bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bradykinin B1 and B2 receptors, tumour necrosis factor α and inflammatory hyperalgesia
Authors: Poole S , Lorenzetti B B , Cunha J M , Cunha F Q , Ferreira S H 
Published: January 2005

The effects of BK agonists and antagonists, and other hyperalgesic/antihyperalgesic drugs were measured (3 h after injection of hyperalgesic drugs) in a model of mechanical hyperalgesia (the end‐point of which was indicated by a brief apnoea, the retraction of the head and forepaws, and muscular tremor).
DALBK inhibited responses to carrageenin, bradykinin, DABK, and kallidin.
Responses to kallidin and DABK were inhibited by indomethacin or atenolol and abolished by the combination of indomethacin+atenolol.
DALBK or HOE 140, given 30 min before, but not 2 h after, carrageenin, BK, DABK and kallidin reduced hyperalgesic responses to these agents.
A small dose of DABK+a small dose of BK evoked a response similar to the response to a much larger dose of DABK or BK, given alone.
Responses to BK were antagonized by HOE 140 whereas DALBK antagonized only responses to larger doses of BK. The combination of a small dose of DALBK with a small dose of HOE 140 abolished the response to BK.
The hyperalgesic response to LPS (1 μg) was inhibited by DALBK or HOE 140 and abolished by DALBK+HOE 140. The hyperalgesic response to LPS (5 μg) was not antagonized by DALBK+HOE 140.
These data suggest: (a) a predominant role for B2 receptors in mediating hyperalgesic responses to BK and to drugs that stimulate BK release, and (b) activation of the hyperalgesic cytokine cascade independently of both B1 and B2 receptors if the hyperalgesic stimulus is of sufficient magnitude.

British Journal of Pharmacology (1999) 126, 649–656; doi:10.1038/sj.bjp.0702347
GABAB receptor‐mediated stimulation of adenylyl cyclase activity in membranes of rat olfactory bulb
Authors: Olianas Maria C , Onali Pierluigi 
Published: January 2005

Previous studies have shown that GABAB receptors facilitate cyclic AMP formation in brain slices likely through an indirect mechanism involving intracellular second messengers. In the present study, we have investigated whether a positive coupling of GABAB receptors to adenylyl cyclase could be detected in a cell‐free preparation of rat olfactory bulb, a brain region where other Gi/Go‐coupled neurotransmitter receptors have been found to stimulate the cyclase activity.
The GABAB receptor agonist (−)‐baclofen significantly increased basal adenylyl cyclase activity in membranes of the granule cell and external plexiform layers, but not in the olfactory nerve‐glomerular layer. The adenylyl cyclase stimulation was therefore examined in granule cell layer membranes.
The (−)‐baclofen stimulation (pD2=4.53) was mimicked by 3‐aminopropylphosphinic acid (pD2=4.60) and GABA (pD2=3.56), but not by (+)‐baclofen, 3‐aminopropylphosphonic acid, muscimol and isoguvacine. The stimulatory effect was counteracted by the GABAB receptor antagonists CGP 35348 (pA2=4.31), CGP 55845 A (pA2=7.0) and 2‐hydroxysaclofen (pKi=4.22). Phaclofen (1 mM) was inactive.
The (−)‐baclofen stimulation was not affected by quinacrine, indomethacin, nordihydroguaiaretic acid and staurosporine, but was completely prevented by pertussis toxin and significantly reduced by the α subunit of transducin, a βγ scavenger. The βγ subunits of transducin stimulated the cyclase activity and this effect was not additive with that produced by (−)‐baclofen.
In the external plexiform and granule cell layers, but not in the olfactory nerve‐glomerular layer, (−)‐baclofen enhanced the adenylyl cyclase stimulation elicited by the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) 38.
Conversely, the adenylyl cyclase activity stimulated by either forskolin or Ca2+/calmodulin‐(Ca2+/CaM) was inhibited by (−)‐baclofen in all the olfactory bulb layers examined.
These data demonstrate that in specific layers of rat olfactory bulb activation of GABAB receptors enhances basal and neurotransmitter‐stimulated adenylyl cyclase activities by a mechanism involving βγ subunits of Gi/Go. This positive coupling is associated with a widespread inhibitory effect on forskolin‐ and Ca2+/CaM‐stimulated cyclic AMP formation.

British Journal of Pharmacology (1999) 126, 657–664; doi:10.1038/sj.bjp.0702349
Agonist‐inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656 and AM630
Authors: Ross Ruth A , Brockie Heather C , Stevenson Lesley A , Murphy Vicki L , Templeton Fiona , Makriyannis Alexandros , Pertwee Roger G 
Published: January 2005

We have tested our prediction that AM630 is a CB2 cannabinoid receptor ligand and also investigated whether L759633 and L759656, are CB2 receptor agonists.
Binding assays with membranes from CHO cells stably transfected with human CB1 or CB2 receptors using [3H]‐CP55940, confirmed the CB2‐selectivity of L759633 and L759656 (CB2/CB1 affinity ratios=163 and 414 respectively) and showed AM630 to have a Ki at CB2 receptors of 31.2 nM and a CB2/CB1 affinity ratio of 165.
In CB2‐transfected cells, L759633 and L759656 were potent inhibitors of forskolin‐stimulated cyclic AMP production, with EC50 values of 8.1 and 3.1 nM respectively and CB1/CB2 EC50 ratios of >1000 and >3000 respectively.
AM630 inhibited [35S]‐GTPγS binding to CB2 receptor membranes (EC50=76.6 nM), enhanced forskolin‐stimulated cyclic AMP production in CB2‐transfected cells (5.2 fold by 1 μM), and antagonized the inhibition of forskolin‐stimulated cyclic AMP production in this cell line induced by CP55940.
In CB1‐transfected cells, forskolin‐stimulated cyclic AMP production was significantly inhibited by AM630 (22.6% at 1 μM and 45.9% at 10 μM) and by L759633 at 10 μM (48%) but not 1 μM. L759656 (10 μM) was not inhibitory. AM630 also produced a slight decrease in the mean inhibitory effect of CP55940 on cyclic AMP production which was not statistically significant.
We conclude that AM630 is a CB2‐selective ligand that behaves as an inverse agonist at CB2 receptors and as a weak partial agonist at CB1 receptors. L759633 and L759656 are both potent CB2‐selective agonists.

British Journal of Pharmacology (1999) 126, 665–672; doi:10.1038/sj.bjp.0702351
Endothelium‐derived relaxing, contracting and hyperpolarizing factors of mesenteric arteries of hypertensive and normotensive rats
Authors: Sunano S , Watanabe H , Tanaka S , Sekiguchi F , Shimamura K 
Published: January 2005

Differences in the acetylcholine (ACh)‐induced endothelium‐dependent relaxation and hyperpolarization of the mesenteric arteries of Wistar Kyoto rats (WKY) and stroke‐prone spontaneously hypertensive rats (SHRSP) were studied.
Relaxation was impaired in preparations from SHRSP and tendency to reverse the relaxation was observed at high concentrations of ACh in these preparations.
Relaxation was partly blocked by NG‐nitro‐L‐arginine (L‐NOARG, 100 μM) and, in the presence of L‐NOARG, tendency to reverse the relaxation was observed in response to higher concentrations of ACh, even in preparations from WKY. The relaxation remaining in the presence of L‐NOARG was also smaller in preparations from SHRSP.
The tendency to reverse the relaxation observed at higher concentrations of ACh in preparations from SHRSP or WKY in the presence of L‐NOARG were abolished by indomethacin (10 μM).
Elevating the K+ concentration of the incubation medium decreased relaxation in the presence of both indomethacin and L‐NOARG.
Relaxation in the presence of L‐NOARG and indomethacin was reduced by the application of both apamin (5 μM) and charybdotoxin (0.1 μM). This suggests that the relaxation induced by ACh is brought about by both endothelium‐derived relaxing factor (EDRF, nitric oxide (NO)) and hyperpolarizing factor (EDHF), which activates Ca2+‐sensitive K+ channels.
Electrophysiological measurement revealed that ACh induced endothelium‐dependent hyperpolarization of the smooth muscle of both preparations in the presence of L‐NOARG and indomethacin; the hyperpolarization being smaller in the preparation from SHRSP than that from WKY.
These results suggest that the release of both NO and EDHF is reduced in preparations from SHRSP. In addition, indomethacin‐sensitive endothelium‐derived contracting factor (EDCF) is released from both preparations; the release being increased in preparations from SHRSP.

British Journal of Pharmacology (1999) 126, 709–716; doi:10.1038/sj.bjp.0702355
Functional and molecular biological evidence for a possible β3‐adrenoceptor in the human detrusor muscle
Authors: Igawa Yasuhiko , Yamazaki Yoshinobu , Takeda Hiroo , Hayakawa Kohichi , Akahane Masuo , Ajisawa Yukiyoshi , Yoneyama Takehisa , Nishizawa Osamu , Andersson Karl‐Erik 
Published: January 2005

The possible existence of a β3‐adrenergic receptor (β3‐AR) in the human detrusor muscle was investigated by in vitro functional studies and analysis of mRNA expression.
Isoprenaline, noradrenaline and adrenaline each produced a concentration‐dependent relaxation of the human detrusor. The rank order for their relaxing potencies was isoprenaline (pD2 6.37±0.07) noradrenaline (pD2 6.07±0.12) adrenaline (pD2 5.88±0.11).
Neither dobutamine (β1‐ and β2‐AR agonist) nor procaterol (β2‐AR agonist) produced any significant relaxation at concentrations up to 10−5 M. BRL37344A, CL316243 and CGP‐12177A (β3‐AR agonists), relaxed the preparations significantly at concentrations higher than 10−6 M. The pD2 values for BRL37344A, CL316243 and CGP‐12177A were 6.42±0.25, 5.53±0.09 and 5.74±0.14, respectively.
CGP‐20712A (10−7–10−5 M), a β1‐AR antagonist, did not affect the isoprenaline‐induced relaxation. On the other hand, ICI‐118,551, a β2‐AR antagonist, produced a rightward parallel shift of the concentration‐relaxation curve for isoprenaline only at the highest concentration used (10−5 M) and its pKB value was 5.71±0.19. Moreover, SR58894A (10−7–10−5 M), a β3‐AR antagonist, caused a rightward shift of the concentration‐relaxation curve for isoprenaline in a concentration‐dependent manner. The pA2 value and slope obtained from Schild plots were 6.24±0.20 and 0.68±0.31.
The β1‐, β2‐ and β3‐AR mRNAs were all positively expressed in detrusor smooth muscle preparations in a reverse transcription polymerase chain reaction assay.
In conclusion, the present results provide the first evidence for the existence of the β3‐AR subtype in the human detrusor. They also suggest that the relaxation induced by adrenergic stimulation of the human detrusor is mediated mainly through β3‐AR activation.

British Journal of Pharmacology (1999) 126, 819–825; doi:10.1038/sj.bjp.0702358
Effects of varying the expression level of recombinant human mGlu1α receptors on the pharmacological properties of agonists and antagonists
Authors: Hermans Emmanuel , Challiss R A John , Nahorski Stefan R 
Published: January 2005

Different expression levels of the human type 1α metabotropic glutamate (mGlu1α) receptor were obtained in transfected Chinese hamster ovary cells using an isopropyl β‐D‐thiogalactopyranoside (IPTG) inducible system. Expression of mGlu1α receptors could not be detected using immunoblotting or immunocytochemical approaches in non‐induced cells, however, controlled expression could be induced following IPTG addition in a time‐ and concentration‐dependent manner.
In induced cells (100 μM IPTG, 20 h) the agonists L‐quisqualate or 1‐aminocyclopentane‐1S,3R‐dicarboxylic acid stimulated large increases in [3H]‐inositol (poly)phosphate (in the presence of Li+) and inositol, 1,4,5‐trisphosphate levels.
Induction with 1–100 μM IPTG allowed the receptor density to be increased incrementally and this not only resulted in an increase in the maximum response to L‐quisqualate, 1‐aminocyclopentane‐1S,3R‐dicarboxylic acid and (S)‐3,5‐dihydroxy‐phenylglycine, but also in an increase in the respective potencies of each agent to activate phosphoinositide hydrolysis.
The intrinsic activity of the partial agonist 1‐aminocyclopentane‐1S,3R‐dicarboxylic acid dramatically increased with increasing receptor expression.
The activities of the competitive mGlu1α receptor antagonists (S)‐α‐methyl‐4‐carboxyphenylglycine and (S)‐4‐carboxy‐3‐hydroxyphenylglycine for inhibition of the effects of L‐quisqualate or (S)‐3,5‐dihydroxyphenylglycine were found to be independent of the receptor expression level.
When the mGlu1α receptor was expressed at very high levels, no evidence for receptor constitutive activity could be detected, and none of the antagonists tested revealed either any intrinsic activity or negative efficacy.
These data demonstrate that both the potency and efficacy of mGlu1α receptor agonists are influenced by expression level, whilst mGlu1α receptor antagonist activities are independent of expression level.

British Journal of Pharmacology (1999) 126, 873–882; doi:10.1038/sj.bjp.0702359
The subtype 2 of angiotensin II receptors and pressure‐natriuresis in adult rat kidneys
Authors: Liu K L , Lo M , Grouzmann E , Mutter M , Sassard J 
Published: January 2005

The present work examined the effects of the subtype 2 of angiotensin II (AT2) receptors on the pressure‐natriuresis using a new peptide agonist, and the possible involvement of cyclic guanosine 3′, 5′ monophosphate (cyclic GMP) in these effects.
In adult anaesthetized rats (Inactin, 100 mg kg−1, i.p.) deprived of endogenous angiotensin II by angiotensin converting enzyme inhibition (quinapril, 10 mg kg−1, i.v.), T2‐(Ang II 4–8)2 (TA), a highly specific AT2 receptor agonist (5, 10 and 30 μg kg−1 min−1, i.v.) or its solvent was infused in four groups. Renal functions were studied at renal perfusion pressures (RPP) of 90, 110 and 130 mmHg and urinary cyclic GMP excretion when RPP was at 130 mmHg. The effects of TA (10 μg kg−1 min−1) were reassessed in animals pretreated with PD 123319 (PD, 50 μg kg−1 min−1, i.v.), an AT2 receptor antagonist and the action of the same dose of PD alone was also determined.
Increases in RPP from 90 to 130 mmHg did not change renal blood flow (RBF) but induced 8 and 15 fold increases in urinary flow and sodium excretion respectively. The 5 μg kg−1 min−1 dose of TA was devoid of action. The 10 and 30 μg kg−1 min−1 doses did not alter total RBF and glomerular filtration rate, but blunted pressure‐diuresis and natriuresis relationships. These effects were abolished by PD.
TA decreased urinary cyclic GMP excretion. After pretreatment with PD, this decrease was reversed to an increase which was also observed in animals receiving PD alone.
In conclusion, renal AT2 receptors oppose the sodium and water excretion induced by acute increases in blood pressure and this action cannot be directly explained by changes in cyclic GMP.

British Journal of Pharmacology (1999) 126, 826–832; doi:10.1038/sj.bjp.0702362
Neural modulation of the cyclic electrical and mechanical activity in the rat colonic circular muscle: putative role of ATP and NO
Authors: Plujà Lídia , Fernández Ester , Jiménez Marcel 
Published: January 2005

The rat colonic circular muscle displays cyclic episodes of myenteric potential oscillations (MPOs), each of them associated with a spontaneous contraction. Nifedipine 1 μM abolished both MPOs and their associated contractions. TTX (1 μM) increased the amplitude and frequency of spontaneous contractions.
Electrical field stimulation (EFS) induced a non‐adrenergic non‐cholinergic (NANC) inhibitory junction potential (IJP), with two phases: an initial fast hyperpolarization (characterized by IJP amplitude) and a sustained hyperpolarization (characterized by IJP duration).
Sodium nitroprusside (10 μM) hyperpolarized and abolished spontaneous contractions even in presence of TTX or 1 μM apamin. ATP (100 μM) also hyperpolarized and abolished spontaneous contractions but its effects were decreased by TTX and abolished by apamin.
Suramin (100 μM) or apamin reduced the amplitude of the IJPs, but did not affect their duration. Incubation with L‐NOARG (1 mM) reduced the duration but not the amplitude of the IJPs. In presence of L‐NOARG plus suramin or L‐NOARG plus apamin, both duration and amplitude of the IJPs were reduced but a residual IJP could still be recorded.
We conclude that the mechanical and electrical cyclic activity of the rat colonic circular muscle is modulated but not originated by the enteric nervous system and involves L‐type calcium channel activity. EFS induces release of NANC inhibitory neurotransmitters which hyperpolarize and relax smooth muscle cells. Both ATP and NO are involved in IJP generation: ATP is responsible for the first phase of the IJPs involving activation of apamin‐sensitive potassium channels, whereas NO initiates the second phase which is independent of the activation of such channels.

British Journal of Pharmacology (1999) 126, 883–892; doi:10.1038/sj.bjp.0702363
Selective activation of excitation‐contraction coupling pathways by ETA and ETB receptors in guinea‐pig tracheal smooth muscle
Authors: Inui Takashi , Ninomiya Haruaki , Sasaki Yukio , Makatani Maki , Urade Yoshihiro , Masaki Tomoh , Yamamura Takaki 
Published: January 2005

Signalling events responsible for endothelinA (ETA) and ETB receptor‐induced contraction were examined in epithelium‐denuded guinea‐pig tracheal smooth muscle strips. Selective stimulation of each subtype was achieved by a combination of ET‐1 (100 nM) and ETA and ETB receptor‐selective antagonists, BQ‐123 (10 μM) and BQ‐788 (3 μM), respectively.
Both ETA and ETB receptors induced long‐lasting contraction that was totally dependent on Ca2+ influx. Stimulation of ETA receptor induced both transient and sustained (Ca2+)i increases whereas that of ETB receptor induced only a sustained increase. Suppression of the transient (Ca2+)i increase by U73122 (3 μM) did not affect the ETA‐induced sustained (Ca2+)i increase and tension development. Stimulation of ETA receptor, but not ETB, induced phosphoinositide breakdown and protein kinase C (PKC). The activated PKC contributed to the contraction by increasing the Ca2+‐sensitivity of the contractile apparatus.
Thus, ETA receptor is coupled both with phospholipase C/Ca2+/PKC signalling and Ca2+ influx pathways whereas ETB receptor was coupled only with the latter.
Stimulation of ETB receptor, but not ETA, caused membrane depolarization measured with a fluorescent indicator, bis‐(1,3 dibutylbarbituric acid)‐trimethine oxonol. Both nifedipine (1 μM) and verapamil (10 μM) abolished ETB‐induced Ca2+ influx and contraction, while they barely affected ETA‐induced responses.
Therefore, the Ca2+ influx pathways activated by each subtype appeared to be completely different; ETA and ETB receptors opens voltage‐independent Ca2+ channels and L‐type voltage‐dependent Ca2+ channels, respectively.

British Journal of Pharmacology (1999) 126, 893–902; doi:10.1038/sj.bjp.0702365
Inhibition of inflammatory actions of aminobisphosphonates by dichloromethylene bisphosphonate, a non‐aminobisphosphonate
Authors: Endo Yasuo , Shibazaki Masahiko , Yamaguchi Kouji , Nakamura Masanori , Kosugi Hiroshi 
Published: January 2005

When injected intraperitoneally into mice in doses larger than those used clinically, all the amino derivatives of bisphosphonates (aminoBPs) tested induce a variety of inflammatory reactions such as induction of histidine decarboxylase (HDC, the histamine‐forming enzyme), hypertrophy of the spleen, atrophy of the thymus, hypoglycaemia, ascites and accumulation of exudate in the thorax, and an increase in the number of macrophages and/or granulocytes in the peritoneal cavity of blood. On the other hand, dichloromethylene bisphosphonate (Cl2MBP) a typical non‐aminoBP, has no such inflammatory actions. In the present study, we found that this agent can suppress the inflammatory actions of aminoBPs.
Cl2MBP, when injected into mice before or after injection of 4‐amino‐1‐hydroxybutylidene‐1,1‐bisphosphonic acid (AHBuBP; a typical aminoBP), inhibited the induction of HDC activity by AHBuBP in a dose‐ and time‐dependent manner. The increase in HDC activity induced by AHBuBP was largely suppressed by the injection of an equimolar dose of Cl2MBP. Cl2MBP also inhibited other AHBuBP‐induced inflammatory reactions, as well as the inflammatory actions of two other aminoBPs. However, Cl2MBP did not inhibit the increase in HDC activity induced by lipopolysaccharide (LPS).
We have previously reported that AHBuBP augments the elevation of HDC activity and the production of interleukin‐1β (IL‐1β) that are induced by LPS. These actions of AHBuBP were also inhibited by Cl2MBP.
Based on these results and reported actions of bisphosphonates, the mechanisms underlying the contrasting effects of aminoBPs and Cl2MBP, a non‐aminoBP are discussed. The results suggest that combined administration of Cl2MBP and an aminoBP in patients might be a useful way of suppressing the inflammatory side effects of aminoBPs.

British Journal of Pharmacology (1999) 126, 903–910; doi:10.1038/sj.bjp.0702367
Beta‐adrenoceptor agonist stimulation of pulmonary nitric oxide production in the rabbit
Authors: Adding L Christofer , Agvald Per , Artlich Andreas , Persson Magnus G , Gustafsson Lars E 
Published: January 2005

Nitric oxide (NO) is continuously produced in the lung and is present in exhaled air. We examined the effect of β‐adrenoceptor stimulation on the production of pulmonary NO in rabbits.
Exhaled NO was measured by chemiluminescence in anaesthetized and mechanically ventilated rabbits and in buffer‐perfused rabbit lungs.
Intravenous infusions of adrenaline (0.1–10 μg kg−1  min−1) elicited dose‐dependent increases in exhaled NO. The increases in exhaled NO comprised an initial peak followed by a lower plateau level. The increase in exhaled NO was inhibited by propranolol (1 mg kg−1) but not by phentolamine (1 mg kg−1).
Prenalterol, a β1‐adrenoceptor agonist, and terbutaline, a β2‐adrenoceptor agonist, also caused dose‐dependent increases in exhaled NO. However, prenalterol was >100 times more potent than terbutaline.
Infusions of forskolin (0.01–0.03 μmol kg−1  min−1), an adenylate cyclase stimulator, elicited dose‐dependent decreases in blood pressure and concomitant increases in heart rate but caused no alterations in exhaled NO.
Nimodipine, a L‐type calcium channel blocker, antagonized the increases in exhaled NO in response to prenalterol infusions.
The increases in exhaled NO in response to adrenaline and prenalterol were also present in blood‐free, buffer perfused lungs during constant‐flow conditions.
These results demonstrate that pulmonary nitric oxide production can be enhanced by β‐adrenoceptor stimulation. Furthermore, the results indicate that the β‐adrenergic stimulation of pulmonary NO production is not critically dependent on cyclic AMP formation but may require intact calcium‐channels.

British Journal of Pharmacology (1999) 126, 833–839; doi:10.1038/sj.bjp.0702369
Deficiency of nitric oxide in polycation‐induced airway hyperreactivity
Authors: Meurs Herman , Schuurman Fineke E , Duyvendak Michiel , Zaagsma Johan 
Published: January 2005

Using a perfused guinea‐pig tracheal tube preparation, we investigated the role of endogenous nitric oxide (NO) in polycation‐induced airway hyperreactivity (AHR) to methacholine. Intraluminal (IL) administration of the NO synthase inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME; 100 μM) caused a 1.8 fold increase in the maximal contractile response (Emax) to IL methacholine compared to control, without an effect on the pEC50 (−log10 EC50). The polycation poly‐L‐arginine (100 μg ml−1, IL) similarly enhanced the Emax for methacholine; however, the pEC50 value was also increased, by one log10 unit. L‐NAME had no effect on the enhanced methacholine response of poly‐L‐arginine‐treated airways, while the enhanced agonist response was completely normalized by the polyanion heparin (25 u ml−1, IL). In addition, the effect of L‐NAME was fully restored in the poly‐L‐arginine plus heparin treated airways. The results indicate that, in addition to enhanced epithelial permeability, a deficiency of endogenous NO contributes to polycation‐induced AHR. The latter finding may represent a novel mechanism of AHR induced by eosinophil‐derived cationic proteins in allergic asthma.British Journal of Pharmacology (1999) 126, 559–562; doi:10.1038/sj.bjp.0702372