bluuebunny/crossref_metadata_2025_split huggingface dataset:
Involvement of the BLT2 receptor in the itch‐associated scratching induced by 12‐(S)‐lipoxygenase products in ICR mice
Authors: Kim H J , Kim D K , Kim H , Koh J Y , Kim K M , Noh M S , Lee S , Kim S , Park S H , Kim J J , Kim S Y , Lee C H 
Published: June 2008

Background and purpose:Recently, we reported that 12(S)‐HPETE (12(S)‐hydroperoxyeicosa‐5Z,8Z,10E,14Z‐tetraenoic acid) induces scratching in ICR mice. We hypothesized that 12(S)‐HPETE might act as an agonist of the low‐affinity leukotriene B4 receptor BLT2. To confirm the involvement of the BLT2 receptor in 12(S)‐HPETE‐induced scratching, we studied the scratch response using the BLT2 receptor agonists compound A (4′‐{[pentanoyl (phenyl) amino]methyl}‐1,1′‐biphenyl‐2‐carboxylic acid) and 12(S)‐HETE (12(S)‐hydroxyeicosa‐5Z,8Z,10E,14Z‐tetraenoic acid).Experimental approach:A video recording was used to determine whether the BLT2 receptor agonists caused itch‐associated scratching in ICR mice. Selective antagonists and several chemicals were used.Key results:Both 12(S)‐HETE and compound A dose dependently induced scratching in the ICR mice. The dose–response curve for compound A showed peaks at around 0.005–0.015 nmol per site. Compound A‐ and 12(S)‐HETE‐induced scratching was suppressed by capsaicin and naltrexon. We examined the suppressive effects of U75302 (6‐[6‐(3‐hydroxy‐1E,5Z‐undecadienyl)‐2‐pyridinyl]‐1,5‐hexanediol, the BLT1 receptor antagonist) and LY255283 (1‐[5‐ethyl‐2‐hydroxy‐4‐[[6‐methyl‐6‐(1H‐tetrazol‐5‐yl)heptyl]oxy]phenyl]‐ethanone, the BLT2 receptor antagonist) on the BLT2 agonist‐induced scratching. LY255283 suppressed compound A‐ and 12(S)‐HETE‐induced scratching, but U75302 did not. LY255283 required a higher dose to suppress the compound A‐induced scratching than it did to suppress the 12(S)‐HETE‐induced scratching. One of the BLT2 receptor agonists, 12(R)‐HETE (12(R)‐hydroxyeicosa‐5Z,8Z,10E,14Z‐tetraenoic acid), also induced scratching in the ICR mice.Conclusions and implications:Our present results corroborate the hypothesis that the BLT2 receptor is involved in 12(S)‐lipoxygenase‐product‐induced scratching in ICR mice. We also confirmed that this animal model could be a valuable means of evaluating the effects of BLT2 receptor antagonists.British Journal of Pharmacology (2008) 154, 1073–1078; doi:10.1038/bjp.2008.220; published online 9 June 2008
Key clinical considerations for demonstrating the utility of preclinical models to predict clinical drug‐induced torsades de pointes
Authors: Sager P T 
Published: June 2008

While the QT/QTc interval is currently the best available clinical surrogate for the development of drug‐induced torsades de pointes, it is overall an imperfect biomarker. In addition to low specificity for predicting arrhythmias, other issues relevant to using QT as a biomarker include (1) an apparent dissociation, for some drugs (for example, amiodarone, sodium pentobarbital, ranolazine) between QT/QTc interval prolongation and TdP risk, (2) Lack of clarity regarding what determines the relationship between QTc prolongation and TdP risk for an individual drug, (3) QT measurement issues, including effects of heart rate and autonomic perturbations, (4) the significant circadian changes to the QT/QTc interval and (5) concerns that the development, regulatory and commercial implications of finding even a mild QT prolongation effect during clinical development has significant impact the pharmaceutical discovery pipeline. These issues would be significantly reduced, clinical development simplified and marketing approval for some drugs might be accelerated if there were a battery of preclinical tests that could reliably predict a drug's propensity to cause TdP in humans, even in the presence of QTc interval prolongation. This approach is challenging and for it to be acceptable to pharmaceutical developers, the scientific community and regulators, it would need to be scientifically well validated. A very high‐negative predictive value demonstrated in a wide range of drugs with different ionic effects would be critical. This manuscript explores the issues surrounding the use of QT as a clinical biomarker and potential approaches for validating preclinical assays for this purpose against clinical data sets. British Journal of Pharmacology (2008) 154, 1544–1549; doi:fn1; published online 9 June 2008
Anti‐inflammatory actions of aprotinin provide dose‐dependent cardioprotection from reperfusion injury
Authors: Carter J M , Buerke U , Rössner E , Russ M , Schubert S , Schmidt H , Ebelt H , Pruefer D , Schlitt A , Werdan K , Buerke M 
Published: June 2008

Background and purpose:Myocardial injury following ischaemia and reperfusion has been attributed to activation and transmigration of polymorphonuclear leukocytes (PMNs) with release of mediators including oxygen‐derived radicals and proteases causing damage.Experimental approach:We studied the serine protease inhibitor aprotinin in an in vivo rabbit model of 1 h of myocardial ischaemia followed by 3 h of reperfusion (MI+R). Aprotinin (10 000 Ukg−1) or its vehicle were injected 5 min prior to the start of reperfusion.Key results:Myocardial injury was significantly reduced with aprotinin treatment as indicated by a reduced necrotic area (11±2.7% necrosis as percentage of area at risk after aprotinin; 24±3.1% after vehicle; P<0.05) and plasma creatine kinase activity (12.2±1.5 and 17.3±2.3 IU g−1 protein in aprotinin and vehicle groups, respectively, P<0.05). PMN infiltration (assessed by myeloperoxidase activity) was significantly decreased in aprotinin‐treated animals compared to vehicle (P<0.01). Histological analysis also revealed a substantial increase in PMN infiltration following MI+R and this was significantly reduced by aprotinin therapy (44±15 vs 102±2 PMN mm2 in aprotinin vs vehicle‐treated animals, P<0.05). In parallel in vitro experiments, aprotinin inhibited neutrophil‐endothelium interaction by reducing PMN adhesion on isolated, activated aortic endothelium. Finally, immunohistochemical analysis illustrated aprotinin significantly reduced myocardial apoptosis following MI+R.Conclusions and implications:Inhibition of serine proteases by aprotinin inhibits an inflammatory cascade initiated by MI+R. The cardioprotective effect appears to be at least partly due to reduced PMN adhesion and infiltration with subsequently reduced myocardial necrosis and apoptosis.British Journal of Pharmacology (2008) 155, 93–102; doi:10.1038/bjp.2008.223; published online 9 June 2008
The PKs PKA and ERK 1/2 are involved in phosphorylation of TH at Serine 40 and 31 during morphine withdrawal in rat hearts
Authors: Almela P , Milanés M V , Laorden M L 
Published: June 2008

Background and purpose:Our previous studies have shown that morphine withdrawal induced hyperactivity of cardiac noradrenergic pathways. The purpose of the present study was to evaluate the effects of morphine withdrawal on site‐specific phosphorylation of TH in the heart.Experimental approach:Dependence on morphine was induced by a 7‐day s.c. implantation of morphine pellets in rats. Morphine withdrawal was precipitated on day 8 by an injection of naloxone (2 mg kg−1). TH phosphorylation was determined by quantitative blot immunolabelling using phosphorylation state‐specific antibodies.Key results:Naloxone‐induced morphine withdrawal induced phosphorylation of TH at serine (Ser)40 and Ser31 in the right ventricle, associated with both an increase in total TH levels and an enhancement of TH activity. When HA‐1004 (PK A inhibitor) was infused, concomitantly with morphine, it diminished the increase in noradrenaline turnover, total TH levels and TH phosphorylation at Ser40 in morphine‐withdrawn rats. In contrast, the infusion of calphostin C (PKC inhibitor), did not modify the morphine withdrawal‐induced increase in noradrenaline turnover and total TH levels. In addition, we show that the ability of morphine withdrawal to stimulate phosphorylation at Ser31 was reduced by SL327, an inhibitor of ERK 1/2 activation.Conclusions and implications:The present findings demonstrate that the enhancement of total TH levels and the increased phosphorylation state of TH during morphine withdrawal were dependent on PKA and ERK activities and suggest that these transduction pathways might contribute to the activation of the cardiac catecholaminergic neurons in response to morphine withdrawal.British Journal of Pharmacology(2008)155, 73–83; doi:10.1038/bjp.2008.224; published online 9 June 2008
Antiepileptic effects of two Rho‐kinase inhibitors, Y‐27632 and fasudil, in mice
Authors: İnan S Y , Büyükafşar K 
Published: June 2008

Background and purpose:Rho/Rho‐kinase signalling is involved in many cellular events, including some in the CNS. However, the role of this pathway in epilepsy has not yet been assessed. Therefore, we determined the effects of two Rho‐kinase inhibitors, Y‐27632 and fasudil, on seizures induced by pentylenetetrazole (PTZ) or maximal electroconvulsive shock (MES).Experimental approach:Effects of Y‐27632 (5–10 mg kg−1) and fasudil (5–25 mg kg−1) on duration of myoclonic jerks, clonic and tonic convulsions, tonic hindlimb extensions and percentage of tonic convulsion index, as well as recovery latency for righting reflex were investigated in mice stimulated with PTZ (65 mg kg−1) or MES (50 Hz, 50 mA and 0.4 s). These inhibitors were also tested on a model of kindling induced by PTZ (35 mg kg−1, for 11 days). Membrane and cytosolic levels of RhoA protein were measured in brain homogenates from kindled mice.Key results:Y‐27632 and fasudil diminished onset of myoclonic jerks, clonic convulsions and tonic hindlimb extensions in mice given PTZ. These inhibitors suppressed the percentage of tonic convulsion index and recovery latency for righting reflex in the mice excited with MES. Western blotting demonstrated that Rho translocation to plasma membrane increased in the brain homogenates obtained from PTZ‐kindled mice. However, the Rho‐kinase inhibitors at the given doses did not change motor coordination of the mice.Conclusions and implications:Rho/Rho‐kinase signalling may play a role in epilepsy induced by PTZ and MES. Furthermore, Rho‐kinase inhibitors could be novel important antiepileptic agents.British Journal of Pharmacology (2008) 155, 44–51; doi:10.1038/bjp.2008.225; published online 9 June 2008
Blockade of adenosine A2B receptors ameliorates murine colitis
Authors: Kolachala V L , Ruble B K , Vijay‐Kumar M , Wang L , Mwangi S , Figler H E , Figler R A , Srinivasan S , Gewirtz A T , Linden J , Merlin D , Sitaraman S V 
Published: June 2008

Background and purpose:The adenosine 2B (A2B) receptor is the predominant adenosine receptor expressed in the colon. Acting through the A2B receptor, adenosine mediates chloride secretion, as well as fibronectin and interleukin (IL)‐6 synthesis and secretion in intestinal epithelial cells. A2B receptor mRNA and protein expression are increased during human and murine colitis. However, the effect of the A2B receptor in the activation of the intestinal inflammatory response is not known. In this study, we examined the effect of A2B receptor antagonism on murine colitis.Experimental approach:Dextran sodium sulphate (DSS)‐treated mice and piroxicam‐treated IL‐10−/− mice were used as animal models of colitis. The A2B receptor‐selective antagonist, ATL‐801, was given in the diet.Key results:Mice fed ATL‐801 along with DSS showed a significantly lower extent and severity of colitis than mice treated with DSS alone, as shown by reduced clinical symptoms, histological scores, IL‐6 levels and proliferation indices. The administration of ATL‐801 prevented weight loss, suppressed the inflammatory infiltrate into colonic mucosa and decreased epithelial hyperplasia in piroxicam‐treated IL‐10−/− mice. IL‐6 and keratinocyte‐derived chemokine (KC) concentrations in the supernatants of colonic organ cultures from colitic mice were significantly reduced by ATL‐801 administration.Conclusions and implications:Taken together, these data demonstrate that the intestinal epithelial A2B receptor is an important mediator of pro‐inflammatory responses in the intestine and that A2B receptor blockade may be an effective therapeutic strategy to treat inflammatory bowel disease.British Journal of Pharmacology (2008) 155, 127–137; doi:10.1038/bjp.2008.227; published online 9 June 2008
Differential modulation of AP‐1‐ and CRE‐driven transcription by cannabinoid agonists emphasizes functional selectivity at the CB1receptor
Authors: Bosier B , Hermans E , Lambert D M 
Published: June 2008

Background and purpose:Long‐term adaptations to pharmacological stimuli frequently originate from modulation of complex intracellular signalling pathways. We previously reported that HU210 and CP55940, two CB1cannabinoid receptor agonists, induced opposite effects on TH expression. Herein, we characterized their influence on cAMP response element (CRE) and activator protein 1 (AP‐1)‐mediated regulation of gene transcription.Experimental approach:The activity of the agonists was examined on transfected N1E‐115 cells in which expression of the luciferase reporter gene was controlled by transcription promoters consisting of repeats of either CRE or AP‐1 elements. In addition, the implication of classical signalling pathways was investigated using a variety of kinase inhibitors.Key results:Consistent with the CB1‐mediated reduction of cAMP accumulation, both ligands decreased CRE‐driven luciferase expression with similar potencies. HU210 also exhibited a concentration‐dependent reduction of luciferase activity in cells engineered to examine AP‐1‐controlled transcription, whereas such response was not obtained with CP55940. Responses were all inhibited by SR141716A and were modified inPertussistoxin‐treated cells, suggesting agonist‐selective regulations of distinct Gi/o‐dependent mechanisms through CB1receptor activation. Finally, PKC inhibitors efficiently inhibited the paradoxical effect of HU210 on AP‐1‐mediated transcription, indicating selective regulation of PKC‐dependent responses.Conclusions and implications:Together, our results demonstrate that two cannabinoid ligands, commonly used as reference agonists acting on the same receptor with similar affinities, differentially modulate gene transcription through distinct controls of AP‐1. This could reflect activation of distinct subsets of Gi/o‐proteins, supporting the concept of functional selectivity at CB1receptors.British Journal of Pharmacology(2008)155, 24–33; doi:10.1038/bjp.2008.230; published online 9 June 2008
Bimodal effects of the Kv7 channel activator retigabine on vascular K+currents
Authors: Yeung S Y M , Schwake M , Pucovský V , Greenwood I A 
Published: June 2008

Background and purpose:This study investigated the functional and electrophysiological effects of the Kv7 channel activator, retigabine, on murine portal vein smooth muscle.Experimental approach:KCNQ gene expression was determined by reverse transcriptase polymerase chain reaction (RT‐PCR) and immunocytochemical experiments. Whole cell voltage clamp and current clamp were performed on isolated myocytes from murine portal vein. Isometric tension recordings were performed on whole portal veins. K+currents generated by KCNQ4 and KCNQ5 expression were recorded by two‐electrode voltage clamp inXenopusoocytes.Key results:KCNQ1, 4 and 5 were expressed in mRNA derived from murine portal vein, either as whole tissue or isolated myocytes. Kv7.1 and Kv7.4 proteins were identified in the cell membranes of myocytes by immunocytochemistry. Retigabine (2–20 μM) suppressed spontaneous contractions in whole portal veins, hyperpolarized the membrane potential and augmented potassium currents at −20 mV. At more depolarized potentials, retigabine and flupirtine, decreased potassium currents. Both effects of retigabine were prevented by prior application of the Kv7 blocker XE991 (10 μM). Recombinant KCNQ 4 or 5 channels were only activated by retigabine or flupirtine.Conclusions and implications:The Kv7 channel activators retigabine and flupirtine have bimodal effects on vascular potassium currents, which are not seen with recombinant KCNQ channels. These results provide support for KCNQ4‐ or KCNQ5‐encoded channels having an important functional impact in the vasculature.British Journal of Pharmacology(2008)155, 62–72; doi:10.1038/bjp.2008.231; published online 9 June 2008
Therapeutic options in inflammatory bowel disease: experimental evidence of a beneficial effect of kinin B1 receptor blockade
Authors: Marceau F , Regoli D 
Published: June 2008

A surprising proportion of patients with inflammatory bowel disease (IBD) remain refractory to all classes of drugs presently in clinical use. Kinins are inflammatory mediators of potential relevance in IBD, because at least the kinin B1 receptor subtype is upregulated in human or animal intestinal inflammation and also both B1 and B2 receptors for kinins support inflammation and epithelial electrogenic ion transport that leads to secretory diarrhoea. In this issue of the BJP, Hara et al. report the therapeutic effect of a modern and selective nonpeptide kinin B1 receptor antagonist, SSR240612 ((2R)‐2‐(((3R)‐3‐(1,3‐benzodioxol‐5‐yl)‐3‐(((6‐ methoxy‐2‐naphthyl)sulphonyl)amino)propanoyl)amino)‐3‐(4‐((2R,6S)‐ 2,6‐dimethylpiperidinyl)methyl)phenyl)‐N‐isopropyl‐N‐ methylpropanamide hydrochloride), with benefits such as decreased neutrophil influx and improved macroscopic tissue scoring. The results were corroborated using kinin B1 receptor gene‐knockout mice. Further, kinin B1 receptor upregulation in this inflammatory model is partially dependent on TNF‐α, a recognized target for IBD pharmacotherapy. More work is warranted to evaluate the value of the kinin B1 receptor antagonists as a novel anti‐inflammatory therapeutic option for IBD.British Journal of Pharmacology (2008) 154, 1163–1165; doi:fn1; published online 9 June 2008
On the fitting of binding data when receptor dimerization is suspected
Authors: Giraldo J 
Published: June 2008

Mechanistic and empirical modelling are compared in context of dimeric receptors. In particular, the supposed advantages of the two‐state dimer model for fitting of binding data with respect to classical approaches such as the two‐independent sites model are investigated. The two models are revisited from both the mechanistic and empirical point of views. The problem of overparameterized models and the benefits of the concurrent use of mechanistic and empirical models for mechanism analysis are discussed. The pros and cons of mathematical models are examined with special emphasis given to the interpretation of the connection between the shapes of the curves and receptor cooperativity. It is shown that a given pharmacological phenotype (curve shape) can be obtained from different receptor genotypes (as, for instance, non‐interconvertible monomeric receptor species, receptor‐G protein interactions and dimeric receptors), though values of the Hill coefficient greater than one are indicative of receptor oligomerization. The existence of a relationship between the recently defined dimer cooperativity index and the more familiar Hill coefficient is proven.British Journal of Pharmacology(2008)155, 17–23; doi:10.1038/bjp.2008.234; published online 9 June 2008
Anthracycline toxicity to cardiomyocytes or cancer cells is differently affected by iron chelation with salicylaldehyde isonicotinoyl hydrazone
Authors: Šimůnek T , Štěrba M , Popelová O , Kaiserová H , Adamcová M , Hroch M , Hašková P , Poňka P , Geršl V 
Published: June 2008

Background and purpose:The clinical utility of anthracycline antineoplastic drugs is limited by the risk of cardiotoxicity, which has been traditionally attributed to iron‐mediated production of reactive oxygen species (ROS).Experimental approach:The aims of this study were to examine the strongly lipophilic iron chelator, salicylaldehyde isonicotinoyl hydrazone (SIH), for its ability to protect rat isolated cardiomyocytes against the toxicity of daunorubicin (DAU) and to investigate the effects of SIH on DAU‐induced inhibition of proliferation in a leukaemic cell line. Cell toxicity was measured by release of lactate dehydrogenase and staining with Hoechst 33342 or propidium iodide and lipid peroxidation by malonaldehyde formation.Key results:SIH fully protected cardiomyocytes against model oxidative injury induced by hydrogen peroxide exposure. SIH also significantly but only partially and with no apparent dose‐dependency, reduced DAU‐induced cardiomyocyte death. However, the observed protection was not accompanied by decreased lipid peroxidation. In the HL‐60 acute promyelocytic leukaemia cell line, SIH did not blunt the antiproliferative efficacy of DAU. Instead, at concentrations that reduced DAU toxicity to cardiomyocytes, SIH enhanced the tumoricidal action of DAU.Conclusions and implications:This study demonstrates that iron is most likely involved in anthracycline cardiotoxicity and that iron chelation has protective potential, but apparently through mechanism(s) other than by inhibition of ROS‐induced injury. In addition to cardioprotection, iron chelation may have considerable potential to improve the therapeutic action of anthracyclines by enhancing their anticancer efficiency and this potential warrants further investigation.British Journal of Pharmacology (2008) 155, 138–148; doi:10.1038/bjp.2008.236; published online 9 June 2008
Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension
Authors: Oka M , Fagan K A , Jones P L , McMurtry I F 
Published: June 2008

A burgeoning body of evidence suggests that RhoA/Rho kinase (ROCK) signalling plays an important role in the pathogenesis of various experimental models of pulmonary hypertension (PH), including chronic hypoxia‐, monocrotaline‐, bleomycin‐, shunt‐ and vascular endothelial growth factor receptor inhibition plus chronic hypoxia‐induced PH. ROCK has been incriminated in pathophysiologic events ranging from mediation of sustained abnormal vasoconstriction to promotion of vascular inflammation and remodelling. In addition, the 3‐hydoxy‐3‐methylglutaryl CoA reductase inhibitors, statins, which inhibit activation of RhoA by preventing post‐translational isoprenylation of the protein and its translocation to the plasma membrane ameliorate PH in several different rat models, and may also be effective in PH patients. Also, phosphorylation of RhoA and prevention of its translocation to the plasma membrane are involved in the protective effect of the type 5‐PDE inhibitor, sildenafil, against hypoxia‐ and bleomycin‐induced PH. Collectively, these and other observations indicate that independent of the cause of PH, activation of the RhoA/ROCK pathway serves as a point of convergence of various signalling cascades in the pathogenesis of the disease. We propose that ROCK inhibitors and other drugs that inhibit this pathway might be useful in the treatment of various forms of PH.British Journal of Pharmacology (2008) 155, 444–454; doi:10.1038/bjp.2008.239; published online 9 June 2008