bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cannabinoids reduce granuloma‐associated angiogenesis in rats by controlling transcription and expression of mast cell protease‐5
Authors: De Filippis D , Russo A , D'Amico A , Esposito G , Concetta P , Cinelli M , Russo G , Iuvone T 
Published: June 2008

Background and purpose:Chronic inflammatory conditions, such as granulomas, are associated with angiogenesis. Mast cells represent the main cell type orchestrating angiogenesis, through the release of their granule content. Therefore, compounds able to modulate mast cell behaviour may be considered as a new pharmacological approach to treat angiogenesis‐dependent events. Here, we tested the effect of selective cannabinoid (CB) receptor agonists in a model of angiogenesis‐dependent granuloma formation induced by λ‐carrageenin in rats.Experimental approach:Granulomas were induced by λ‐carrageenin‐soaked sponges implanted subcutaneously on the back of male Wistar rats. After 96 h, implants were removed and granuloma formation was measured (wet weight); angiogenesis was evaluated by histological analysis and by the measurement of haemoglobin content. Mast cells in the granulomas were evaluated histologically and by RT‐PCR and immunoblotting analysis for mast cell‐derived proteins (rat mast cell protease‐5 (rMCP‐5) and nerve growth factor). Selective CB1 and CB2 receptor agonists, ACEA and JWH‐015 (0.001–0.1 mg mL−1), were given locally only once, at the time of implantation.Key results:The CB1 and CB2 receptor agonists decreased the weight and vascularization of granulomas after 96 h. This treatment also reduced mast cell number and activation in granulomatous tissue. Specifically, these compounds prevented the transcription and expression of rMCP‐5, a protein involved in sprouting and advance of new blood vessels.Conclusion and implications:Modulation of mast cell function by cannabinoids reduced granuloma formation and associated angiogenesis. Therefore cannabinoid‐related drugs may be useful in the management of granulomatous diseases accompanied by angiogenesis.British Journal of Pharmacology (2008) 154, 1672–1679; doi:10.1038/bjp.2008.211; published online 16 June 2008
Oxytocin‐induced contractions within rat and rabbit ejaculatory tissues are mediated by vasopressin V1Areceptors and not oxytocin receptors
Authors: Gupta J , Russell R J , Wayman C P , Hurley D , Jackson V M 
Published: June 2008

Background and purpose:Oxytocin is believed to be involved in ejaculation by increasing sperm number and contracting ejaculatory tissues. However, oxytocin may mediate these effects via oxytocin or vasopressin (AVP) receptors. The aim of this study was to determine the effect of oxytocin and AVP on peripheral tissues involved in ejaculation and to identify the receptor subtype(s) involved.Experimental approach:Standard tissue bath techniques were used to measure isometric tension from tissues involved in ejaculation and erection.Key results:Oxytocin and AVP failed to elicit a tonic contractile response in rat and rabbit testes, vas deferens, epididymis, seminal vesicles and prostate. In contrast, oxytocin and AVP elicited large tonic contractions in erectile (corpus spongiosum and corpus cavernosum) and ejaculatory (prostatic urethra, bladder neck and ejaculatory duct) tissues in a concentration‐dependent manner. The selective oxytocin agonist, [Thr4,Gly7]‐oxytocin and the V2agonist, [deamino‐Cys1,Val4,D‐Arg8]‐vasopressin (dDAVP), failed to contract tissues. Oxytocin and AVP‐induced contractions were weakly antagonized by the selective oxytocin antagonist, L‐368899 but potently antagonized by the V1Aantagonist, SR49059. The V1Bantagonist SSR149415 failed to antagonize AVP contractions except in rabbit bladder neck. Neither L‐368899 nor SR49059 antagonized endothelin‐1‐induced contractions.Conclusions and implications:The contractile effect of oxytocin on rat and rabbit ejaculatory and erectile tissues is mediated via V1Areceptors. Endothelin‐1‐induced contractions are not due to endogenous oxytocin or AVP release. V1Areceptor antagonists may have a therapeutic role in both erectile dysfunction and premature ejaculation.British Journal of Pharmacology(2008)155, 118–126; doi:10.1038/bjp.2008.226; published online 16 June 2008
A dose escalation study in sheep of the effects of the benzodiazepine CNS 7056 on sedation, the EEG and the respiratory and cardiovascular systems
Authors: Upton R N , Martinez A M , Grant C 
Published: June 2008

Background and purpose:CNS 7056 is a new, rapidly metabolized benzodiazepine. The effects of escalating doses of CNS 7056 on sedation, and respiratory and cardiovascular function, were examined in conscious, chronically instrumented sheep for the first time.Experimental approach:Three sheep were given doses of CNS 7056 (0, 0.037, 0.074, 0.18, 0.37, 0.74, 2.21, 4.41 and 8.82 mg kg−1) as 2 min intravenous infusions in order on consecutive days. A range of physiological variables, including the EEG, were measured.Key results:Sheep became transiently drowsy for the lowest (0.037 and 0.074 mg kg−1) doses of CNS 7056, whereas the highest (8.82 mg kg−1) dose produced profound loss of consciousness (LOC) for over 30 min. The EEG alpha power correlated well (r=0.91) with duration of LOC and had a high signal‐to‐noise ratio. CNS 7056 reduced respiratory rate (maximum 33%) and dose‐dependently increased arterial carbon dioxide tension (maximum 12%). There was a transient, dose‐related reduction in arterial oxygen tension (maximum 34%), but haemoglobin desaturation was minimal (maximum 4%). CNS 7056 produced a dose‐related transient drop in mean arterial blood pressure (maximum 12%) but cardiac output was unchanged.Conclusions and implications:Doses of 0.37–2.21 mg kg−1 of CNS 7056 produced sedation for 9–25 min without excessive respiratory or cardiovascular depression, and would be suitable for pharmacokinetic studies. The power in the alpha band of the EEG can be used as a continuous measure of the sedative effects of CNS 7056.British Journal of Pharmacology (2008) 155, 52–61; doi:10.1038/bjp.2008.228; published online 16 June 2008
Low concentrations of tetrodotoxin interact with tetrodotoxin‐resistant voltage‐gated sodium channels
Authors: Farmer C E , Smith K J , Docherty R J 
Published: June 2008

Background and purpose:Tetrodotoxin (TTX) is used to distinguish between two classes of voltage‐gated sodium channel (VGSC)—TTX sensitive (TTXS) and TTX resistant (TTXR). The resistance of TTXR VGSCs is thought to result from a low binding affinity of TTX, although at high TTX concentrations channel block does occur. Here, we show that, at concentrations below those which produce block, TTX can bind to TTXR VGSCs.Experimental approach:Whole‐cell voltage clamp recordings were made from dissociated rat dorsal root ganglion neurones that expressed both TTXS and TTXR sodium currents. Voltage‐gated calcium currents were blocked by 10 μM extracellular lanthanum chloride. TTXS, but not TTXR, current was suppressed by using a holding potential of −50 mV, and the effect of TTX on the isolated TTXR current was explored.Key results:Extracellular application of 0.5 μM TTX produced a 40% increase in TTXR current amplitude, a negative shift in the voltage‐dependence of current activation (approximately −8 mV) and inactivation (approximately −10 mV) and increased rates of current activation and inactivation. The effect of TTX on current amplitude was dose‐dependent (EC50=364 nM). Removal of lanthanum prevented the effect of TTX on TTXR current amplitude, whereas reducing extracellular calcium did not.Conclusions and implications:The findings are consistent with an interpretation that TTX relieves a tonic block of the TTXR VGSC by lanthanum. We conclude that TTX binds to the TTXR VGSC at low concentrations, without blocking it. This appears to be the first demonstration of a clear distinction between binding affinity and blocking potency of a channel‐blocking agent.British Journal of Pharmacology (2008) 155, 34–43; doi:10.1038/bjp.2008.235; published online 16 June 2008
Inhibition of fatty acid amide hydrolase by kaempferol and related naturally occurring flavonoids
Authors: Thors L , Belghiti M , Fowler C J 
Published: June 2008

Background and purpose:Recent studies have demonstrated that the naturally occurring isoflavone compounds genistein and daidzein inhibit the hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) in the low micromolar concentration range. The purpose of the present study was to determine whether this property is shared by flavonoids.Experimental approach:The hydrolysis of anandamide in homogenates and intact cells was measured using the substrate labelled in the ethanolamine part of the molecule.Key results:Twenty compounds were tested. Among the commonly occurring flavonoids, kaempferol was the most potent, inhibiting FAAH in a competitive manner with a Ki value of 5 μM. Among flavonoids with a more restricted distribution in nature, the two most active toward FAAH were 7‐hydroxyflavone (IC50 value of 0.5–1 μM depending on the solvent used) and 3,7‐dihydroxyflavone (IC50 value 2.2 μM). All three compounds reduced the FAAH‐dependent uptake of anandamide and its metabolism by intact RBL2H3 basophilic leukaemia cells.Conclusions and implications:Inhibition of FAAH is an additional in vitro biochemical property of flavonoids. Kaempferol, 7‐hydroxyflavone and 3,7‐dihydroxyflavone may be useful as templates for the synthesis of novel compounds, which target several systems that are involved in the control of inflammation and cancer.British Journal of Pharmacology (2008) 155, 244–252; doi:10.1038/bjp.2008.237; published online 16 June 2008
Cellular basis of drug‐induced torsades de pointes
Authors: Roden D M 
Published: June 2008

Striking QT prolongation and the morphologically distinctive ventricular tachycardia torsades de pointes can occur in up to 5% of patients treated with certain antiarrhythmic drugs. This adverse drug reaction also occurs, albeit far less frequently, during therapy with a range of drugs not used for cardiovascular indications; examples include certain antibiotics, antipsychotics and antihistamines. The common mechanism for drug‐induced torsades de pointes is inhibition of a specific repolarizing potassium current, IKr. The key question facing clinicians, regulators and those who develop drugs is why torsades de pointes only occurs in some patients exposed to IKrblock. This paper reviews the clinical, cellular, molecular and genetic features of the arrhythmia that may provide an answer to this question and proposes future studies in this area.British Journal of Pharmacology(2008)154, 1502–1507; doi:fn1; published online 16 June 2008
Sensitive and reliable proarrhythmiain vivoanimal models for predicting drug‐induced torsades de pointes in patients with remodelled hearts
Authors: Sugiyama A 
Published: June 2008

As an increasing number of non‐cardiac drugs have been reported to cause QT interval prolongation and torsades de pointes (TdP), we extensively studied the utility of atrioventricular (AV) block animals as a model to predict their torsadogenic action in human. The present review highlights suchin vivoproarrhythmia models. In the case of the canine model, test substances were administered p.o. at conscious state >4 weeks after the induction of AV block, with subsequent Holter ECG monitoring to evaluate drug effects. Control AV block dogs (no pharmacological treatment) survive for several years without TdP attack. For pharmacologically treated dogs, drugs were identified as high, low or no risk. High‐risk drugs induced TdP at 1–3 times the therapeutic dose. Low‐risk drugs did not induce TdP at this dose range, but induced it at higher doses. No‐risk drugs never induced TdP at any dose tested. Electrophysiological, anatomical histological and biochemical adaptations against persistent bradycardia‐induced chronic heart failure were observed in AV block dogs. Recently, we have developed another highly sensitive proarrhythmia model using a chronic AV block cynomolgus monkey, which possesses essentially the same pathophysiological adaptations and drug responses as those demonstrated in the canine model. As a common remodelling process leading to a diminished repolarization reserve may present in patients who experience drug‐induced TdP and in the AV block animals, thein vivoproarrhythmia models described in this review may be useful for predicting the risk of pharmacologically induced TdP in humans.British Journal of Pharmacology(2008)154, 1528–1537; doi:fn1; published online 16 June 2008
Emodin is a novel alkaline nuclease inhibitor that suppresses herpes simplex virus type 1 yields in cell cultures
Authors: Hsiang C‐Y , Ho T‐Y 
Published: June 2008

Background and purpose:Most antiviral therapies directed against herpes simplex virus (HSV) infections are limited to a small group of nucleoside analogues that target the viral polymerase. Extensive clinical use of these drugs has led to the emergence of resistant viral strains, mainly in immunocompromised patients. This highlights the need for the development of new anti‐herpesviral drugs with novel targets. Herein the effects of a plant anthraquinone, emodin, on the HSV‐1 alkaline nuclease activity and virus yields were investigated.Experimental approach:HSV‐1 alkaline nuclease activity was examined by nuclease activity assay. Inhibition of virus yields was measured by plaque reduction assay and immunohistochemical staining. Interaction between emodin and alkaline nuclease was analysed by docking technology.Key results:Emodin specifically inhibited the nuclease activity of HSV‐1 UL12 alkaline nuclease in a biochemical assay. Plaque reduction assay revealed that emodin reduced the plaque formation with an EC50 of 21.5±4.4 μM. Immunohistochemical staining using the anti‐nucleocapsid protein antibody demonstrated that emodin induced the accumulation of viral nucleocapsids in the nucleus in a dose‐dependent manner. Docking analysis further suggested that the inhibitory effect of emodin on the UL12 activity may result from the interaction between emodin and critical catalytic amino acid residues of UL12.Conclusions and implications:Our findings suggest that emodin is a potent anti‐HSV agent that inhibits the yields of HSV‐1 via the suppression of a novel target, UL12.British Journal of Pharmacology (2008) 155, 227–235; doi:10.1038/bjp.2008.242; published online 16 June 2008
Prediction of clinical response based on pharmacokinetic/pharmacodynamic models of 5‐hydroxytryptamine reuptake inhibitors in mice
Authors: Kreilgaard M , Smith D G , Brennum L T , Sánchez C 
Published: June 2008

Background and purpose:Bridging the gap between preclinical research and clinical trials is vital for drug development. Predicting clinically relevant steady‐state drug concentrations (Css) in serum from preclinical animal models may facilitate this transition. Here we used a pharmacokinetic/pharmacodynamic (PK/PD) modelling approach to evaluate the predictive validity of 5‐hydroxytryptamine (5‐HT; serotonin) transporter (SERT) occupancy and 5‐hydroxytryptophan (5‐HTP)‐potentiated behavioral syndrome induced by 5‐HT reuptake inhibitor (SRI) antidepressants in mice.Experimental approach:Serum and whole brain drug concentrations, cortical SERT occupancy and 5‐HTP‐potentiated behavioral syndrome were measured over 6 h after a single subcutaneous injection of escitalopram, paroxetine or sertraline. [3H]2‐(2‐dimethylaminomethylphenylsulphanyl)‐5‐methyl‐phenylamine ([3H]MADAM) was used to assess SERT occupancy. For PK/PD modelling, an effect‐compartment model was applied to collapse the hysteresis and predict the steady‐state relationship between drug exposure and PD response.Key results:The predicted Css for escitalopram, paroxetine and sertraline at 80% SERT occupancy in mice are 18 ng mL−1, 18 ng mL−1 and 24 ng mL−1, respectively, with corresponding responses in the 5‐HTP behavioral model being between 20–40% of the maximum.Conclusions and implications:Therapeutically effective SERT occupancy for SRIs in depressed patients is approximately 80%, and the corresponding plasma Css are 6–21 ng mL−1, 21‐95 ng mL−1 and 20–48 ng mL−1 for escitalopram, paroxetine and sertraline, respectively. Thus, PK/PD modelling using SERT occupancy and 5‐HTP‐potentiated behavioral syndrome as response markers in mice may be a useful tool to predict clinically relevant plasma Css values.British Journal of Pharmacology (2008) 155, 276–284; doi:10.1038/bjp.2008.243; published online 16 June 2008
Metabolic responses to BRL37344 and clenbuterol in soleus muscle and C2C12 cells via different atypical pharmacologies and β2‐adrenoceptor mechanisms
Authors: Ngala R A , O'Dowd J , Wang S J , Agarwal A , Stocker C , Cawthorne M A , Arch J R S 
Published: June 2008

Background and purpose:Picomolar concentrations of the β3‐adrenoceptor agonist BRL37344 stimulate 2‐deoxyglucose uptake in soleus muscle via undefined receptors. Higher concentrations alter uptake, apparently via β2‐adrenoceptors. Effects of BRL37344 and β2‐adrenoceptor agonists are compared.Experimental approach:Mouse soleus muscles were incubated with 2‐deoxy[1‐14C]‐glucose, [1‐14C]‐palmitate or [2‐14C]‐pyruvate, and BRL37344, β2‐adrenoceptor agonists and selective β‐adrenoceptor antagonists. Formation of 2‐deoxy[1‐14C]‐glucose‐6‐phosphate or14CO2was measured. 2‐Deoxy[1‐14C]‐glucose uptake and β‐adrenoceptor mRNA were measured in C2C12 cells.Key results:10 pMBRL37344, 10 pMclenbuterol and 100 pMsalbutamol stimulated 2‐deoxyglucose uptake in soleus muscle by 33–54%. The effect of BRL37344 was prevented by 1 μMatenolol but not by 300 nMCGP20712A or IC3118551, or 1 μMSR59230A; that of clenbuterol was prevented by ICI118551 but not atenolol. 10 nMBRL37344 st4mulated 2‐deoxyglucose uptake, whereas 100 nMclenbuterol and salbutamol inhibited uptake. These effects were blocked by ICI118551. Similar results were obtained in C2C12 cells, in which only β2‐adrenoceptor mRNA could be detected by RT‐PCR. 10 nMBRL37344 and 10 pMclenbuterol stimulated muscle palmitate oxidation. In the presence of palmitate, BRL37344 no longer stimulated 2‐deoxyglucose uptake and the effect of clenbuterol was not significant.Conclusions and implications:Stimulation of glucose uptake by 10 pMBRL37344 and clenbuterol involves different atypical pharmacologies. Nanomolar concentrations of BRL37344 and clenbuterol, probably acting via β2‐adrenoceptors, have opposite effects on glucose uptake. The agonists preferentially stimulate fat rather than carbohydrate oxidation, but stimulation of endogenous fat oxidation cannot explain why 100 nMclenbuterol inhibited 2‐deoxyglucose uptake.British Journal of Pharmacology(2008)155, 395–406; doi:fn1; published online 16 June 2008
The α1A‐adrenoceptor gene is required for the α1L‐adrenoceptor‐mediated response in isolated preparations of the mouse prostate
Authors: Gray K T , Short J L , Ventura S 
Published: June 2008

Background and purpose:This study investigated whether deletion of the α1A‐adrenoceptor gene influences contractile responses of mouse prostate to noradrenaline. Responses of mouse prostate to noradrenaline are known to be mediated by α1L‐adrenoceptors, which are thought to be a functional phenotype of α1A‐adrenoceptor.Experimental approach:Prostate tissues from α1A‐adrenoceptor knockout mice which were homozygous (α1A−/−) and heterozygous (α1A+/−) for the disrupted α1A‐adrenoceptor gene, as well as wild‐type (α1A+/+) littermates were mounted in glass‐isolated organ baths. Electrical field stimulation of nerves and exogenous application of noradrenaline were used to investigate the effects of α1A‐adrenoceptor disruption on prostate contractility.Key results:Frequency–response curves to electrical field stimulation (0.5 ms pulse duration, 60 V, 0.1–20 Hz) yielded frequency‐dependent contractions. At frequencies of 10 and 20 Hz, prostates from α1A−/− mice elicited an approximately 30% decreased response compared with prostates from α1A+/+ mice. Prazosin (0.3 μM) attenuated responses to electrical field stimulation in prostates from α1A+/+ and α1A+/− mice but not from α1A−/− mice. Increasing concentrations of exogenously administered noradrenaline (10 nM–1 mM) produced mean concentration–response curves in prostates from α1A+/+ and α1A+/− mice, which were not different. Maximum responses to noradrenaline were decreased by approximately 80% in prostates from α1A−/− mice compared with α1A+/+ mice. Prazosin attenuated responses to noradrenaline in all genotypes.Conclusions and implications:α1L‐Adrenoceptor‐mediated responses in mouse prostate are abolished in α1A−/− mice, demonstrating that the α1A‐adrenoceptor gene is essential to the manifestation of the prostatic α1L‐adrenoceptor phenotype. This implies that α1L‐adrenoceptors are indeed a functional phenotype of α1A‐adrenoceptor.British Journal of Pharmacology(2008)155, 103–109; doi:fn1; published online 16 June 2008
Mechanisms of augmented vasoconstriction induced by 5‐hydroxytryptamine in aortic rings from spontaneously hypertensive rats
Authors: Budzyn K , Ravi R M , Miller A A , Sobey C G 
Published: June 2008

Background and purpose:To test whether development of enhanced vasoconstriction to 5‐hydroxytryptamine (5‐HT; serotonin) in SHR was temporally related to hypertension, elevated vascular superoxide (O2−) levels, decreased NO bioavailability, or increased contractile effects of cyclooxygenase or rho‐kinase and/or PKC.Experimental approach:We examined systolic blood pressure (SBP), vascular O2−, and 5‐HT‐induced contractile responses of aortic segments from 4‐ and 8‐week‐old WKY and SHR.Key results:SBP was 35% higher in SHR than WKY at 4 weeks and 60% higher at 8 weeks. Contractile responses to 5‐HT were similar in WKY and SHR at 4 weeks, but were markedly augmented in SHR at 8 weeks. The NO synthase inhibitor, L‐NAME, enhanced contractile responses to 5‐HT markedly in both strains at 4 weeks and in WKY at 8 weeks, but only very modestly in SHR at 8 weeks. These functional differences were associated with higher O2− levels in SHR versus WKY at 8 weeks, but not at 4 weeks. The rho‐kinase inhibitor, Y‐27632, and the PKC inhibitor, Ro 31‐8220, each only modestly attenuated contractions in WKY and SHR in each age group, and their effects in each strain were more pronounced at 8 weeks. The cyclooxygenase inhibitor, indomethacin, had no effect on contractile responses.Conclusions and implications:Development of augmented vascular contractile responses to 5‐HT in SHR is preceded by hypertension. It is associated with increased vascular O2− levels and reduced modulatory effects of NO, and is unlikely to be due to enhanced activity of rho‐kinase, PKC or cyclooxygenase.British Journal of Pharmacology (2008) 155, 210–216; doi:10.1038/bjp.2008.247; published online 16 June 2008