bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of resveratrol, a phytoalexin derived from red wines, on chronic inflammation induced in an experimentally induced colitis model
Authors: Martín Antonio Ramón , Villegas Isabel , Sánchez‐Hidalgo Marina , De La Lastra Catalina Alarcón 
Published: February 2006

Neutrophil infiltration, proinflammatory cytokines, eicosanoid generation and oxidative stress have been implicated in colitis. Resveratrol is a polyphenolic compound found in grapes and wine, with multiple pharmacological actions, including anti‐inflammatory, antioxidant, antitumour and immunomodulatory activities. In a previous report, we documented that resveratrol decreases the degree of inflammation associated with acute experimental colonic inflammation, but its effects on chronic experimental colitis remain undetermined.The aim of this research was to investigate the effects of resveratrol on the chronic colonic injury caused by intracolonic instillation of trinitrobenzenesulphonic acid (TNBS) in rats. The inflammatory response was assessed by histology and myeloperoxidase activity. Tumour necrosis factor alpha (TNF‐α) production, histological and histochemical analysis of the lesions were also carried out. We determined the production of prostaglandin (PG) E2and D2in colon mucosa, as well as cyclooxygenase (COX)‐1 and ‐2 and nuclear transcription factor NF‐kappa B (NF‐κB) p65 protein expression. Finally, since resveratrol has been found to modulate apoptosis, we intended to elucidate its effects on colonic mucosa under chronic inflammatory conditions.Resveratrol (10 mg kg−1 day−1) significantly attenuated the damage score and corrected the disturbances in morphology associated to injury. In addition, the degree of neutrophil infiltration and the levels of TNF‐αwere significantly ameliorated. Resveratrol did not modify PGD2levels but returned the decreased PGE2values to basal levels and also reduced COX‐2 and the NF‐κB p65 protein expression. Furthermore, treatment of rats with resveratrol caused a significant increase of TNBS‐induced apoptosis in colonic cells.In conclusion, resveratrol reduces the damage in chronic experimentally induced colitis, alleviates the oxidative events, returns PGE2production to basal levels and stimulates apoptosis in colonic cells.British Journal of Pharmacology(2006)147, 873–885. doi:10.1038/sj.bjp.0706469
Aminoglutethimide prevents excitotoxic and ischemic injuries in cortical neurons
Authors: Shirakawa Hisashi , Katsuki Hiroshi , Kume Toshiaki , Kaneko Shuji , Akaike Akinori 
Published: February 2006

Aminoglutethimide is a clinically available drug that suppresses steroid biosynthesis by inhibiting enzymes such as cytochromeP450scc and aromatase. Because several members of neurosteroids regulate glutamate receptors, we investigated the effect of aminoglutethimide on cell death induced by overactivation of glutamate receptors in CNS neurons.Long‐term pretreatment of organotypic cerebrocortical slice cultures with aminoglutethimide (100–1000 μM) for 6 days or over resulted in concentration‐dependent suppression of neuronal cell death induced by NMDA. Aminoglutethimide (1000 μM) also inhibited neurotoxicity of AMPA and kainate, but not of ionomycin or staurosporine.The protective effect of aminoglutethimide against NMDA cytotoxicity was not mimicked by other steroid synthesis inhibitors including trilostane and exemestane, and was not reversed by concurrent application of steroids such as pregnenolone, estrone, 17β‐estradiol and estriol.In dissociated rat cerebrocortical cell cultures, long‐term treatment with aminoglutethimide (10–1000 μM) attenuated NMDA receptor‐mediated glutamate cytotoxicity but produced no significant effect on glutamate‐induced increases in intracellular Ca2+.Brief as well as long‐term pretreatment with aminoglutethimide (30–1000 μM) prevented NMDA receptor‐dependent ischemic neuronal injury in organotypic cerebrocortical slice cultures, which was associated with suppression of glutamate release during the ischemic insult.These results indicate that aminoglutethimide, irrelevant to its actions on neurosteroid synthesis, protects CNS neurons from excitotoxic and ischemic injuries. Development of aminoglutethimide analogs possessing neuroprotective properties may be of therapeutic value.British Journal of Pharmacology(2006)147, 729–736. doi:10.1038/sj.bjp.0706636
Mixedβ3‐adrenoceptor agonist andα1‐adrenoceptor antagonist properties of nebivolol in rat thoracic aorta
Authors: Rozec Bertrand , Quang Thuy Tran , Noireaud Jacques , Gauthier Chantal 
Published: February 2006

Nebivolol, a selectiveβ‐adrenoceptor (β1‐AR) antagonist, induces vasodilatation by an endothelium‐ and NO‐cGMP‐dependent pathway. However, the mechanisms involved in the vascular effect of nebivolol have not been established. Thus, we evaluated the role ofα1andβ3‐ARs in nebivolol‐induced vasodilatation.The responses to nebivolol were investigatedin vitroin thoracic aortic rings isolated from male Sprague–Dawley rats.Nebivolol (0.1–10 μM) significantly shifted the concentration–response curve to phenylephrine, anα1‐AR agonist, to the right in a concentration‐dependent manner (pA2=6.5). Conversely, the concentration–response curve to endothelin 1 (ET1) was unaffected by nebivolol.In ET1‐precontracted rings, nebivolol induced a concentration‐dependent relaxation, which was unaffected by nadolol (aβ1/β2‐AR antagonist) but was significantly reduced by L‐748,337 (aβ3‐AR antagonist), endothelium removal or pretreatment with L‐NMMA (an NOS inhibitor). Similar results were obtained with aβ3‐AR agonist, SR 58611A.It was concluded that, in rat aorta, nebivolol‐induced relaxation results from both inhibition ofα1‐ARs and activation ofβ3‐ARs. In addition, we confirmed that the endothelium and the NO pathway are involved in the vascular effect of nebivolol. The identification of these vascular targets of nebivolol indicate that it has therapeutic potential for the treatment of pathological conditions associated with an elevation of sympathetic tone, such as heart failure and hypertension.British Journal of Pharmacology(2006)147, 699–706. doi:10.1038/sj.bjp.0706648
A novel steroid‐like compound F90927 exerting positive‐inotropic effects in cardiac muscle
Authors: Pignier Christophe , Keller Markus , Vié Bruno , Vacher Bernard , Santelli Maurice , Niggli Ernst , Egger Marcel , Le Grand Bruno 
Published: February 2006

Here we report a novel steroid‐like compound F90363, exhibiting positive inotropy in vivo and in vitro in various cardiac muscle preparations.
F90363 is a racemic mixture composed of the stereoisomers (−)‐F90926 and (+)‐F90927. Only F90927 exerted positive inotropy, while F90926 induced a weak negative inotropy, but only at concentrations 103 times higher than F90927 and most likely resulting from an unspecific interaction.
The rapid time course of the action of F90927 suggested a direct interaction with a cellular target rather than a genomic alteration. We could identify the L‐type Ca2+ current ICa(L) as a main target of F90927, while excluding other components of cardiac Ca2+ signalling as potential contributors. In addition, several other signaling pathways known to lead to positive inotropy (e.g. α‐ and β‐adrenergic stimulation, cAMP pathways) could be excluded as targets of F90927.
However, vessel contraction and stiffening of the cardiac muscle at high doses (>30 μM, 0.36 mg kg−1, respectively) prevent the use of F90927 as a candidate for drug development. Since the compound may still find valuable applications in research, the aim of the present study was to identify the cellular target and the mechanism of inotropy of F90927.

British Journal of Pharmacology (2006) 147, 772–782. doi:10.1038/sj.bjp.0706673
Agonist‐specific activation of theβ2‐adrenoceptor/Gs‐protein andβ2‐adrenoceptor/Gi‐protein pathway in adult rat ventricular cardiomyocytes
Authors: Pönicke Klaus , Gröner Ferdinand , Heinroth‐Hoffmann Ingrid , Brodde Otto‐Erich 
Published: February 2006

In rat ventricular cardiomyocytesβ2‐adrenoceptors (AR) couple to Gs‐ and Gi‐protein, and evidence has accumulated thatβ2‐AR agonists can differentially activate either Gs‐ or Gs‐ and Gi‐protein.In this study, in isolated adult rat ventricular cardiomyocytes, we assessed the effects of pertussis toxin (PTX) onβ2‐AR agonist (terbutaline (TER), salbutamol (SAL) and fenoterol (FEN)) evoked inhibition of phenylephrine (PE)‐induced increase in the rate of protein synthesis (assessed as [3H]phenylalanine incorporation) to find out whichβ2‐AR agonist activates selectively Gs‐ or Gs‐ and Gi‐protein.PE (1 μM) increased the rate of protein synthesis from 100% to 130±2% (n=34). FEN, TER and SAL (1 nM–10 μM) inhibited PE‐induced increase in the rate of protein synthesis concentration‐dependently. FEN inhibited PE effects almost completely (from 132±3 to 101±1%), whereas TER and SAL caused only partial inhibition (from 131±2 to 114±2 and 129±1 to 111±2%, respectively).Pretreatment of cardiomyocytes with PTX (250 ng ml−1for 16 h at 37°C) did not affect FEN effects, but converted TER‐ and SAL‐evoked partial inhibition into complete inhibition.Inhibitory effects of the threeβ2‐AR agonists were markedly attenuated byβ1‐AR selective antagonist CGP 20712A (CGP) (300 nM); in contrast,β2‐AR selective antagonist ICI 118,551 (55 nM) inhibited the inhibitory effects of the threeβ2‐AR agonists only in PTX‐pretreated cardiomyocytes, withβ1‐AR blocked by CGP.We conclude that, in adult rat ventricular cardiomyocytes, FEN activates selectively the Gsprotein‐pathway, while TER and SAL activate the Gs‐ and Gi‐protein pathways. Part of the effects of these threeβ2‐AR agonists appears to be mediated byβ1‐AR.British Journal of Pharmacology(2006)147, 714–719. doi:10.1038/sj.bjp.0706674
Downregulation of propranolol‐sensitive β‐adrenoceptor signaling after inhibition of nitric oxide synthesis
Authors: Whalen Erin J , Bates James N , Johnson Alan Kim , Lewis Stephen J 
Published: February 2006

The β‐adrenoceptor agonist, isoprenaline, elicits vasodilation and tachycardia in anesthetized rats via activation of propranolol‐sensitive β1‐ and β2‐adrenoceptors and also by propranolol‐insensitive β1‐ and β3‐adrenoceptors.
The aim of this study was to determine whether the relative contribution of propranolol‐sensitive and ‐insensitive β‐adrenoceptors to the changes in heart rate (HR) and vascular resistances elicited by isoprenaline is altered after blockade of nitric oxide (NO) synthase, in pentobarbital‐anesthetized rats.
The hemodynamic responses elicited by isoprenaline (0.1 and 0.5 μg kg−1, i.v.) were determined before and after injection of saline or the NO synthase inhibitor, NG‐nitro‐L‐arginine methylester (L‐NAME, 50 μmol kg−1, i.v.), and again after injection of the β1‐ and β2‐adrenoceptor antagonist, propranolol (1 mg kg−1, i.v.). The responses elicited by the above doses of isoprenaline were also determined before and during infusion of the α1‐adrenoceptor agonist, phenylephrine (3 μg kg−1 min−1, i.v.), and again 15–20 min after injection of propranolol (1.0 mg kg−1, i.v.).
Both doses of isoprenaline elicited tachycardia and reductions in vascular resistances. Propranolol eliminated the responses elicited by the lower dose of isoprenaline and substantially diminished the responses elicited by the higher dose of the β1‐, β2‐ and β3‐adrenoceptor agonist. The maximal vasodilator responses elicited by both doses of isoprenaline were not diminished whereas the maximal increases in HR were higher after injection of L‐NAME. The ability of propranolol to diminish the hemodynamic actions of isoprenaline was substantially diminished in L‐NAME‐treated rats, whereas propranolol retained its potency in rats that received an equi‐pressor infusion of the α1‐adrenoceptor agonist, phenylephrine.
The finding that the maximal vasodilator responses elicited by isoprenaline were not diminished by L‐NAME suggests that the vasodilation elicited by this drug was due to direct activation of β‐adrenoceptors on vascular smooth muscle and that the full compliment of isoprenaline‐sensitive receptors was not changed after inhibition of NO synthesis. However, these results suggest that the activities of propranolol‐sensitive β‐adrenoceptors are downregulated, whereas propranolol‐insensitive β‐adrenoceptors are upregulated upon the loss of exposure to endothelial nitrosyl factors.

British Journal of Pharmacology (2006) 147, 755–764. doi:10.1038/sj.bjp.0706675
Species‐dependent smooth muscle contraction to Neuromedin U and determination of the receptor subtypes mediating contraction using NMU1 receptor knockout mice
Authors: Prendergast Clodagh E , Morton Magda F , Figueroa Katherine W , Wu Xiaodong , Shankley Nigel P 
Published: February 2006

The peptide ligand neuromedin U (NMU) has been implicated in an array of biological activities, including contraction of uterine, intestinal and urinary bladder smooth muscle. However, many of these responses appear to be species‐specific. This study was undertaken to fully elucidate the range of smooth muscle‐stimulating effects of NMU in rats, mice and guinea‐pigs, and to examine the extent of the species differences. In addition, the NMU1 receptor knockout mouse was used to determine which receptor subtype mediates the contractile responses generated by NMU in the mouse.
A range of isolated organ in vitro bioassays were carried out, which were chosen to re‐confirm previous literature reports (uterine and stomach fundus contraction) and also to explore potentially novel smooth muscle responses to NMU. This investigation uncovered a number of previously unidentified NMU‐mediated responses: contraction of rat lower esophageal sphinster (LES), rat ileum, mouse gallbladder, enhancement of electrically evoked contractions in rat and mouse vas deferens, and a considerable degree of cross‐species differences.
Studies using the NMU1 receptor knockout mice revealed that in the mouse fundus and gallbladder assays the NMU contractile response was mediated entirely through the NMU1 receptor subtype, whereas, in assays of mouse uterus and vas deferens, the response to NMU was unchanged in the NMU1 receptor knockout mouse, suggesting that the NMU response may be mediated through the NMU2 receptor subtype. NMU receptor subtype‐selective antagonists are required to further elucidate the role of the individual receptor subtypes.

British Journal of Pharmacology (2006) 147, 886–896. doi:10.1038/sj.bjp.0706677
Mechanism of hERG K+channel blockade by the fluoroquinolone antibiotic moxifloxacin
Authors: Alexandrou Ari J , Duncan Rona S , Sullivan Anneli , Hancox Jules C , Leishman Derek J , Witchel Harry J , Leaney Joanne L 
Published: February 2006

The fluoroquinolone antibiotic moxifloxacin has been associated with the acquired long QT syndrome and is used as a positive control in the evaluation of the QT‐interval prolonging potential of new drugs. In common with other QT‐prolonging agents, moxifloxacin is known to inhibit the hERG potassium K+channel, but at present there is little mechanistic information available on this action. This study was conducted in order to characterise the inhibition of hERG current (IhERG) by moxifloxacin, and to determine the role in drug binding of the S6 aromatic amino‐acid residues Tyr652 and Phe656.hERG currents were studied using whole‐cell patch clamp (at room temperature and at 35–37°C) in an HEK293 cell line stably expressing hERG channels.Moxifloxacin reversibly inhibited currents in a dose‐dependent manner. We investigated the effects of different voltage commands to elicit hERG currents on moxifloxacin potency. Using a ‘step‐ramp’ protocol, the IC50was 65 μMat room temperature and 29 μMat 35°C. When a ventricular action potential waveform was used to elicit currents, the IC50was 114 μM.Block of hERG by moxifloxacin was found to be voltage‐dependent, occurred rapidly and was independent of stimulation frequency.Mutagenesis of the S6 helix residue Phe656 to Ala failed to eliminate or reduce the moxifloxacin‐mediated block whereas mutation of Tyr652 to Ala reduced moxifloxacin block by ∼66%.Our data demonstrate that moxifloxacin blocks the hERG channel with a preference for the activated channel state. The Tyr652 but not Phe656 S6 residue is involved in moxifloxacin block of hERG, concordant with an interaction in the channel inner cavity.British Journal of Pharmacology(2006)147, 905–916. doi:10.1038/sj.bjp.0706678
ROS‐sensitive cytochrome P450 activity maintains endothelial dilatation in ageing but is transitory in dyslipidaemic mice
Authors: Krummen Stéphane , Drouin Annick , Gendron Marie‐Ève , Falck John R , Thorin Eric 
Published: February 2006

Risk factors for cardiovascular diseases (CVD) have been proposed to accelerate the vascular endothelial dysfunction that develops during the normal ageing process. The objective of this work was to study the impact of dyslipidaemia (DL) on the dilatory efficacy of the non‐NO/non‐PGI2 endothelium‐derived hyperpolarising factor (EDHF) through maturation and ageing.
We isolated and pressurised (80 mmHg) gracilis arterial segments from 3, 12 and 20‐month‐old (m/o) DL mice expressing the human apolipoprotein B‐100 and wild‐type (WT) C57BL/6 mice. EDHF‐dependent dilatations to acetylcholine (ACh) were measured in the presence of L‐NNA (100 μM, NOS inhibitor) and indomethacin (INDO; 10 μM, COX inhibitor). Data are expressed as mean±s.e.m.
EDHF‐mediated maximal dilatation of arteries isolated from WT mice declined by 44% with ageing, from 86±3% at 3 months to 66±8% at 12 and 48±4% at 20 months of age (P<0.05). This decline was magnified by DL to 73%, characterised by an early increased efficacy at 3 m/o (95±2%, P<0.05) and a worsening of the dysfunction at 20 m/o (26±2%, P<0.05).
17‐Octadecynoic acid (17‐ODYA), a cytochrome P450/epoxygenase inhibitor, reduced by 56% (P<0.05) ACh‐induced EDHF‐dependent dilatation of arteries isolated from 3 m/o DL – but not WT – mice, an effect of 17‐ODYA disappearing in older DL mice. 17‐ODYA, however, reduced (P<0.05) ACh‐induced EDHF‐dependent dilatation in arteries isolated from 12 m/o WT mice by 35% and from 20 m/o WT mice by 31% (P<0.05).
Reactive oxygen species production was increased in arteries isolated from 12 m/o DL mice. The antioxidant N‐acetyl‐L‐cystein (NAC) restored the 17‐ODYA‐sensitive responses in arteries isolated from 12 – but not 20 – m/o DL mice (84±3% from an Emax of 57±8%; P<0.05). NAC did not affect the dilatation of arteries isolated from WT mice.
Our data suggest that the decline in EDHF‐dependent dilatation is hastened by DL despite the early expression of a 17‐ODYA‐sensitive pathway increasing the efficacy of the non‐NO/non‐PGI2 endothelium‐dependent dilatation. Acute free radical production contributes to the endothelial dysfunction in the presence of DL only, by abrogating this latter pathway. This 17‐ODYA‐sensitive pathway, however, appears in 12 m/o WT mice and remains active at 20 m/o.

British Journal of Pharmacology (2006) 147, 897–904. doi:10.1038/sj.bjp.0706679
The proconvulsant effect of sildenafil in mice: role of nitric oxide–cGMP pathway
Authors: Riazi Kiarash , Roshanpour Maryam , Rafiei‐Tabatabaei Neda , Homayoun Houman , Ebrahimi Farzad , Dehpour Ahmad Reza 
Published: February 2006

Recent evidence indicates that sildenafil may exert some central effects through enhancement of nitric oxide (NO)‐mediated effects. NO is known to have modulatory effects on seizure threshold, raising the possibility that sildenafil may alter seizure susceptibility through NO‐mediated mechanisms. This study was performed to examine whether sildenafil influences the threshold of clonic and/or generalized tonic seizures through modulation of nitric oxide (NO)–cGMP pathway.
The effect of sildenafil (1–40 mg kg−1) was investigated on clonic seizures induced by intravenous administration of GABA antagonists pentylenetetrazole (PTZ) and bicuculine and on generalized tonic seizures induced by intraperitoneal administration of high dose PTZ in male Swiss mice. The interaction of sildenafil‐induced effects with NO–cGMP pathway was examined using nitric oxide synthase (NOS) inhibitor, N(G)‐nitro‐L‐arginine methyl ester (L‐NAME), NOS substrate L‐arginine, NO donor, sodium nitroprusside (SNP) and guanylyl cyclase inhibitor methylene blue (MB).
Sildenafil induced a dose‐dependent proconvulsant effect in both models of clonic, but not generalized tonic type of seizures. Pretreatment with either MB or L‐NAME inhibited the proconvulsant effect of sildenafil, indicating the mediation of this effect by NO–cGMP pathway. In addition, a subeffective dose of sildenafil induced an additive proconvulsant effect when combined with either L‐arginine or SNP.
Sildenafil induces a proconvulsant effect on clonic seizure threshold that interacts with both exogenously and endogenously released NO and may be linked to activation of NO–cGMP pathway.

British Journal of Pharmacology (2006) 147, 935–943. doi:10.1038/sj.bjp.0706680
Cannabinoid agonists induce relaxation in the bovine ophthalmic artery: evidences for CB1receptors, nitric oxide and potassium channels
Authors: Romano Maria Rosaria , Lograno Marcello D 
Published: February 2006

Glaucoma pathophysiology appears to involve vascular deficits, which may contribute to initiation and progression of the disease.Anandamide, the endogenous cannabinoid ligand, and WIN55212‐2, a synthetic cannabinoid agonist, are able to evoke concentration‐dependent relaxations in bovine ophthalmic artery rings, precontracted with 5‐hydroxytryptamine (5‐HT) (1 μM). Endothelium removal reduces cannabinoid agonist potency and efficacy.The selective cannabinoid 1 (CB1) receptor antagonists SR141716A (100 nM) and AM251 (100 nM) cause a shift to the right in the concentration–response curves to anandamide and WIN55212‐2 in arterial rings both in the presence and in the absence of endothelium.In endothelium‐intact arteries, the nitric oxide synthase inhibitor,NG‐monomethyl‐L‐arginine (L‐NMMA, 300 μM), completely blocked the anandamide‐ and WIN55212‐2‐relaxant responses; by contrast, the nitric oxide donorS‐nitroso‐N‐acetylpenicillamine (SNAP, 100 μM) induced an increase in vasorelaxant responses to cannabinoid agonists.Relaxations to anandamide and WIN55212‐2 were inhibited by iberiotoxin (IbTX, 200 nM), a blocker of large conductance, Ca2+‐activated K+channel (BKCa), and by 4‐aminopyridine (4‐AP; 1 mM), a blocker of delayed rectifier K+channel, whereas the blockade ofKATPchannels by glibenclamide (5 μM) and of small conductance Ca2+‐activated K+channels (SKCa) by apamin (100 nM) did not produce any effects.These data suggest that anandamide and WIN55212‐2 relax the bovine ophthalmic artery by involving CB1the cannabinoid receptor‐sensitive pathway. In endothelium‐intact arteries, relaxation occurs through activation of nitric oxide synthase cyclic GMP and Ca2+‐activated K+channels. They also cause endothelium‐independent relaxation by involving potassium channel opening.British Journal of Pharmacology(2006)147, 917–925. doi:10.1038/sj.bjp.0706687