bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accelerated intimal hyperplasia and increased endogenous inhibitors for NO synthesis in rabbits with alloxan‐induced hyperglycaemia
Authors: Masuda Hiroshi , Goto Moritaka , Tamaoki Satoru , Azuma Hiroshi 
Published: January 2005

We examined whether endogenous inhibitors of NO synthesis are involved in the augmentation of intimal hyperplasia in rabbits with hyperglycaemia induced by alloxan.
Four weeks after the endothelial denudation of carotid artery which had been performed 12 weeks after alloxan, the intimal hyperplasia was greatly augmented with hyperglycaemia. The degree of hyperplasia was assessed using three different parameters of histopathological findings as well as changes in luminal area and intima : media ratio.
There were positive and significant correlations between intima : media ratio, plasma glucose, and concentrations of NG‐monomethyl‐L‐arginine (L‐NMMA) and NG, NG‐dimethyl‐L‐arginine (ADMA) in endothelial cells, that is, the intima : media ratio became greater as plasma glucose and endothelial L‐NMMA and ADMA were increased. Furthermore, endothelial L‐NMMA and ADMA were increased in proportion to the increase in plasma glucose.
In contrast, there were inverse and significant correlations between cyclic GMP production by carotid artery strips with endothelium and plasma glucose, between cyclic GMP production and endothelial L‐NMMA and ADMA, and between the intima : media ratio and cyclic GMP production.
Exogenously applied L‐NMMA and ADMA inhibited cyclic GMP production in a concentration‐dependent manner. IC50 values were determined to be 12.1 μM for the former and 26.2 μM for the latter. The cyclic GMP production was abolished after the deliberate removal of endothelium from the artery strips.
These results suggest that the augmentation of intimal hyperplasia with hyperglycaemia is closely related to increased accumulation of L‐NMMA and ADMA with hyperglycaemia, which would result in an accelerated reduction in NO production/release by endothelial cells.

British Journal of Pharmacology (1999) 126, 211–218; doi:10.1038/sj.bjp.0702298
Modulation of acute and chronic inflammatory processes by cacospongionolide B, a novel inhibitor of human synovial phospholipase A2
Authors: Pastor Pablo García , De Rosa Salvatore , De Giulio Alfonso , Payá Miguel , Alcaraz M José 
Published: January 2005

Cacospongionolide B is a novel marine metabolite isolated from the sponge Fasciospongia cavernosa. In in vitro studies, this compound inhibited phospholipase A2 (PLA2), showing selectivity for secretory PLA2 (sPLA2) versus cytosolic PLA2 (cPLA2), and its potency on the human synovial enzyme (group II) was similar to that of manoalide.
This activity was confirmed in vivo in the 8 h zymosan‐injected rat air pouch, on the secretory enzyme accumulating in the pouch exudate. Cacospongionolide B, that is bioavailable when is given orally, reduced the elevated levels of sPLA2 present in paw homogenates of rats with adjuvant arthritis.
This marine metabolite showed topical anti‐inflammatory activity on the mouse ear oedema induced by 12‐O‐tetradecanoylphorbol acetate (TPA) and decreased carrageenin paw oedema in mice after oral administration of 5, 10 or 20 mg kg−1.
In the mouse air pouch injected with zymosan, cacospongionolide B administered into the pouch, induced a dose‐dependent reduction in the levels of eicosanoids and tumour necrosis factor α (TNFα) in the exudates 4 h after the stimulus. It also had a weak effect on cell migration.
The inflammatory response of adjuvant arthritis was reduced by cacospongionolide B, which did not significantly affect eicosanoid levels in serum, paw or stomach homogenates and did not induce toxic effects.
Cacospongionolide B is a new inhibitor of sPLA2 in vitro and in vivo, with anti‐inflammatory properties in acute and chronic inflammation. This marine metabolite was active after oral administration and able to modify TNFα levels, and may offer an interesting approach in the search for new anti‐inflammatory agents.

British Journal of Pharmacology (1999) 126, 301–311; doi:10.1038/sj.bjp.0702302
Bronchoconstrictor effect of thrombin and thrombin receptor activating peptide in guinea‐pigs in vivo
Authors: Cicala Carla , Bucci Mariarosaria , De Dominicis Gianfranco , Harriot Pat , Sorrentino Ludovico , Cirino Giuseppe 
Published: January 2005

Several thrombin cellular effects are dependent upon stimulation of proteinase activated receptor‐1 (PAR‐1) localized over the cellular surface. Following activation by thrombin, a new N‐terminus peptide is unmasked on PAR‐1 receptor, which functions as a tethered ligand for the receptor itself. Synthetic peptides called thrombin receptor activating peptides (TRAPs), corresponding to the N‐terminus residue unmasked, reproduce several thrombin cellular effects, but are devoid of catalytic activity. We have evaluated the bronchial response to intravenous administration of human α‐thrombin or a thrombin receptor activating peptide (TRAP‐9) in anaesthetized, artificially ventilated guinea‐pigs.
Intravenous injection of thrombin (100 u kg−1) caused bronchoconstriction that was recapitulated by injection of TRAP‐9 (1 mg kg−1). Animal pretreatment with the thrombin inhibitor Hirulog™ (10 mg kg−1  i.v.) prevented thrombin‐induced bronchoconstriction, but did not affect bronchoconstriction induced by TRAP‐9. Both agents did not induce bronchoconstriction when injected intravenously to rats.
The bronchoconstrictor effect of thrombin and TRAP‐9 was subjected to tolerance; however, in animals desensitized to thrombin effect, TRAP‐9 was still capable of inducing bronchoconstriction, but not vice versa.
Depleting animals of circulating platelets prevented bronchoconstriction induced by both thrombin and TRAP‐9.
Bronchoconstriction was paralleled by a biphasic change in arterial blood pressure, characterized by a hypotensive phase followed by a hypertensive phase. Thrombin‐induced hypotension was not subject to tolerance and was inhibited by Hirulog™; conversely, hypertension was subject to tolerance and was not inhibited by Hirulog™. Hypotension and hypertension induced by TRAP‐9 were neither subject to tolerance nor inhibited by Hirulog™.
Our results indicate that thrombin causes bronchoconstriction in guinea‐pigs through a mechanism that requires proteolytic activation of its receptor and the exposure of the tethered ligand peptide. Platelet activation might be triggered by the thrombin effect.

British Journal of Pharmacology (1999) 126, 478–484; doi:10.1038/sj.bjp.0702303
Anaphylactic bronchoconstriction in BP2 mice: interactions between serotonin and acetylcholine
Authors: Eum Seok‐Yong , Norel Xavier , Lefort Jean , Labat Carlos , Vargaftig B Boris , Brink Charles 
Published: January 2005

Immunized BP2 mice developed an acute bronchoconstriction in vivo and airway muscle contraction in vitro in response to ovalbumin (OA) and these contractions were dose dependent.
Methysergide or atropine inhibited OA‐induced bronchoconstriction in vivo and airway muscle contraction in vitro.
Neostigmine potentiated the OA‐induced bronchoconstriction in vivo and airway muscle contraction in vitro of BP2 mice. This potentiation was markedly reduced by the administration of methysergide or atropine and when the two antagonists were administered together, the responses were completely inhibited.
Neostigmine also potentiated the serotonin (5‐HT)‐ and acetylcholine (ACh)‐induced bronchoconstriction and this potentiation was significantly reversed by atropine.
These results indicate that OA provokes a bronchoconstriction in immunized BP2 mice by stimulating the release of 5‐HT, which in turn acts via the cholinergic mediator, ACh.

British Journal of Pharmacology (1999) 126, 312–316; doi:10.1038/sj.bjp.0702304
Taurine modulates IKr but not IKs in guinea‐pig ventricular cardiomyocytes
Authors: Satoh Hiroyasu 
Published: January 2005

Effects of taurine on the delayed rectifier K+ current (IK) in isolated guinea‐pig ventricular cardiomyocytes were examined at different intracellular Ca2+ concentration ([Ca2+]i), using whole‐cell voltage and current clamp techniques. Experiments were performed at 36°C.
Addition of taurine (10–20 mM) decreased the action potential duration (APD) at pCa 8, but increased the APD at pCa 6. Taurine (20 mM) enhanced IK at 70 mV by 22.4±3.1% (n=6, P<0.01) at pCa 8, whereas taurine inhibited the IK by 27.1±2.7% (n=6, P<0.01) at pCa 6. These responses behaved in a concentration‐dependent manner.
The IK is composed of the rapid and slow components (IKr and IKs). When [Ca2+]i was pCa 6, taurine at 20 mM reduced the tail current of IKr at 70 mV by 16.5±2.7% (n=5, P<0.05) and that of IKs at 70 mV by 27.1±2.8% (n=6, P<0.01). In contrast, at pCa 8, the tail currents of IKr and IKs at 70 mV were enhanced by 13.4±3.2% (n=7, P<0.05) and by 22.4±3.1% (n=7, P<0.01), respectively. The voltages of half‐maximum activation (V1/2) for IKr and IKs were not modified by taurine.
Addition of E‐4031 (5 μM) to taurine had a complete blockade of the tail current of IKr, but not IKs. The remained tail current (IKs) in the presence of E‐4031 (5 μM) was not affected by taurine (20 mM), but was blocked by 293B (30 μM).
These results indicate that taurine modulates IKr but not IKs, depending on [Ca2+]i, resulting in regulation of the APD.

British Journal of Pharmacology (1999) 126, 87–92; doi:10.1038/sj.bjp.0702308
Improvement by nefiracetam of β‐amyloid‐(1‐42)‐induced learning and memory impairments in rats
Authors: Yamada Kiyofumi , Tanaka Tomoko , Mamiya Takayoshi , Shiotani Tadashi , Kameyama Tsutomu , Nabeshima Toshitaka 
Published: January 2005

We have previously demonstrated that continuous i.c.v. infusion of amyloid β‐peptide (Aβ), the major constituent of senile plaques in the brains of patients with Alzheimer's disease, results in learning and memory deficits in rats.
In the present study, we investigated the effects of nefiracetam [N‐(2,6‐dimethylphenyl)‐2‐(2‐oxo‐1‐pyrrolidinyl) acetamide, DM‐9384] on Aβ‐(1–42)‐induced learning and memory deficits in rats.
In the Aβ‐(1–42)‐infused rats, spontaneous alternation behaviour in a Y‐maze task, spatial reference and working memory in a water maze task, and retention of passive avoidance learning were significantly impaired as compared with Aβ‐(40–1)‐infused control rats.
Nefiracetam, at a dose range of 1–10 mg kg−1, improved learning and memory deficits in the Aβ‐(1–42)‐infused rats when it was administered p.o. 1 h before the behavioural tests.
Nefiracetam at a dose of 3 mg kg−1 p.o. increased the activity of choline acetyltransferase in the hippocampus of Aβ‐(1–42)‐infused rats.
Nefiracetam increased dopamine turnover in the cerebral cortex and striatum of Aβ‐(1–42)‐infused rats, but failed to affect the noradrenaline, serotonin and 5‐hydroxyindoleacetic acid content.
These results suggest that nefiracetam may be useful for the treatment of patients with Alzheimer's disease.

British Journal of Pharmacology (1999) 126, 235–244; doi:10.1038/sj.bjp.0702309
Role of K+ channels in A2A adenosine receptor‐mediated dilation of the pressurized renal arcuate artery
Authors: Prior H M , Yates M S , Beech D J 
Published: January 2005

Adenosine A2A receptor‐mediated renal vasodilation was investigated by measuring the lumenal diameter of pressurized renal arcuate arteries isolated from the rabbit.
The selective A2A receptor agonist CGS21680 dilated the arteries with an EC50 of 130 nM. The CGS21680‐induced vasodilation was, on average, 34% less in endothelium‐denuded arteries.
The maximum response and the EC50 for CGS21680‐induced vasodilation in endothelium‐intact arteries were not significantly affected by incubation with the K+ channel blockers apamin (100 nM), iberiotoxin (100 nM), 3,4‐diaminopyridine (1 mM), glibenclamide (1 μM) or Ba2+ (10 μM). However, a cocktail mixture of these blockers did significantly inhibit the maximum response by almost 40%, and 1 mM Ba2+ alone or 1 mM Ba2+ in addition to the cocktail inhibited the maximum CGS21680‐response by 58% and about 75% respectively.
CGS21680‐induced vasodilation was strongly inhibited when the extracellular K+ level was raised to 20 mM even though the dilator response to 1 μM levcromakalim, a KATP channel opener drug, was unaffected.
CGS21680‐induced vasodilation was inhibited by 10 μM ouabain, an inhibitor of Na+/K+‐ATPase, but ouabain had a similar inhibitory effect on vasodilation induced by 30 nM nicardipine (a dihydropyridine Ca2+ antagonist) or 1 μM levcromakalim.
The data suggest that K+ channel activation does play a role in A2A receptor‐mediated renal vasodilation. The inhibitory effect of raised extracellular K+ levels on the A2A response may be due to K+‐induced stimulation of Na+/K+‐ATPase.

British Journal of Pharmacology (1999) 126, 494–500; doi:10.1038/sj.bjp.0702310
Endothelium‐dependent hyperpolarization in resting and depolarized mammary and coronary arteries of guinea‐pigs
Authors: Hammarström Anna K M , Parkington Helena C , Tare Marianne , Coleman H A 
Published: January 2005

The membrane potential responses in guinea‐pig coronary and mammary arteries attributable to endothelium‐derived nitric oxide (NO), prostaglandin (PG) and hyperpolarizing factor (EDHF), and to exogenous NO and the prostacyclin analogue, iloprost, were compared at rest and when depolarized with the thromboxane analogue, U46619.
In the coronary artery, stimulation of the endothelium with acetylcholine (ACh) evoked hyperpolarization attributable to NO and a PG with similar pD2s at rest and in the presence of U46619. However, in depolarized tissues, the pD2 of the response attributed to EDHF required a 10 fold lower concentration of ACh compared with at rest.
In the mammary artery, lower concentrations of ACh were required to evoke NO‐ and EDHF‐dependent hyperpolarizations in depolarized mammary artery compared with at rest, while PG‐dependent hyperpolarization did not occur until the concentration of ACh was increased some 10 fold both at rest and in U46619.
The smooth muscle of the coronary artery of guinea‐pigs was some 4 fold more sensitive to exogenous NO and iloprost than was the mammary artery.
In conclusion, the membrane potential response in arteries at rest, that is, in the absence of constrictor, may be extrapolated to events in the presence of constrictor when NO and PG are under study. However, the sensitivity to ACh and the magnitude of the hyperpolarization attributed to EDHF obtained in tissues at rest may underestimate these parameters in depolarized tissues.

British Journal of Pharmacology (1999) 126, 421–428; doi:10.1038/sj.bjp.0702313
Block by fluoxetine of volume‐regulated anion channels
Authors: Maertens Chantal , Wei Lin , Voets Thomas , Droogmans Guy , Nilius Bernd 
Published: January 2005

We have used the whole‐cell patch clamp technique to study the effect of fluoxetine, a commonly used antidepressant drug, on the volume‐regulated anion channel (VRAC) in calf pulmonary artery endothelial (CPAE) cells. We also examined its effects on other Cl− channels, i.e. the Ca2+‐activated Cl− current (ICl,Ca) and the cystic fibrosis transmembrane conductance regulator (CFTR) to assess the specificity of this compound for VRAC.
At pH 7.4 fluoxetine induced a fast and reversible block of the volume‐sensitive chloride current (ICl,swell), with a Ki value of 6.0±0.5 μM (n=6‐9). The blocking efficiency increased with increasing extracellular pH (Ki=0.32±0.01 μM at pH 8.8, n=3‐9), indicating that the blockade is mediated by the uncharged form of fluoxetine.
Fluoxetine inhibited Ca2+‐activated Cl− currents, ICl,Ca, activated by loading CPAE cells via the patch pipette with 1000 nM free Ca2+ (Ki=10.7±1.6 μM at pH 7.4, n=3‐5). The CFTR channel, transiently transfected in CPAE cells, was also inhibited with a Ki value of 26.9±9.4 μM at pH 7.4 (n=3).
This study describes for the first time the effects of fluoxetine on anion channels. Our data reveal a potent block of VRAC at fluoxetine concentrations close to plasma concentrations. The results suggest a hydrophobic interaction with high affinity between uncharged fluoxetine and volume‐activated chloride channels. Ca2+‐activated Cl− currents and CFTR are also blocked by fluoxetine, revealing a novel characteristic of the drug as a chloride channel modulator.

British Journal of Pharmacology (1999) 126, 508–514; doi:10.1038/sj.bjp.0702314
Cell type‐specific ATP‐activated responses in rat dorsal root ganglion neurons
Authors: Ueno Shinya , Tsuda Makoto , Iwanaga Toshihiko , Inoue Kazuhide 
Published: January 2005

The aim of our study is to clarify the relationship between expression pattern of P2X receptors and the cell type of male adult rat (Wistar) dorsal root ganglion (DRG) neurons. We identified the nociceptive cells of acutely dissociated DRG neurons from adult rats type using capsaicin sensitivity.
Two types of ATP‐activated currents, one with fast, the other with slow desensitization, were found under voltage‐clamp conditions. In addition, cells with fast but not slow desensitization responded to capsaicin, indicating that there was a relationship between current kinetics and capsaicin‐sensitivity.
Both types of neurons were responsive to ATP and α, β methylene‐ATP (α,βmeATP). The concentration of α,βmeATP producing half‐maximal activation (EC50) of neurons with fast desensitization was less (11 μM) than that of neurons with slow desensitization (63 μM), while the Hill coefficients were similar. Suramin and pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid tetrasodium (PPADS) antagonized α,βmeATP‐induced currents in both types of neurons.
In situ hybridization revealed that small cells of the DRG predominantly expressed mRNAs of P2X3 and medium‐sized cells expressed mRNAs of P2X2 and P2X3. In contrast, both of mRNAs were not detected in large cells of the DRG.
These results suggest that capsaicin‐sensitive, small‐sized DRG neurons expressed mainly the homomeric P2X3 subunit and that capsaicin‐insensitive, medium‐sized DRG neurons expressed the heteromultimeric receptor with P2X2 and P2X3.

British Journal of Pharmacology (1999) 126, 429–436; doi:10.1038/sj.bjp.0702319
Endogenous nitric oxide in the maintenance of rat microvascular integrity against widespread plasma leakage following abdominal laparotomy
Authors: László Ferenc , Whittle Brendan J R 
Published: January 2005

The role of nitric oxide (NO) in the maintenance of microvascular integrity during minor surgical manipulation has been evaluated in the rat.
The NO synthase inhibitors, NG‐nitro‐L‐arginine methyl ester (L‐NAME, 5 mg kg−1, s.c.) and NG‐monomethyl‐L‐arginine (L‐NMMA, 50 mg kg−1, s.c.) had no effect on microvascular leakage of radiolabelled albumin over 1 h in the stomach, duodenum, jejunum, colon, lung and kidney in the un‐operated conscious or pentobarbitone‐anaesthetized rat.
In contrast, in anaesthetized rats with a midline abdominal laparotomy (5 cm), L‐NAME (1–5 mg kg−1, s.c.) or L‐NMMA (12.5–50 mg kg−1, s.c.) dose‐dependently increased gastrointestinal, renal and pulmonary vascular leakage, effects reversed by L‐arginine pretreatment (300 mg kg−1, s.c., 15 min). These actions were not observed in anaesthetized rats that had only received a midline abdominal skin incision (5 cm).
Pretreatment with a rabbit anti‐rat neutrophil serum (0.4 ml kg−1, i.p.), 4 h before laparotomy, abolished the plasma leakage induced by L‐NAME in all the organs investigated.
These results indicate that the following abdominal laparotomy, inhibition of constitutive NO synthase provokes vascular leakage in the general microcirculation, by a process that may involve neutrophils. Such effects could thus confound studies on the microvascular actions of NO synthase inhibitors using acute surgically prepared in vivo models. The findings thus suggest that constitutively‐formed NO has a crucial role in the maintenance of acute microvascular integrity following abdominal surgical intervention.

British Journal of Pharmacology (1999) 126, 515–521; doi:10.1038/sj.bjp.0702322
Neurogenic plasma leakage in mouse airways
Authors: Baluk Peter , Thurston Gavin , Murphy Thomas J , Bunnett Nigel W , McDonald Donald M 
Published: January 2005

This study sought to determine whether neurogenic inflammation occurs in the airways by examining the effects of capsaicin or substance P on microvascular plasma leakage in the trachea and lungs of male pathogen‐free C57BL/6 mice.
Single bolus intravenous injections of capsaicin (0.5 and 1 μmol kg−1, i.v.) or substance P (1, 10 and 37 nmol kg−1, i.v.) failed to induce significant leakage in the trachea, assessed as extravasation of Evans blue dye, but did induce leakage in the urinary bladder and skin.
Pretreatment with captopril (2.5 mg kg−1, i.v.), a selective inhibitor of angiotensin converting enzyme (ACE), either alone or in combination with phosphoramidon (2.5 mg kg−1, i.v.), a selective inhibitor of neutral endopeptidase (NEP), increased baseline leakage of Evans blue in the absence of any exogenous inflammatory mediator. The increase was reversed by the bradykinin B2 receptor antagonist Hoe 140 (0.1 mg kg−1, i.v.).
After pretreatment with phosphoramidon and captopril, capsaicin increased the Evans blue leakage above the baseline in the trachea, but not in the lung. This increase was reversed by the tachykinin (NK1) receptor antagonist SR 140333 (0.7 mg kg−1, i.v.), but not by the NK2 receptor antagonist SR 48968 (1 mg kg−1, i.v.).
Experiments using Monastral blue pigment as a tracer localized the leakage to postcapillary venules in the trachea and intrapulmonary bronchi, although the labelled vessels were less numerous in mice than in comparably treated rats. Blood vessels of the pulmonary circulation were not labelled.
We conclude that neurogenic inflammation can occur in airways of pathogen‐free mice, but only after the inhibition of enzymes that normally degrade inflammatory peptides. Neurogenic inflammation does not involve the pulmonary microvasculature.

British Journal of Pharmacology (1999) 126, 522–528; doi:10.1038/sj.bjp.0702323
Modulation of ET‐1‐induced contraction of human bronchi by airway epithelium‐dependent nitric oxide release via ETA receptor activation
Authors: Naline Emmanuel , Bertrand Claude , Biyah Keltoum , Fujitani Yasushi , Okada Toshikazu , Bisson Alain , Advenier Charles 
Published: January 2005

The purpose of this work was to investigate whether endothelin‐1 (ET‐1) was able to induce the release of an inhibitory factor from the airway epithelium in isolated human bronchi and to identify this mediator as well as the endothelin receptor involved in this phenomenon.
In intact bronchi, ET‐1 induced a concentration‐dependent contraction (−logEC50=7.92±0.09, n=18) which was potentiated by epithelium removal (−logEC50=8.65±0.11, n=17). BQ‐123, an ETA receptor antagonist, induced a significant leftward shift of the ET‐1 concentration‐response curve (CRC). This leftward shift was abolished after epithelium removal.
L‐NAME (3×10−3 M), an inhibitor of nitric oxide (NO) synthase, induced a significant leftward shift of the ET‐1 CRC, and abolished the potentiation by BQ‐123 (10−8 M) of ET‐1‐induced contraction.
In intact preparations, the ETB receptor antagonist BQ‐788 induced only at 10−5 M a slight rightward shift of the ET‐1 CRC. In contrast, in epithelium‐denuded bronchi or in intact preparations in the presence of L‐NAME, BQ‐788 displayed a non‐competitive antagonism toward ET‐1‐induced contraction.
IRL 1620, a selective ETB receptor agonist, induced a contraction of the isolated bronchus (−logEC50=7.94±0.11, n=19). This effect was not modified by epithelium removal or by BQ‐123. BQ‐788 exerted a competitive antagonism against IRL 1620 which was similar in the presence or absence of epithelium.
These results show that ET‐1 exerts two opposite effects on the human airway smooth muscle. One is contractile via ETB‐receptor activation, the other is inhibitory and responsible of NO release which counteracts via ETA‐receptor activation the contraction.

British Journal of Pharmacology (1999) 126, 529–535; doi:10.1038/sj.bjp.0702327