bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro neuronal and vascular responses to 5‐HT in rats chronically exposed to MDMA
Authors: Cannon Dara M , Keenan Alan K , Guiry Patrick J , Buon Christophe , Baird Alan W , McBean Gethin J 
Published: January 2005

This study examined the effects of chronic exposure of rats to 3,4‐methylenedioxymethamphetamine (MDMA) on [3H]5‐hydroxytryptamine ([3H]5‐HT) re‐uptake into purified rat brain synaptosomes, 5‐HT‐induced isometric contraction of aortic rings and [3H]5‐HT re‐uptake into rat aorta.
Rats were administered MDMA (20 mg kg−1 i.p.) twice daily over 4 days. One, 7, 14 or 21 days post treatment, whole brain synaptosomes and descending thoracic aortic rings were prepared for investigation.
Chronic MDMA treatment significantly reduced the maximum rate (Vmax) of specific high‐affinity [3H]5‐HT re‐uptake 1 day after treatment and for up to 21 days post‐final administration of MDMA. Direct application of MDMA (100 μM) abolished synaptosomal re‐uptake of [3H]5‐HT in vitro.
Chronic MDMA administration significantly reduced the maximum contraction (Emax) to 5‐HT at 1 and 7 days after treatment, but not at 14 or 21 days.
Chronic MDMA administration had no effect on sodium‐dependent [3H]5‐HT re‐uptake into aorta 1 day after treatment, nor did 100 μM MDMA have any direct effect on [3H]5‐HT uptake into aortic rings in vitro.
These results show, for the first time, an altered responsiveness of vascular tissue to MDMA after chronic administration. In addition, they demonstrate a difference in the sensitivity of central and peripheral 5‐HT uptake systems to chronic MDMA exposure, and suggest that the action of MDMA in the cardiovascular system does not arise from a direct effect of MDMA on peripheral 5‐HT transport.

British Journal of Pharmacology (2001) 134, 1455–1460; doi:10.1038/sj.bjp.0704402
Pharmacological delayed preconditioning against ischaemia‐induced ventricular arrhythmias: effect of an adenosine A1‐receptor agonist
Authors: Tissier Renaud , Souktani Rachid , Parent de Curzon Olivier , Lellouche Nicolas , Henry Patrick , Giudicelli Jean‐François , Berdeaux Alain , Ghaleh Bijan 
Published: January 2005

The goal of this study was to investigate the effects of the delayed pharmacological preconditioning produced by an adenosine A1‐receptor agonist (A1‐DPC) against ventricular arrhythmias induced by ischaemia and reperfusion, compared to those of ischaemia‐induced delayed preconditioning (I‐DPC).
Eighty‐nine instrumented conscious rabbits underwent a 2 consecutive days protocol. On day 1, rabbits were randomly divided into four groups: ‘Control’ (saline, i.v.), ‘I‐DPC’ (six 4‐min coronary artery occlusion/4‐min reperfusion cycles), ‘A1‐DPC100’ (N6‐cyclopentyladenosine, 100 μg kg−1, i.v.), and ‘A1‐DPC400’ (N6‐cyclopentyladenosine, 400 μg kg−1, i.v.). On day 2, i.e., 24 h later, the incidence and severity of ventricular arrhythmias during a 30‐min coronary artery occlusion and subsequent reperfusion were analysed in all animals, using an arrhythmia score.
I‐DPC, A1‐DPC100 and A1‐DPC400 significantly reduced the infarct size (34±5, 42±3 and 43±7% of the area at risk, respectively) as compared to Control (55±3% of the area at risk).
During both ischaemia and reperfusion, neither the incidence nor the severity of ventricular arrhythmias were altered by A1‐DPC100, A1‐DPC400 or I‐DPC as compared to Control.
Thus, despite reduction of infarct size induced by delayed preconditioning, A1‐DPC as well as I‐DPC failed to exert any anti‐arrhythmic effect in the conscious rabbit model of ischaemia‐reperfusion.

British Journal of Pharmacology (2001) 134, 1532–1538; doi:10.1038/sj.bjp.0704407
Antianginal effects of hydroxyfasudil, a Rho‐kinase inhibitor, in a canine model of effort angina
Authors: Utsunomiya T , Satoh S , Ikegaki I , Toshima Y , Asano T , Shimokawa H 
Published: January 2005

The effects of Rho‐kinase inhibitor, fasudil, and of a more specific Rho‐kinase inhibitor, hydroxyfasudil, on pacing‐induced myocardial ischaemia were determined in anaesthetized open‐chest dogs.
The dogs were subjected to left anterior descending coronary artery (LAD) stenosis producing a sufficient ischaemia as measured by ST‐segment depression on electrocardiograms only when the hearts were paced 60 beats min−1 above the baseline. After a recovery (nonpacing) period, drugs or saline were infused intravenously over 30 min. The animals were again subjected to 5 min of pacing 25 min after the initiation of the treatment. Hydroxyfasudil (0.1 and 0.3 mg kg−1) and fasudil (0.3 mg kg−1) suppressed the ST‐segment depression.
Hydroxyfasudil and fasudil also increased the regional blood flow of the LAD perfused endomyocardium region in the canine model of effort angina.
To determine the flow profile for hydroxyfasudil in dogs, blood flow in three vascular beds was measured. Hydroxyfasudil (0.3 mg kg−1 for 30 min) significantly increased coronary blood flow and vertebral blood flow, without significantly changing the femoral blood flow.
Hydroxyfasudil had no inotropic or chronotropic effect on the isolated hearts of guinea‐pigs. Hydroxyfasudil (2 mg kg−1 for 20 min) did not affect the PR or QTc interval in anaesthetized dogs.
Inhibition of Rho‐kinase appears to protect myocardium subjected to pacing‐induced ischaemia through the increase in the regional myocardial blood flow. Hydroxyfasudil may be categorized as a novel type of anti‐anginal drug, without any inotropic or chronotropic effects.

British Journal of Pharmacology (2001) 134, 1724–1730; doi:10.1038/sj.bjp.0704410
Hydrogen peroxide induces a greater contraction in mesenteric arteries of spontaneously hypertensive rats through thromboxane A2 production
Authors: Gao Y J , Lee R M K W 
Published: January 2005

Hydrogen peroxide (H2O2) caused a transient contraction in endothelium‐intact (E+) and ‐denuded (E−) mesenteric arteries (MA) from 8 – 10‐month‐old spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto rats (WKY) in a concentration‐dependent manner (10−5 M to 10−3 M).
The contraction to H2O2 in MA (E+ or E−) was greater in SHR than in WKY. Removal of endothelium potentiated the contraction to H2O2 in WKY but not in SHR. Tachyphylaxis to H2O2 was less prominent in SHR than in WKY.
The contraction of aorta to H2O2 (5×10−4 M), expressed as a percentage of 80 mM KCl‐induced contraction, was approximately half of that found in the MA. A greater contraction was found in E+ but not E− SHR aortic rings.
The contraction of MA to H2O2 (5×10−4 M) was greatly inhibited by SQ 29548 and ICI 192605 (thromboxane A2 (TXA2)/prostaglandin H2 receptor antagonists), quinacrine (a phospholipase A2 (PLA2) inhibitor), indomethacin and diclofenac (cyclooxygenase (COX) inhibitors), and furegrelate (a TXA2 synthase inhibitor).
Production of thromboxane B2 induced by H2O2 (5×10−4 M) was greater in SHR MA than in WKY, and was inhibited by quinacrine, indomethacin and diclofenac, and furegrelate, but not by SQ 29584 and ICI 192605.
These results suggested (1) that SHR MA exhibits a higher contraction involving an increased smooth muscle reactivity and less tachyphylaxis to H2O2 than WKY; (2) that a greater production of TXA2 through activation of PLA2‐COX‐TXA2 synthase pathway appeared to be responsible for the enhanced contraction in SHR MA. The enhanced vascular response to H2O2 may be related to hypertension in SHR.

British Journal of Pharmacology (2001) 134, 1639–1646; doi:10.1038/sj.bjp.0704420
A kinetic study on the stereospecific inhibition of KCNQ1 and IKs by the chromanol 293B
Authors: Seebohm G , Lerche C , Pusch M , Steinmeyer K , Brüggemann A , Busch A E 
Published: January 2005

Recently we and others have demonstrated a stereoselective inhibition of slowly activating human IKs (KCNQ1/MinK) and homomeric KCNQ1 potassium channels by the enantiomers of the chromanol 293B. Here, we further characterized the mechanism of the 293B block and studied the influence of the 293B enantiomers on the gating kinetics of both channels after their heterologous expression in Xenopus oocytes.
Kinetic analysis of currents partially blocked with 10 μM of each 293B enantiomer revealed that only 3R,4S‐293B but not 3S,4R‐293B exhibited a time‐dependent block of IKs and KCNQ1 currents, indicating preferential open channel block activity.
Inhibition of both KCNQ1 and IKs channels by 3R,4S‐293B but not by 3S,4R‐293B increased during a 2 Hz train of stimuli.
At high extracellular potassium concentrations the inhibition of KCNQ1 by 3R,4S‐293B and 3S,4R‐293B was unaffected. Drug inhibition of KCNQ1 and IKs by both enantiomers also did not display a significant voltage‐dependence, indicating that 293B does not strongly interact with permeant ions in the pore.
The inhibitory properties of 3R,4S‐293B on IKs‐channels but not those of 3S,4R‐293B fulfill the theoretical requirements for a novel class III antiarrhythmic drug, i.e. positive use‐dependency. This enantiomer therefore represents a valuable pharmacological tool to evaluate the therapeutic efficiency of IKsblockade.

British Journal of Pharmacology (2001) 134, 1647–1654; doi:10.1038/sj.bjp.0704421
Stimulation of nitric oxide synthesis by the aqueous extract of Panax ginseng root in RAW 264.7 cells
Authors: Friedl Roswitha , Moeslinger Thomas , Kopp Brigitte , Spieckermann Paul Gerhard 
Published: January 2005

In this study, we investigated the effect of Panax ginseng root aqueous extracts upon inducible nitric oxide synthesis in RAW 264.7 cells. Panax ginseng root extract has been used in the Asian world for centuries as a traditional herb to enhance physical strength and resistance and is becoming more and more popular in Europe and North America.
Incubation of murine macrophages (RAW 264.7 cells) with increasing amounts of aqueous extracts of Panax ginseng (0.05 – 0.8 μg μl−1) showed a dose dependent stimulation of inducible nitric oxide synthesis.
Polysaccharides isolated from Panax ginseng showed strong stimulation of inducible nitric oxide synthesis, whereas a triterpene‐enriched fraction from an aqueous extract of Panax ginseng did not show any stimulation.
Inducible nitric oxide synthase protein expression was enhanced in a dose dependent manner as revealed by immunoblotting when cells were incubated with increasing amounts of Panax ginseng extract. This was associated with an incline in inducible nitric oxide synthase mRNA‐levels as determined by semiquantitative polymerase chain reaction and electromobility shift assay studies indicated enhanced nuclear factor‐κB DNA binding activity.
As nitric oxide plays an important role in immune function, Panax ginseng treatment could modulate several aspects of host defense mechanisms due to stimulation of the inducible nitric oxide synthase.

British Journal of Pharmacology (2001) 134, 1663–1670; doi:10.1038/sj.bjp.0704425
In vitro and in vivo assessment of cellular permeability and pharmacodynamics of S‐nitrosylated Captopril, a nitric oxide donor
Authors: Jia Lee , Wong Hong 
Published: January 2005

The present studies were aimed at testing the hypothesis that S‐nitrosylated captopril (CapNO), a novel crystalline nitric oxide (NO) donor, readily permeates both in vitro and in vivo endothelial monolayers, resulting in its pharmacodynamic effects.
CapNO and Captopril (Cap) were added to apical side of endothelial monolayers formed on microporous membranes, and the permeated drugs were collected from basolateral side and detected by a HPLC method. The permeability coefficient (Papp; cm sec−1) of CapNO across the endothelial monolayers was 6.0×10−5, higher than that of Cap (3.13×10−5), indicating the enhancement effect of the attached NO group in CapNO on cellular permeability. The Papp of CapNO and Cap across Caco‐2 cells were 3.15×10−5 and 1.53×10−5, respectively. The low Papp of CapNO to Caco‐2 cells may be attributed to the high membrane resistance of Caco‐2 cells.
A bolus injection of CapNO to epicardial coronary artery of chronically‐instrumented awake dogs caused significant increases in coronary blood flow and coronary diameters dose‐dependently without significant changes in aortic pressure. In contrast, the equimolar doses of Cap did not produce haemodynamic responses.
Intravenous CapNO caused an instant increase in the regional cerebral blood flow determined by H2‐clearance, whereas the equimolar doses of Cap did not enhance the cerebral blood flow.
These results conclude that the NO group, an active component of CapNO, enhances both in vitro and in vivo endothelial permeability to the entire compound, resulting in instant increases in blood flow and vascular diameters. In contrast, the equimolar Cap does not have the instant vascular effects.

British Journal of Pharmacology (2001) 134, 1697–1704; doi:10.1038/sj.bjp.0704431
Interactive contribution of NK1 and kinin receptors to the acute inflammatory oedema observed in response to noxious heat stimulation: studies in NK1 receptor knockout mice
Authors: Rawlingson Andrew , Gerard Norma P , Brain Susan D 
Published: January 2005

Scald injury in Sv129+C57BL/6 mice induced a temperature and time dependent oedema formation as calculated by the extravascular accumulation of [125I]‐albumin. Oedema formation was suppressed in NK1 knockout mice compared to wildtypes at 10 (P<0.01) and 30 min (P<0.001). However, at 60 min a similar degree of extravasation was observed in the two groups.
Kinin B1 (des‐Arg10 Hoe 140; 1 μmol kg−1) and B2 (Hoe 140; 100 nmol kg−1) antagonists caused an inhibition of oedema in wildtype mice at 10 and 30 min (P<0.001), but not at 60 min or at 30 min in NK1 receptor knockout mice.
The inhibition of thermic oedema by des‐Arg10 Hoe 140 was reversed by des‐Arg9 bradykinin (0.1 μmol kg−1; P<0.01) and also observed with a second B1 receptor antagonist (des‐Arg9 Leu8 bradykinin; 3 μmol kg−1; P<0.01). Furthermore des‐Arg10 Hoe 140 had no effect on capsaicin (200 μg ear−1) ear oedema, but this was significantly reduced with Hoe 140 (P<0.05).
Scalding induced a large neutrophil accumulation at 4 h, as assessed by myeloperoxidase assay (P<0.001). This was not suppressed by NK1 receptor deletion or kinin antagonists.
These results confirm an essential role for the NK1 receptor in mediating the early, but not the delayed phase of oedema formation or neutrophil accumulation in response to scalding. The results also demonstrate a pivotal link between the kinins and sensory nerves in the microvascular response to burn injury, and for the first time show a rapid involvement of the B1 receptor in murine skin.

British Journal of Pharmacology (2001) 134, 1805–1813; doi:10.1038/sj.bjp.0704436
RETRACTED: Pyrrolidine dithiocarbamate attenuates the development of acute and chronic inflammation
Authors: Cuzzocrea Salvatore , Chatterjee Prabal K , Mazzon Emanuela , Dugo Laura , Serraino Ivana , Britti Domenico , Mazzullo Giuseppe , Caputi Achille P , Thiemermann Christoph 
Published: January 2005

The nuclear factor‐κB (NF‐κB) is a transcription factor which plays a pivotal role in the induction of genes involved in physiological processes as well as in the response to injury and inflammation. Dithiocarbamates are antioxidants which are potent inhibitors of NF‐κB.
We postulated that pyrrolidine dithiocarbamate (PDTC) would attenuate inflammation. In the present study we investigate the effects of PDTC in animal models of acute and chronic inflammation (carrageenan‐induced pleurisy and collagen‐induced arthritis).
We report here for the first time that PDTC (given at 100, 30 or 10 mg kg−1 i.p. in the pleurisy model or at 10 mg kg−1 i.p. every 48 h in the arthritis model) exerts potent anti‐inflammatory effects (e.g. significant reduction of (A) pleural exudate formation, (B) polymorphonuclear cell infiltration, (C) lipid peroxidation, (D) inducible nitric oxide synthase (iNOS) activity and nitric oxide production (E) plasma and pleural exudates levels of interleukin‐1β and tumour necrosis factor‐α, (F) histological injury and (G) delayed development of clinical indicators).
Furthermore, PDTC reduced immunohistochemical evidence of (A) formation of nitrotyrosine, (B) activation of poly (ADP‐ribose) polymerase (PARP), (C) expression of iNOS and (D) expression of cyclo‐oxygenase‐2 (COX‐2) in the lungs of carrageenan‐treated mice and in the joints from collagen‐treated mice.
Additionally, Western blotting and immunohistochemical analysis of lung tissue revealed that PDTC prevented degradation of IKB‐α and translocation of NF‐κB from the cytoplasm into the nucleus.
Taken together, our results clearly demonstrate that prevention of the activation of NF‐κB by PDTC reduces the development of acute and chronic inflammation. Therefore, inhibition of NF‐κB may represent a novel approach for the therapy of inflammation.

British Journal of Pharmacology (2002) 135, 496–510; doi:10.1038/sj.bjp.0704463
The role of migrating leukocytes in IL‐1β‐induced up‐regulation of kinin B1 receptors in rats
Authors: Campos Maria M , De Souza Glória E P , Ricci Natasha D , Pesquero Jorge L , Teixeira Mauro M , Calixto João B 
Published: January 2005

The present study examines the role of migrating leukocytes in the ability of IL‐1β to induce the functional up‐regulation of B1 receptors, as assessed by kinin B1 agonist‐induced oedema in the rat paw.
Pre‐treatment with the PAF receptor antagonist WEB 2086 inhibited des‐Arg9‐BK‐induced oedema in IL‐1β‐treated paws, while the LTB4 receptor antagonist CP105696 had no effect. Des‐Arg9‐BK‐induced paw oedema was also inhibited by pre‐treatment with the selectin blocker fucoidin or by an anti‐CD‐18 monoclonal antibody.
I.d. injection of IL‐1β produced a 5 – 10‐fold increase of myeloperoxidase (MPO) activity in the rat paw. The increase in MPO activity was significantly inhibited by WEB 2086 (46±9%), fucoidin (68±5%) or the CD‐18 antibody (84±3%). In contrast, i.d. injection of TNFα a dose known to upregulate the B1 receptor functionally did not induce any significant increase in MPO activity.
Des‐Arg9‐BK alone had no effect in MPO activity but enhanced (by about 40%) the response induced by IL‐1β, an effect prevented by the B1 receptor antagonist des‐Arg9‐[Leu8]‐BK.
The concentration of TNF‐α was increased in the paws after i.d. injection of IL‐1β. Pre‐treatment with fucoidin, WEB 2086, anti‐CD‐18 or CP 105695, significantly reversed the local increases in TNF‐α concentrations (80±2; 75±4, 73±3 and 40±2%), respectively.
Finally, IL‐1β induced an increase of B1 receptor mRNA levels in the rat paw, an effect which was prevented by fucoidin treatment.
Taken together, these results indicate that up‐regulation of B1 receptors in the rat paw following IL‐1β seems to involve the local recruitment of neutrophils and subsequent local TNF‐α production. The cross‐talk between kinins, cytokines and leukocytes implicate B1 receptors in chronic inflammatory diseases.

British Journal of Pharmacology (2002) 135, 1107–1114; doi:10.1038/sj.bjp.0704488
Intracellular distribution of peroxynitrite during doxorubicin cardiomyopathy: evidence for selective impairment of myofibrillar creatine kinase
Authors: Mihm Michael J , Yu Fushun , Weinstein David M , Reiser Peter J , Bauer John Anthony 
Published: January 2005

Cardiac peroxynitrite and protein nitration are increased during doxorubicin cardiotoxicity, but the intracellular targets and functional consequences have not been defined. We investigated the intracellular distribution of protein nitration during doxorubicin cardiotoxicity in mice. Following in vivo cardiac function assessments by echocardiography, cardiac tissues were prepared for immunohistochemistry and electron microscopy 5 days after doxorubicin (20 mg kg−1) or vehicle control. Increased cardiac 3‐nitrotyrosine was observed using light microscopy in doxorubicin treated animals. Immunogold electron microscopy (55,000×) revealed increased myofibrillar and mitochondrial 3‐nitrotyrosine levels following doxorubicin, but cellular 3‐nitrotyrosine density was 2 fold higher in myofibrils. We therefore investigated the actions of peroxynitrite on intact cardiac contractile apparatus. Skinned ventricular trabeculae were exposed to physiologically relevant peroxynitrite concentrations (50 or 300 nM) for 1 h, then Ca2+ induced contractile responses were measured in the presence of ATP (4 mM) or phosphocreatine (12 mM) as high energy phosphate supplier. ATP maximal force generation was unaltered after 50 nM peroxynitrite, but phosphocreatine/ATP response was reduced (0.99±0.63 vs 1.59±0.11), suggesting selective inactivation of myofibrillar creatine kinase (MM‐CK). Reduction of ATP maximal force was observed at 300 nM peroxynitrite and phosphocreatine/ATP response was further reduced (0.64±0.30). Western blotting showed concentration dependent nitration of MM‐CK in treated trabeculae. Similarly, cardiac tissues from doxorubicin treated mice demonstrated increased nitration and inactivation of MM‐CK compared to controls. These results demonstrate that peroxynitrite‐related protein nitration are mechanistic events in doxorubicin cardiomyopathy and that the cardiac myofibril is an important oxidative target in this setting. Furthermore, MM‐CK may be a uniquely vulnerable target to peroxynitrite in vivo. British Journal of Pharmacology (2002) 135, 581–588; doi:10.1038/sj.bjp.0704495
A NO‐releasing derivative of acetaminophen spares the liver by acting at several checkpoints in the Fas pathway  THIS ARTICLE HAS BEEN RETRACTED
Authors: Fiorucci Stefano , Antonelli Elisabetta , Mencarelli Andrea , Palazzetti Barbara , Alvarez‐Miller Lorena , Muscara Marcelo , Del Soldato Piero , Sanpaolo Laura , Wallace John L , Morelli Antonio 
Published: January 2005

NCX‐701 is a nitric oxide (NO)‐releasing acetaminophen (APAP) derivative.
In the present study we demonstrated that NCX‐701 is as effective as APAP in controlling body temperature in a rat model of endotoxin‐induced fever.
Liver toxicity is a major complication of APAP overdosing. To investigate whether NCX‐701 is hepatotoxic, BALB/C mice were injected with 100 – 500 mg kg−1 APAP or NCX‐701 alone or in combination (i.e. 500 mg kg−1 of both compounds). Our results demonstrated that although APAP caused a dose‐dependent liver injury, NCX‐701 was completely devoid of liver toxicity. At the dose of 500 mg kg−1 APAP caused an ∼40 fold increase of AST plasma levels and extensive centrilobular necrosis.
APAP and NCX‐701 share the same metabolic pathway as demonstrated by the time‐course of APAP‐glucuronide concentrations in plasma and liver.
NCX‐701 was safe in mice with pre‐existing chronic liver disease. Indeed, while C57BL6 transgenic mice expressing the hepatitis B virus (HBV) at the age of 8 months were significantly more susceptible to liver damage induced by APAP (500 mg kg−1) than their congenic littermates, treating HBV‐transgenic mice with NCX‐701, 500 mg kg−1, caused no damage.
Co‐administration of NCX‐701 at the dose 500 mg kg−1 to mice treated with APAP, 500 mg kg−1, completely protected against liver damage induced by APAP.
APAP, but not NCX‐701, upregulated liver Fas and Fas Ligand mRNA expression in vivo. Incubating mouse hepatocytes with APAP, but not with NCX‐701, increased cell surface Fas expression and sensitized hepatocytes to death induced by challenge with a Fas‐agonistic antibody.
Collectively, these observations suggest that APAP toxicity is Fas mediated and that NCX‐701 spares the liver by acting at several checkpoints in the Fas pathway.

British Journal of Pharmacology (2002) 135, 589–599; doi:10.1038/sj.bjp.0704500