on the nitrergic control of the urethra in anaesthetized female rats
Authors: Wibberley Alexandra , Nunn Philip A , Naylor Alasdair M , Ramage Andrew G
Published: January 2005

The effects of L‐NAME and zaprinast were investigated (i.v.) on reflex‐evoked changes in bladder and urethral pressures in urethane‐anaesthetized female rats.

L‐NAME attenuated reflex‐evoked urethral relaxations (65±10%), while zaprinast potentiated these responses (68±24%). L‐NAME and zaprinast also increased baseline urethral pressure and urethral striated muscle (EUS‐EMG) activity. These drugs had little effect on the bladder.

Following pre‐treatment with α‐bungarotoxin (i.v.) to block urethral striated muscle, L‐NAME and zaprinast failed to increase baseline urethral pressure. Further zaprinast failed to alter the size of reflex‐evoked urethral relaxations.

Intra‐urethral zaprinast caused a significant increase while sodium nitroprusside (SNP) and isoprenaline caused decreases in urethral pressure (+14±3%, −25±5%, −29±7%, respectively). These changes were associated with increases in EUS‐EMG activity. After chlorisondamine (i.v.), zaprinast caused a significant fall in urethral pressure, while the decrease in urethral pressure caused by SNP and isoprenaline was potentiated. No changes in EUS‐EMG activity occurred.

These results indicate that a nitrergic pathway mediates reflex‐evoked urethral smooth muscle relaxations. The data also indicates that there is a background release of NO, which reduces sphincter skeletal muscle activity. Further, the ability of zaprinast to potentiate nitrergic evoked urethral relaxations involves an increase in striated muscle tone. This appears to be an indirect result of smooth muscle relaxation and is mediated, at least in part, by a chlorisondamine‐sensitive mechanism.

British Journal of Pharmacology (2002) 136, 399–414; doi:10.1038/sj.bjp.0704735
Central injections of nocistatin or its C‐terminal hexapeptide exert anxiogenic‐like effect on behaviour of mice in the plus‐maze test
Authors: Gavioli Elaine C , Rae Giles A , Calo' Girolamo , Guerrini Remo , De Lima Thereza C M
Published: January 2005

Nocistatin (NST) antagonizes several actions of nociceptin/orphanin FQ (N/OFQ), but acts on distinct receptors. As N/OFQ exerts anxiolytic‐like actions in various tests, its behavioural actions in the elevated plus‐maze (EPM) test were compared with those of bovine NST.

Five minutes after i.c.v. treatment, mice were placed on the EPM for 5 min and entries into and time spent on open and closed arms were recorded alongside other parameters.

NST (0.1 – 3 pmol) reduced percentages of entries into (control 39.6±3.1%, peak effect at 1 pmol NST 8.5±2.9%) and time spent on open arms (control 30.8±2.3%, NST 2.7±1.5%). The C‐terminal hexapeptide of NST (NST‐C6; 0.01 – 10 pmol) closely mimicked these actions of NST, with peak effects at 0.1 pmol.

N/OFQ (1 – 100 pmol) increased percentages of entries into (control 38.5±3.4%; peak effect at 10 pmol N/OFQ 67.9±4.9%) and time spent on open arms (control 32.0±3.8%; N/OFQ 74.9±5.8%). Closed arm entries, an index of locomotor activity, were unchanged by all peptides.

Effects of NST or NST‐C6, but not N/OFQ, were still detectable 15 min after injection. Behaviour of animals co‐injected with NST (1 pmol) or NST‐C6 (0.1 pmol) plus N/OFQ (10 pmol) was indistinguishable from that of controls.

These results reveal potent anxiogenic‐like actions of NST and NST‐C6, and confirm the anxiolytic‐like properties of N/OFQ. As NST and N/OFQ both derive from preproN/OF, anxiety may be modulated in opposing directions depending on how this precursor is processed.

British Journal of Pharmacology (2002) 136, 764–772; doi:10.1038/sj.bjp.0704739
Effects of nitric oxide donors on cardiac contractility in wild‐type and myoglobin‐deficient mice
Authors: Wegener J W , Gödecke A , Schrader J , Nawrath H
Published: January 2005

The effects of the nitric oxide (NO) donors S‐nitroso‐N‐acetylpenicillamine (SNAP), sodium(Z)‐1‐(N,N‐diethylamino)diazen‐1‐ium‐1,2‐diolate (DEA‐NONOate), and (Z)‐1‐[N‐(2‐Aminoethyl)‐N‐(2‐ammonioethyl)amino]diazen‐1‐ium‐1,2‐diolate (DETA‐NONOate) on force of contraction (Fc) were studied in atrial and ventricular muscle strips obtained from wild‐type (WT) and myoglobin‐deficient (myo−/−) mice.

SNAP slightly reduced Fc in preparations from WT mice at concentrations above 100 μM; this effect was more pronounced in myo−/− mice.

DEA‐NONOate reduced Fc in preparations from myo−/− mice to a larger extent than those from WT mice.

DETA‐NONOate reduced Fc in preparations from myo−/− but not from WT mice.

Pre‐incubation with an inhibitor of the soluble guanylyl cyclase (1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one; 100 μM) prevented the effects of SNAP, DEA‐NONOate and DETA‐NONOate on Fc in myo−/− mice.

It is suggested that, in physiological conditions, myoglobin acts as intracellular scavenger preventing NO from reaching its intracellular receptors in cardiomyocytes, whereas, in myoglobin‐deficient conditions, NO is able to reduce contractility via activation of the soluble guanylyl cyclase/cyclic GMP pathway.

British Journal of Pharmacology (2002) 136, 415–420; doi:10.1038/sj.bjp.0704740
Effects of the prostanoids on the proliferation or hypertrophy of cultured murine aortic smooth muscle cells
Authors: Fujino Takayuki , Yuhki Koh‐ichi , Yamada Takehiro , Hara Akiyoshi , Takahata Osamu , Okada Yuji , Xiao Chun‐Yang , Ma Hong , Karibe Hideji , Iwashima Yasunori , Fukuzawa Jun , Hasebe Naoyuki , Kikuchi Kenjiro , Narumiya Shuh , Ushikubi Fumitaka
Published: January 2005

Effects of the prostanoids on the growth of cultured aortic vascular smooth muscle cells (VSMCs) were examined using mice lacking prostanoid receptors.

Proliferation of VSMCs was assessed by measuring [3H]‐thymidine incorporation and the cell number, and their hypertrophy by [14C]‐leucine incorporation and protein content.

In VSMCs from wild‐type mice, expressions of mRNAs for the EP4 and TP were most abundant, followed by those for the IP, EP3 and FP, when examined by competitive reverse transcriptase‐PCR. Those for the EP1, EP2 and DP, however, could not be detected.

AE1‐329, an EP4 agonist, and cicaprost, an IP agonist, inhibited platelet derived growth factor (PDGF)‐induced proliferation of VSMCs from wild‐type mice; these inhibitory effects disappeared completely in VSMCs from EP4−/− and IP−/− mice, respectively. In accordance with these effects, AE1‐329 and cicaprost stimulated cAMP production in VSMCs from wild‐type mice, which were absent in VSMCs from EP4−/− and IP−/− mice, respectively.

Effects of PGE2 on cell proliferation and adenylate cyclase were almost similar with those of AE1‐329 in VSMCs from wild‐type mice, which disappeared in VSMCs from EP4−/− mice.

PGD2 inhibited PDGF‐induced proliferation of VSMCs from both wild‐type and DP−/− mice to a similar extent. This action of PGD2 was also observed in VSMCs from EP4−/− and IP−/− mice.

In VSMCs from wild‐type mice, I‐BOP, a TP agonist, showed potentiation of PDGF‐induced hypertrophy. I‐BOP failed to show this action in VSMCs from TP−/− mice.

The specific agonists for the EP1, EP2 or EP3, and PGF2α showed little effect on the growth of VSMCs.

These results show that PGE2, PGI2 and TXA2 modulate PDGF‐induced proliferation or hypertrophy of VSMCs via the EP4, IP and TP, respectively, and that the inhibitory effect of PGD2 on PDGF‐induced proliferation is not mediated by the DP, EP4 or IP.

British Journal of Pharmacology (2002) 136, 530–539; doi:10.1038/sj.bjp.0704749
Influence of the CB1 receptor antagonist, AM 251, on the regional haemodynamic effects of WIN‐55212‐2 or HU 210 in conscious rats
Authors: Gardiner S M , March J E , Kemp P A , Bennett T
Published: January 2005

In conscious, freely‐moving, male, Sprague‐Dawley rats, the regional haemodynamic responses to the synthetic cannabinoids, WIN‐55212‐2 and HU 210, were compared. The possible involvement of cannabinoid, CB1‐receptors, or β2‐adrenoceptors in the responses to WIN‐55212‐2 and HU 210 were investigated using the CB1‐receptor antagonist, AM 251, or the β2‐adrenoceptor antagonist, ICI 118551, respectively.

Both WIN‐55212‐2 (150 μg kg−1) and HU 210 (100 μg kg−1) had pressor, renal, and mesenteric vasoconstrictor and hindquarters vasodilator actions, although the effects of HU 210 were much more sustained than those of WIN‐55212‐2. Lower doses of the cannabinoids (WIN‐55212‐2, 50 μg kg−1, HU 210, 10 μg kg−1) had less consistent actions.

All the significant cardiovascular effects of WIN‐55212‐2 and HU 210 were antagonized by pretreatment with AM 251 (3 mg kg−1). Furthermore, pretreatment with the β2‐adrenoceptor antagonist, ICI 118551, inhibited the hindquarters vasodilator effects of WIN‐55212‐2 and of HU 210.

On the basis of the present findings, and our earlier work, it is suggested that, in conscious rats, the pressor and vasoconstrictor effects of HU 210 and WIN‐55212‐2 involve cannabinoid‐receptor‐mediated increases in sympathetic activity. The accompanying hindquarters vasodilator actions of these agonists are cannabinoid receptor‐mediated and appear to involve β2‐adrenoceptors.

British Journal of Pharmacology (2002) 136, 581–587; doi:10.1038/sj.bjp.0704750