bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antithrombotic efficacy of a novel factor Xa inhibitor, FXV673, in a canine model of coronary artery thrombolysis
Authors: Rebello Sam S , Bentley Ross G , Morgan Suzanne R , Kasiewski Charles J , Chu Valeria , Perrone Mark H , Leadley Robert J 
Published: January 2005

We compared the antithrombotic efficacy of a potent factor Xa inhibitor, FXV673, to heparin and RPR109891, a GPIIb/IIIa antagonist, when used as adjunctive therapy in a canine model of rt‐PA‐induced coronary thrombolysis.
Thrombus formation was induced by electrolytic injury to stenosed coronary artery. After thrombotic occlusion, a 135 min infusion of saline (n=8), FXV673 (10, 30 or 100 μg kg−1+1, 3, or 10 μg kg−1 min−1, respectively; n=8 per dose), heparin (60 u kg−1+0.7 u kg−1 min−1, n=8), or RPR109891 (30 μg kg−1+0.45 μg kg−1 min−1, n=8), was initiated. Aspirin (5 mg kg−1, i.v.) was administered to all animals. Fifteen minutes after the start of drug infusion, rt‐PA was administered (100 μg kg−1+20 μg kg−1 min−1 for 60 min).
The incidence of reperfusion in the high dose FXV673 (8/8, 100%) was significantly greater than that in the heparin group (4/8, 50%), with a trend to faster reperfusion (23±5 min for FXV673 versus 41±11 min for heparin). Only 2/8 (25%) of the vessels reoccluded in the high dose FXV673 group, compared to 4/4 (100%) and 5/5 (100%) vessels in the heparin and RPR109891 groups, respectively (P<0.05).
Throughout the protocol, blood flow was higher in the FXV673 treated group compared to other groups. FXV673 enhanced vessel patency in a dose‐dependent manner.
Compared to vehicle and heparin groups, the thrombus mass was decreased by 60% in the high dose FXV673. FXV673, heparin and RPR109891 increased the bleeding time by 2.7, 1.7 and 4 fold, and APTT by 2.8, 2.7 and 1.2 fold, respectively.
In conclusion, FXV673 is more effective than heparin and at least as effective as RPR109891 when used as an adjunct during rt‐PA‐induced coronary thrombolysis.

British Journal of Pharmacology (2001) 133, 1190–1198; doi:10.1038/sj.bjp.0704182
High glucose induces cell death of cultured human aortic smooth muscle cells through the formation of hydrogen peroxide
Authors: Peiró Concepción , Lafuente Nuria , Matesanz Nuria , Cercas Elena , Llergo José L , Vallejo Susana , Rodríguez‐Mañas Leocadio , Sánchez‐Ferrer Carlos F 
Published: January 2005

Alterations of the vessel structure, which is mainly determined by smooth muscle cells through cell growth and/or cell death mechanisms, are characteristic of diabetes complications. We analysed the influence of high glucose (22 mM) on cultured human aortic smooth muscle cell growth and death, as hyperglycaemia is considered one of the main factors involved in diabetic vasculopathy.
Growth curves were performed over 96 h in medium containing 0.5% foetal calf serum. Cell number increased by 2–4 fold over the culture period in the presence of 5.5 mM (low) glucose, while a 20% reduction in final cell number was observed with high glucose. Under serum‐free conditions, cell number remained constant in low glucose cultures, but a 40% decrease was observed in high glucose cultures, suggesting that high glucose may induce increased cell death rather than reduced proliferation. Reduced final cell number induced by high glucose was also observed after stimulation with 5 or 10% foetal calf serum.
The possible participation of oxidative stress was investigated by co‐incubating high glucose with different reactive oxygen species scavengers. Only catalase reversed the effect of high glucose. Intracellular H2O2 content, visualized with 2′,7′‐dichlorofluorescein and quantified by flow cytometry, was increased after high glucose treatment.
To investigate the cell death mechanism induced by high glucose, apoptosis and necrosis were quantified. No differences were observed regarding the apoptotic index between low and high glucose cultures, but lactate dehydrogenase activity was increased in high glucose cultures.
In conclusion, high glucose promotes necrotic cell death through H2O2 formation, which may participate in the development of diabetic vasculopathy.

British Journal of Pharmacology (2001) 133, 967–974; doi:10.1038/sj.bjp.0704184
Suppression of poly (ADP‐ribose) polymerase activation by 3‐aminobenzamide in a rat model of myocardial infarction: long‐term morphological and functional consequences
Authors: Liaudet Lucas , Szabó Éva , Timashpolsky Leonid , Virág László , Cziráki Attila , Szabó Csaba 
Published: January 2005

Recent studies demonstrated that inhibition or genetic inactivation of the enzyme poly (ADP‐ribose) polymerase (PARP) is beneficial in myocardial reperfusion injury. PARP activation in the reperfused myocardium has been assumed, but not directly demonstrated. Furthermore, the issue whether pharmacological PARP inhibition affords long‐term functional benefit in the reperfused myocardium has not been explored. These questions were addressed in the present study.
In a rat model of myocardial ischemia (1 h) and reperfusion (up to 24 h), there was a marked and significant activation of PARP in the ischemic borderzone, as determined by poly(ADP‐ribose) (PAR) immunohistochemistry. PAR localized to the nuclei of myocytes and infiltrating mononuclear cells. In the core of the infarction, necrotic tissues and diffuse PAR staining were observed. PARP activation remained markedly detectable 24 h after reperfusion. The PARP inhibitor 3‐aminobenzamide (20 mg kg−1 intraperitoneally 10 min before reperfusion, and every 2 h thereafter for 6 h) markedly reduced the activation of the enzyme in myocytes.
3‐aminobenzamide significantly protected against myocardial morphological and functional alterations at 24 h post‐reperfusion. Notably, infarct size was reduced, circulating creatine kinase activity was attenuated, and myocardial contractility (dP dt−1) was restored by 3‐aminobenzamide.
Our results demonstrate a significant and prolonged activation of PARP in the reperfused myocardium, localizing to the necrotic area and the ischaemic borderzone. Furthermore, the studies demonstrate that PARP inhibition affords long‐term beneficial morphological and functional effects in the reperfused myocardium. These data strengthen the notion that pharmacological PARP inhibition is a viable novel experimental approach for protection against myocardial reperfusion injury.

British Journal of Pharmacology (2001) 133, 1424–1430; doi:10.1038/sj.bjp.0704185
Production of leukotrienes in a model of focal cerebral ischaemia in the rat
Authors: Ciceri Paola , Rabuffetti Monica , Monopoli Angela , Nicosia Simonetta 
Published: January 2005

The aim of this work was to evaluate the role of leukotrienes in brain damage in vivo in a model of focal cerebral ischaemia in the rat, obtained by permanent occlusion of middle cerebral artery.
A significant (P<0.01) elevation of LTC4, LTD4 and LTE4 (cysteinyl‐leukotrienes) levels occurred 4 h after ischaemia induction in the ipsilateral cortices of ischaemic compared to sham‐operated animals (3998±475 and 897±170 fmol g−1 tissue, respectively, P<0.01).
The NMDA receptor antagonist MK‐801 and the adenosine A2A receptor antagonist SCH 58261 were administered in vivo at doses known to reduce infarct size and compared with the leukotriene biosynthesis inhibitor MK‐886.
MK‐886 (0.3 and 2 mg kg−1 i.v.) and MK‐801 (3 mg kg−1 i.p.) decreased cysteinyl‐leukotriene levels (−78%, P<0.05; −100%, P<0.01; −92%, P<0.01, respectively) 4 h after permanent occlusion of the middle cerebral artery, whereas SCH 58261 (0.01 mg kg−1 i.v.) had no significant effects.
MK‐886 (2 mg kg−1 i.v.) was also able to significantly reduce the cortical infarct size by 30% (P<0.05).
We conclude that cysteinyl‐leukotriene formation is associated with NMDA receptor activation, and that it represents a neurotoxic event, the inhibition of which is able to reduce brain infarct area in a focal ischaemic event.

British Journal of Pharmacology (2001) 133, 1323–1329; doi:10.1038/sj.bjp.0704189
Thalidomide impairment of trinitrobenzene sulphonic acid‐induced colitis in the rat–role of endothelial cell‐leukocyte interaction
Authors: Lienenlüke Bianca , Stojanovic Tomislav , Fiebig Thomas , Fayyazi Afshin , Germann Tieno , Hecker Markus 
Published: January 2005

Immune response‐modulating drugs such as thalidomide may be of therapeutic value in the treatment of chronic inflammatory bowel diseases including Crohn's disease (CD). In the present study, we have investigated whether thalidomide exerts this effect by impairing endothelial cell‐leukocyte interaction through down‐regulation of the expression of pro‐inflammatory gene products in these cells.
Transient CD‐like colitis was induced in male Wistar rats by single enema with trinitrobenzene sulphonic acid (TNBS) in ethanol followed by macroscopic scoring, histology, intravital microscopy, RT–PCR and immunohistochemistry (IHC) analyses. Thalidomide or its analogue supidimide were administered in olive oil by intragastric instillation 6 h prior to the induction of colitis and then daily for one week.
Both thalidomide and supidimide (200 mg kg−1 d−1) significantly attenuated TNBS‐induced colitis as compared to vehicle‐treated control animals (44 and 37% inhibition, respectively), and this effect persisted for 7 days post cessation of thalidomide treatment (46% inhibition).
Moreover, thalidomide significantly reduced leukocyte sticking to postcapillary venular endothelial cells in the submucosa (by 45%), improved functional capillary density and perfusion, and attenuated endothelial interleukin‐8 expression, as judged by IHC analysis. According to RT–PCR analysis, both thalidomide and supidimide also significantly reduced vascular cell adhesion molecule‐1 mRNA expression in the affected part of the descending colon.
These findings suggest that thalidomide and one of its derivatives impairs CD‐like TNBS‐induced colitis in the rat by down‐regulating endothelial adhesion molecule and chemokine expression and, as a consequence, the interaction of these cells with circulating leukocytes.

British Journal of Pharmacology (2001) 133, 1414–1423; doi:10.1038/sj.bjp.0704193
Acute and chronic effects of desipramine and clorgyline on α2‐adrenoceptors regulating noradrenergic transmission in the rat brain: a dual‐probe microdialysis study
Authors: Mateo Y , Fernández‐Pastor B , Meana J J 
Published: January 2005

The effects of desipramine (3 mg kg−1 i.p.) and clorgyline (1 mg kg−1 i.p.) on extracellular noradrenaline (NA) in the locus coeruleus (LC) and cingulate cortex were assessed in freely‐moving rats by dual‐probe microdialysis. Functional activities of α2‐adrenoceptors regulating NA release in the LC and cingulate cortex were determined by systemic (0.3 mg kg−1 i.p.) or local (0.1–100 μM) clonidine administration.
Extracellular NA was increased in the LC and cingulate cortex following acute desipramine but not clorgyline treatment. Systemic clonidine decreased NA similarly in desipramine‐, clorgyline‐, and saline‐treated animals, in both brain areas.
Long‐term (twice daily, 14 days) but not short‐term (twice daily, 7 days) desipramine, and long‐term clorgyline (once daily, 21 days) treatments increased NA (3 fold) in cingulate cortex but not in the LC. Following long‐term treatments, responses of NA to systemic clonidine were attenuated in the LC and cingulate cortex.
Clonidine perfusion by reverse dialysis into the cingulate cortex decreased local NA (−55±9%). The effect was attenuated by long‐term desipramine (−31±9%) and clorgyline (−10±2%) treatments.
Clonidine perfusion by reverse dialysis into the LC decreased NA in the LC (−89±2%) and in cingulate cortex (−52±12%). This effect was attenuated in the LC following long‐term desipramine (−72±4%) and clorgyline (−62±12%) treatments but it was not modified in the cingulate cortex (−57±10% and −68±6%, respectively).
These findings demonstrate that chronic desipramine or clorgyline treatments increase NA in noradrenergic terminal areas and desensitize α2‐adrenoceptors modulating local NA release at somatodendritic and terminal levels. However, somatodendritic α2‐adrenoceptors that control LC firing activity are not desensitized.

British Journal of Pharmacology (2001) 133, 1362–1370; doi:10.1038/sj.bjp.0704196
Effects of homologues and analogues of palmitoylethanolamide upon the inactivation of the endocannabinoid anandamide
Authors: Jonsson Kent‐Olov , Vandevoorde Séverine , Lambert Didier M , Tiger Gunnar , Fowler Christopher J 
Published: January 2005

The ability of a series of homologues and analogues of palmitoylethanolamide to inhibit the uptake and fatty acid amidohydrolase (FAAH)‐catalysed hydrolysis of [3H]‐anandamide ([3H]‐AEA) has been investigated.
Palmitoylethanolamide and homologues with chain lengths from 12–18 carbon atoms inhibited rat brain [3H]‐AEA metabolism with pI50 values of ∼5. Homologues with chain lengths eight carbon atoms gave <20% inhibition at 100 μM.
R‐palmitoyl‐(2‐methyl)ethanolamide, palmitoylisopropylamide and oleoylethanolamide inhibited [3H]‐AEA metabolism with pI50 values of 5.39 (competitive inhibition), 4.89 (mixed type inhibition) and 5.33 (mixed type inhibition), respectively.
With the exception of oleoylethanolamide, the compounds did not produce dramatic inhibition of [3H]‐WIN 55,212‐2 binding to human CB2 receptors expressed on CHO cells. Palmitoylethanolamide, palmitoylisopropylamide and R‐palmitoyl‐(2‐methyl)ethanolamide had modest effects upon [3H]‐CP 55,940 binding to human CB1 receptors expressed on CHO cells.
Most of the compounds had little effect upon the uptake of [3H]‐AEA into C6 and/or RBL‐2H3 cells. However, palmitoylcyclohexamide (100 μM) and palmitoylisopropylamide (30 and 100 μM) produced more inhibition of [3H]‐AEA uptake than expected to result from inhibition of [3H]‐AEA metabolism alone.
In intact C6 cells, palmitoylisopropylamide and oleoylethanolamide inhibited formation of [3H]‐ethanolamine from [3H]‐AEA to a similar extent as AM404, whereas palmitoylethanolamide, palmitoylcyclohexamide and R‐palmitoyl‐(2‐methyl)ethanolamide were less effective.
These data provide useful information upon the ability of palmitoylethanolamide analogues to act as ‘entourage’ compounds. Palmitoylisopropylamide may prove useful as a template for design of compounds that reduce the cellular accumulation and metabolism of AEA without affecting either CB1 or CB2 receptors.

British Journal of Pharmacology (2001) 133, 1263–1275; doi:10.1038/sj.bjp.0704199
Effects and mechanisms of emodin on cell death in human lung squamous cell carcinoma
Authors: Lee Hong‐Zin 
Published: January 2005

Emodin (1,3,8‐trihydroxy‐6‐methylanthraquinone) is an active component from the root and rhizome of Rheum palmatum that has been reported to exhibit antitumour effects, but the mechanism is not known. The study investigated the effects and mechanisms of emodin‐induced cell death in human lung squamous carcinoma cell line CH27.
Emodin (50 μM)‐induced CH27 cell apoptosis was confirmed by cell morphological change, sub‐G1 formation in flow cytometry analysis, viability assay and degradation of focal adhesion kinase in this study.
Emodin‐induced apoptosis of CH27 cells does not involve modulation of endogenous Bcl‐XL protein expression, but appears to be associated with the increased expression of cellular Bak and Bax proteins. This study also demonstrated the translocation of Bak and Bax from cytosolic to particulate fractions.
This study has shown that emodin‐treated CH27 cells revealed the increases in the relative abundance of cytochrome c for the indicated time intervals in cytosolic fraction.
This study demonstrates that the activation of caspase‐3, caspase‐9 and caspase‐8 is an important determinant of apoptotic death induced by emodin.
These results suggested that emodin induces CH27 cell death by Bax death pathway and Fas pathway.

British Journal of Pharmacology (2001) 134, 11–20; doi:10.1038/sj.bjp.0704205
Vasorelaxant effects of a nitric oxide‐releasing aspirin derivative in normotensive and hypertensive rats
Authors: Muscará Marcelo N , Lovren Fina , McKnight Webb , Dicay Michael , Soldato Piero del , Triggle Christopher R , Wallace John L 
Published: January 2005

Nonsteroidal anti‐inflammatory drugs have been reported to exacerbate hypertension and to interfere with the effectiveness of some anti‐hypertensive therapies. In this study, we tested the effects of a gastric‐sparing, nitric oxide‐releasing derivative of aspirin (NCX‐4016) on hypertension in rats.
Hypertension was induced by administering L‐NAME in the drinking water (400 mg l−1). Groups of rats were treated daily with aspirin, NCX‐4016 or vehicle.
NCX‐4016 significantly reduced blood pressure relative to the aspirin‐treated group over the 2‐week period of treatment. Aspirin and, to a lesser extent, NCX‐4016 suppressed whole blood thromboxane synthesis.
In anaesthetized rats, acute intravenous administration of NCX‐4016 caused a significant fall in mean arterial pressure in hypertensive rats, but was devoid of such effects in normotensive controls.
In vitro, NCX‐4016 relaxed phenylephrine‐pre‐contracted aortic rings obtained from both normotensive and hypertensive rats, and significantly reduced their responsiveness to the contractile effects of phenylephrine.
These results suggest that NCX‐4016 reduces blood pressure in hypertensive rats, not simply through the direct vasodilatory actions of the nitric oxide released by this compound, but also through possible interference with the effects of endogenous pressor agents. These properties, added to its anti‐thrombotic effects, suggest that NCX‐4016 may be a safer alternative to aspirin for use by hypertensive patients.

British Journal of Pharmacology (2001) 133, 1314–1322; doi:10.1038/sj.bjp.0704209
VEGF stimulation of endothelial cell PAF synthesis is mediated by group V 14 kDa secretory phospholipase A2
Authors: Bernatchez Pascal N , Winstead Michelle V , Dennis Edward A , Sirois Martin G 
Published: January 2005

Vascular endothelial growth factor (VEGF) is a potent inducer of inflammation, and we have shown that this latter effect is mediated through endothelial cell (EC) PAF synthesis. Since the phospholipid remodelling pathway enzymes (CoA‐independent transacylase, CoA‐IT; phospholipase A2, PLA2; and lyso‐PAF acetyltransferase, lyso‐PAF‐AT) may participate in PAF synthesis, we assessed their contribution to VEGF‐induced PAF synthesis in bovine aortic EC (BAEC) and human umbilical vein EC (HUVEC).
VEGF enhanced BAEC and HUVEC PAF synthesis by up to 28 and 4 fold above basal levels respectively.
A pretreatment with a CoA‐IT and lyso‐PAF‐AT inhibitor (Sanguinarin; 500 nM) blocked VEGF‐induced PAF synthesis by 95%, a specific CoA‐IT inhibitor (SKF45905; 10 – 50 μM) was without effect, confirming the crucial role of the PLA2 and lyso‐PAF‐AT.
Treatment with secreted PLA2 (sPLA2) inhibitors which have been shown to inhibit both groups IIA and V sPLA2 (SB203347; 10 μM and LY311727; 100 μM) blocked EC PAF synthesis by up to 90%, whereas selective inhibition of group IIA sPLA2 (LY311727; 1 μM) had no significant effect.
RT – PCR and Western blot analyses demonstrated the presence of group V sPLA2 whereas group IIA sPLA2 was undetected in EC.
Treatment with cytosolic and calcium‐independent PLA2 inhibitors (Arachidonyl trifluoromethyl ketone, Bromoenol lactone, Methyl arachydonyl fluorophosphate, up to 50 μM) did not prevent but rather potentiated the VEGF effect on EC PAF synthesis.
These results provide evidence that with VEGF activation of EC cells, the group V sPLA2 provides substrate for EC PAF formation.

British Journal of Pharmacology (2001) 134, 197–205; doi:10.1038/sj.bjp.0704215
Noradrenaline‐induced changes in intracellular Ca2+ and tension in mesenteric arteries from diabetic rats
Authors: Chow Wing Lim , Zhang Lili , MacLeod Kathleen M 
Published: January 2005

The purpose of this investigation was to determine whether enhanced contractile responses to noradrenaline (NA) of mesenteric arteries from rats with chronic streptozotocin‐induced diabetes are associated with increases in mean cytosolic [Ca2+]i.
[Ca2+]i was measured with fura 2‐AM, and was monitored simultaneously with tension in perfused endothelium‐denuded mesenteric arterial rings from 12 – 14 week diabetic rats and age‐ and gender‐matched control rats.
Basal [Ca2+]i (expressed as Rn, the normalized fura 2 ratio) was not significantly different in arteries from control and diabetic rats. Similarly, no differences between control and diabetic arteries in the tension or [Ca2+]i responses to 80 mM KCl in the presence of phentolamine were detected.
The rate of tension development, peak tension and integrated tension in response to 30 μM NA were all significantly greater in diabetic than control arteries. However, this was not associated with enhancement of the corresponding [Ca2+]i responses in the diabetic arteries.
Peak contractile responses to perfusion with both 0.3 and 3 μM NA, but peak [Ca2+]i only in response to 0.3 μM NA, were significantly greater in diabetic than control arteries.
NA (30 μM) produced a greater increase in both peak tension and [Ca2+]i in diabetic than control arteries perfused with Ca2+‐free solution containing 1 mM EGTA. Neither the rate nor the magnitude of NA‐induced Ca2+ influx appeared to be altered in the diabetic arteries.
The enhanced sustained contractile response of diabetic arteries to NA appears to be dissociated from increases in [Ca2+]i, and may be due to other factors, such as an increase in the Ca2+ sensitivity of the contractile proteins.

British Journal of Pharmacology (2001) 134, 179–187; doi:10.1038/sj.bjp.0704221
Dibutyryl‐cyclic GMP induces peripheral antinociception via activation of ATP‐sensitive K+ channels in the rat PGE2‐induced hyperalgesic paw
Authors: Soares A C , Duarte I D G 
Published: January 2005

Using the rat paw pressure test, in which increased sensitivity is induced by intraplantar injection of prostaglandin E2, we studied the action of several K+ channel blockers in order to determine what types of K+ channels could be involved in the peripheral antinociception induced by dibutyrylguanosine 3 : 5′‐cyclic monophosphate (DbcGMP), a membrane permeable analogue of cyclic GMP.
DbcGMP elicited a dose‐dependent (50, 75, 100 and 200 μg paw−1) peripheral antinociceptive effect. The effect of the 100 μg dose of DbcGMP was considered to be local since only a higher dose (300 μg paw−1) produced antinociception in the contralateral paw.
The antinociceptive effect of DbcGMP (100 μg paw−1) was dose‐dependently antagonized by intraplantar administration of the sulphonylureas tolbutamide (20, 40 and 160 μg) and glibenclamide (40, 80 and 160 μg), selective blockers of ATP‐sensitive K+ channels.
Charybdotoxin (2 μg paw−1), a selective blocker of high conductance Ca2+‐activated K+ channels, and apamin (10 μg paw−1), a selective blocker of low conductance Ca2+‐activated K+ channels, did not modify the peripheral antinociception induced by DbcGMP.
Tetraethylammonium (2 mg paw−1), 4‐aminopyridine (200 μg paw−1) and cesium (800 paw−1), non‐selective voltage‐gated potassium channel blockers, also had no effect.
Based on this experimental evidence, we conclude that the activation of ATP‐sensitive K+ channels could be the mechanism by which DbcGMP induces peripheral antinociception, and that Ca2+‐activated K+ channels and voltage‐dependent K+ channels appear not to be involved in the process.

British Journal of Pharmacology (2001) 134, 127–131; doi:10.1038/sj.bjp.0704224