bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nitropravastatin stimulates reparative neovascularisation and improves recovery from limb Ischaemia in type‐1 diabetic mice
Authors: Emanueli C , Monopoli A , Kraenkel N , Meloni M , Gadau S , Campesi I , Ongini E , Madeddu P 
Published: March 2007

Background and purpose:Mature endothelial cells and their progenitors are dysfunctional in diabetes, resulting in deficient neovascularisation following arterial occlusion. This study aimed to evaluate the therapeutic activity of a nitric oxide (NO) releasing statin in the setting of experimental diabetes and peripheral ischaemia.Experimental approach:The effects of NCX 6550, an NO‐releasing pravastatin derivative, on angiogenesis in ischaemic limbs was studied in normoglycaemic mice or mice made diabetic by treatment with streptozotocin (STZ). Control mice received an equimolar dosage of the parent statin compound, pravastatin. The therapeutic action of NCX 6550 was also tested in mice lacking the gene for endothelial nitric oxide synthase (eNOS).Key Results:In normoglycaemic or STZ‐diabetic CD1 mice, only NCX 6550 stimulated skeletal muscle revascularisation. In addition, NCX 6550 induced greater improvement in limb reperfusion and salvage, than pravastatin. The number of circulating endothelial progenitor cells was decreased in STZ‐diabetic mice, this defect being prevented by NCX 6550 and, to a lesser extent by pravastatin. In vitro, high glucose concentrations reduced the migratory capacity of endothelial progenitor EPCs, which was partly reversed by preincubation with pravastatin and completely reversed by NCX 6550. The postischaemic recovery of eNOS knockout mice was severely impaired as a consequence of depressed angiogenesis and this recovery was improved by treatment with NCX 6550, but not with pravastatin.Conclusions and implications:These findings indicate that incorporation of a bioactive NO moiety improves the therapeutic profile of statins for the treatment of peripheral vascular disease.British Journal of Pharmacology (2007) 150, 873–882. doi:10.1038/sj.bjp.0707142
EPO tecting the Endothelium
Authors: Peterson T E , Katusic Z S 
Published: March 2007

Erythropoietin is a 30.4 kDa protein that is produced and secreted from the kidney in response to anemia and hypobaric hypoxia. Binding of EPO to its receptor (EPO‐R) on bone marrow‐derived erythroid progenitor cells results in the stimulation of red blood cell production. Evidence is accumulating however, that the biological effects of recombinant EPO therapy extend beyond the stimulation of erythropoiesis. The discovery that the EPO‐R is expressed on vascular endothelial cells suggests that the vasculature may be a biological target of EPO. Indeed, several studies have now demonstrated that the protective effect of EPO administration involves the activation of the protein kinase B/Akt pathway which can protect cells from apoptosis. Future work is likely to provide further insight into the mechanisms by which EPO protects vascular endothelial cells from injury and give us a better understanding of the pharmacological doses that are required to achieve this protection.British Journal of Pharmacology (2007) 150, 823–825. doi:10.1038/sj.bjp.0707162
Capsaicin‐induced mucus secretion in rat airways assessedin vivoand non‐invasively by magnetic resonance imaging
Authors: Karmouty‐Quintana H , Cannet C , Sugar R , Fozard J R , Page C P , Beckmann N 
Published: March 2007

Background and purpose:An up‐regulation of the sensory neural pathways in the lung has been implicated in asthma and chronic obstructive pulmonary disease (COPD) and is thought to contribute to mucus hypersecretion, an essential feature of both diseases. The aim of this study was to assess non‐invasively the acute effects (up to 60 min) of sensory nerve stimulation by capsaicin in the lung, using magnetic resonance imaging (MRI).Experimental approach:Male Brown Norway rats were imaged prior to and 10, 30 and 60 min after intra‐tracheal challenge with capsaicin (30μgkg−1) or vehicle (0.5% ethanol solution). In subsequent studies, pre‐treatment with the transient receptor potential vanilloid (TRPV)‐1 antagonist, capsazepine; the dual neurokinin (NK) 1 and NK2 receptor antagonist, DNK333 and the mast cell stabilizer, di‐sodium cromoglycate (DSCG) was used to modulate the effects of capsaicin.Key results:Diffuse fluid signals were detected by MRI in the lung as early as 10 min after capsaicin, remaining constant 30 and 60 min after treatment. Broncho‐alveolar lavage (BAL) fluid analysis performed 60 min after capsaicin revealed increased mucin concentration. Capsazepine (3.5 mgkg−1), DNK333 (10 mgkg−1) but not DSCG (10 mgkg−1) administered prophylactically were able to block the effect of capsaicin in the airways.Conclusions and implications:These observations suggest that the fluid signals detected by MRI after capsaicin administration reflected predominantly the release of mucus following activation of sensory nerves. They point to the opportunity of non‐invasively assessing with MRI the influence of neuronal mechanisms in animal models of asthma and COPD.British Journal of Pharmacology(2007)150, 1022–1030. doi:10.1038/sj.bjp.0707168
Correlation of apparent affinity values from H3‐receptor binding assays with apparent affinity (pKapp) and intrinsic activity (α) from functional bioassays
Authors: Harper E A , Shankley N P , Black J W 
Published: March 2007

Background and purpose:Agonist apparent affinities (pKI′) in histamine H3‐receptor binding assays were higher than expected from apparent affinity values (pKapp) estimated in bioassay. Here, we investigate whether the degree of pKI′ overestimation is related to agonist intrinsic efficacy, by studying the effect of buffer composition on the pKI′ of ligands with varying intrinsic activity.Experimental approach:In the guinea‐pig ileum bioassay, intrinsic activity (α) was determined from the maximal inhibition of the contraction produced by increasing agonist concentration. pKapp values were estimated using the method of Furchgott. The pKL of [3H]clobenpropit in guinea‐pig cerebral cortex was estimated by saturation analysis in 20 mM HEPES‐NaOH buffer (buffer B(0,0,0)), or buffer B(0,0,0) containing 70 mM CaCl2, 100 mM NaCl and 100 mM KCl (buffer B(0.07,0.1,0.1)). PKI values were determined in competition studies in both buffers.Key results:[3H]clobenpropit saturation isotherms had nH values of unity in both buffers. In buffer B(0.07,0.1,0.1), agonist pKI′ values were closer to pKapp values than in buffer B(0,0,0) but were associated with nH values <1. A two‐site analysis of agonist data in buffer B(0.07, 0.1, 0.1) provided a better fit than a one‐site fit and low affinity values (pKIL) were comparable to pKapp. Differences between the pKI′ in buffer B(0,0,0) and pKIL values in buffer B(0.07,0.1,0.1) (ΔpK) were correlated with α.Conclusions and implications:H3‐receptor binding assays conducted in buffer B(0,0,0) and buffer B(0.07,0.1,0.1) can provide a measure of ligand affinity (pKapp) and intrinsic efficacy. The assay predicts that some ligands previously classified as H3‐receptor antagonists may possess residual intrinsic efficacy.British Journal of Pharmacology (2007) 151, 109–124. doi:10.1038/sj.bjp.0707174
Evidence that ATP or a related purine is an excitatory neurotransmitter in the longitudinal muscle of mouse distal colon
Authors: Zizzo M G , Mulè F , Serio R 
Published: March 2007

Background and purpose:This study analysed the contribution of the purinergic system to enteric neurotransmission in the longitudinal muscle of mouse distal colon.Experimental approach:Motor responses to exogenous ATP and to nerve stimulationin vitrowere assessed as changes in isometric tension.Key results:ATP induced a concentration‐dependent contraction, reduced by 4‐[[4‐formyl‐5‐hydroxy‐6‐methyl‐3‐[(phosphonooxy)methyl]‐2‐pyridinyl]azo]‐1,3‐benzene disulphonic acid (PPADS), suramin, P2Y purinoreceptor desensitisation with adenosine 5’‐O‐2‐thiodiphosphate (ADPβS), and atropine, but unaffected by P2X purinoceptor desensitisation with α,β‐methylene ATP (α,β‐meATP) and by 2,2‐dimethyl‐propionic acid 3‐(2‐chloro‐6‐methylaminopurin‐9‐yl)‐2‐(2,2‐dimethyl‐propionyloxymethyl)‐propyl ester (MRS 2395), a P2Y12selective antagonist. The response to ATP was increased by 2′‐deoxy‐N6‐methyl adenosine 3′,5′‐diphosphate (MRS 2179), a P2Y1selective antagonist, tetrodotoxin (TTX) or Nω‐nitro‐L‐arginine methyl ester (L‐NAME). ADPβS, a P2Y‐purinergic agonist, induced muscular contraction, with the same pharmacological profile as the ATP‐induced contraction. ADP, a natural ligand for P2Y1receptors, induced muscular relaxation, antagonized by MRS 2179 and by TTX or L‐NAME. Nerve stimulation elicited a transient nitrergic relaxation, followed by contraction. Contractile responses was reduced by atropine, PPADS, suramin, P2Y purinoceptor desensitisation, but not by P2X purinoceptor desensitisation, MRS 2179 or MRS 2395. None of the purinergic antagonists modified the nerve‐evoked relaxation.Conclusions and implications:In the longitudinal muscle of mouse distal colon, ATP, through ADPβS‐sensitive P2Y purinoceptors, contributed to the excitatory neurotransmission acting directly on smooth muscle and indirectly via activation of cholinergic neurons. Moreover, P2Y1 purinoceptors appear to be located on nitrergic inhibitory neurons. This study provides new insights into the role of purines in the mechanism inducing intestinal transit in mouse colon.British Journal of Pharmacology(2007)151, 152–160. doi:10.1038/sj.bjp.0707188
Calcium and reactive oxygen species increase in endothelial cells in response to releasers of endothelium‐derived contracting factor
Authors: Tang E H C , Leung F P , Huang Y , Feletou M , So K‐F , Man R Y K , Vanhoutte P M 
Published: March 2007

Background and Purpose:Experiments were designed to assess whether or not the intracellular concentration of calcium and reactive oxygen species (ROS) increase in endothelial cells of the rat thoracic aorta in response to releasers of endothelium‐derived contracting factor (EDCF) and if so, whether or not a difference exists between spontaneously hypertensive (SHR) and normotensive (WKY) rats.Experimental approach:Calcium and ROS were measured by confocal microscopy, using Fura‐red in combination with Fluo‐4 and dichlorodihydrofluorescein diacetate, respectively.Key results:Acetylcholine caused a rapid increase in cytosolic calcium concentration in endothelial cells of both SHR and WKY, which was significantly more pronounced in aortae of the former strain. This rise of calcium was not affected by indomethacin (an inhibitor of cyclooxygenase) or Tiron plus diethyldithiocarbamate acid (DETCA) (membrane permeable antioxidants). In the presence of a nitric oxide synthase blocker, acetylcholine also caused a rapid increase in ROS in endothelial cells of SHR but not in those of WKY. The burst of ROS was prevented by indomethacin or Tiron plus DETCA.Conclusions and implications:These experiments show that endothelial cells of SHR are more prone to calcium and ROS overload upon stimulation with acetylcholine. The abnormal accumulation of calcium is a prerequisite to initiate the release of EDCF and can be mimicked using the calcium ionophore A23187. The sequence of events occurring during endothelium‐dependent contractions firstly requires the accumulation of calcium, which then activates cyclooxygenase and produces ROS along with EDCF that in turn stimulates TP‐receptors, resulting in EDCF‐mediated contractions.British Journal of Pharmacology (2007) 151, 15–23. doi:10.1038/sj.bjp.0707190
Pharmacokinetic and pharmacodynamic consequences of inhibition of terazosin metabolism via CYP3A1 and/or 3A2 by DA‐8159, an erectogenic, in rats
Authors: Oh E Y , Bae S K , Kwon J W , You M , Lee D C , Lee M G 
Published: March 2007

Background and purpose:Recently, orthostatic hypotension was observed in patients with benign prostatic hyperplasia who are taking vardenafil (a PDE 5 inhibitor) and terazosin (a long acting alpha blocker). Therefore, this study was performed with DA‐8159 (a long acting PDE 5 inhibitor) and terazosin in rats to find whether or not pharmacokinetic and pharmacodynamic interactions between the two drugs were observed.Experimental approach:Pharmacokinetic and pharmacodynamic (changes in blood pressure) interactions between DA‐8159 and terazosin were evaluated after simultaneous i.v. and p.o. administration of DA‐8159 (30 mg kg−1) and terazosin (5 mg kg−1) to male Sprague–Dawley rats.Key results:After simultaneous i.v. and p.o. administration of terazosin and DA‐8159, the total area under the plasma concentration–time curve from time zero to time infinity (AUC) of terazosin became significantly greater (57.4 and 75.4% increase for i.v. and p.o. administration, respectively) than those of without DA‐8159. The blood pressure dropping effect was considerable after simultaneous p.o. administration of DA‐8159 and terazosin compared with each drug alone.Conclusions and implications:The significantly greater AUC of terazosin after both simultaneous i.v. and p.o. administration of both drugs could be due to the hepatic (both i.v. and p.o.) and intestinal (p.o.) inhibition of the metabolism of terazosin via CYP3A1 and/or 3A2 by DA‐8159, since both DA‐8159 and terazosin are metabolized via CYP3A1 and/or 3A2 in rats. The blood pressure lowering effect after simultaneous p.o. administration of both drugs could be due to significant increase in plasma concentrations of terazosin.British Journal of Pharmacology (2007) 151, 24–34. doi:10.1038/sj.bjp.0707192
NA+‐ and K+‐channels as molecular targets of the alkaloid ajmaline in skeletal muscle fibres
Authors: Friedrich O , V Wegner F , Wink M , Fink R H A 
Published: March 2007

Background and purpose:Ajmaline is a widely used antiarrhythmic drug. Its action on voltage‐gated ion channels in skeletal muscle is not well documented and we have here elucidated its effects on Na+ and K+ channels.Experimental approach:Sodium (INa) and potassium (IK) currents in amphibian skeletal muscle fibres were recorded using ‘loose‐patch’ and two‐microelectrode voltage clamp techniques (2‐MVC). Action potentials were generated using current clamp.Key results:Under ‘loose patch’ clamp conditions, the IC50 for INa was 23.2 μM with Hill‐coefficient h=1.21. For IK, IC50 was 9.2 μM, h=0.87. Clinically relevant ajmaline concentrations (1‐3 μM) reduced peak INa by ∼5% but outward IK values were reduced by ∼20%. Na+ channel steady‐state activation and fast inactivation were concentration‐dependently shifted towards hyperpolarized potentials (∼10 mV at 25 μM). Inactivation curves were markedly flattened by ajmaline. Peak‐IK under maintained depolarisation was reduced to ∼30% of control values by 100 μM ajmaline. IK activation time constants were increased at least two‐fold. Lower concentrations (10 or 25 μM) reduced steady‐state‐IK slightly but peak‐IK significantly. Action potential generation threshold was increased by 10 μM ajmaline and repolarisation prolonged.Conclusions and implications:Ajmaline acts differentially on Na+ and K+ channels in skeletal muscle. This suggests at least multiple sites of action including the S4 subunit. Our data may provide a first insight into specific mechanisms of ajmaline‐ion channel interaction in tissues other than cardiac muscle and could suggest possible side‐effects that need to be further evaluated.British Journal of Pharmacology (2007) 151, 63–74. doi:10.1038/sj.bjp.0707194
Blockade of morphine‐induced behavioral sensitization by a combination of amisulpride and RB101, comparison with classical opioid maintenance treatments
Authors: Cordonnier L , Sanchez M , Roques B P , Noble F 
Published: March 2007

Background and purpose:Maintenance treatments with methadone or buprenorphine are more or less efficient procedures for helping heroin addicts to stop or reduce drug abuse. Another approach to treat opiate dependence could be to target the endogenous opioid system by enhancing the effects of enkephalins by protecting them from enzymic degradation by the dual peptidase inhibitor RB101.Experimental approach:As chronic treatment with the dopamine D2 antagonist amisulpride facilitates RB101‐induced behavioral effects, we chose in this study to treat mice previously sensitized to the hyperlocomotor effects induced by morphine with a combination of amisulpride and RB101.Key results:Expression of morphine‐induced locomotor sensitization was abolished after combined treatment with amisulpride (20 mg.kg−1, i.p.) and RB101 (80 mg.kg−1, i.p.), whereas these drugs were not effective when used alone. We then compared these results with the effects of amisulpride combined with buprenorphine (0.1 mg.kg−1, i.p.) or methadone (2.5 mg.kg−1, i.p.) upon morphine‐induced behavioral sensitization. Whereas the combination of amisulpride and buprenorphine partially blocked the expression of morphine sensitization, amisulpride+methadone was not effective in this paradigm.Conclusions and implications:The combination of amisulpride+RB101 appears to be very efficient in blocking the expression of morphine‐induced behavioral sensitization. This could reflect a reinstatement of a balance between the function of the dopamine and opioid systems and could represent a new approach in maintenance treatments for opiate addiction.British Journal of Pharmacology(2007)151, 75–83. doi:10.1038/sj.bjp.0707195
Mechanisms of G protein activation via the D2 dopamine receptor: evidence for persistent receptor/G protein interaction after agonist stimulation
Authors: Quirk K , Roberts D J , Strange P G 
Published: March 2007

Background and purpose:The aim of this report is to study mechanisms of G protein activation by agonists.Experimental approach:The association and dissociation of guanosine 5′‐O‐(3‐[35S]thio)triphosphate ([35S]GTPγS) binding at G proteins in membranes of CHO cells stably transfected with the human dopamine D2short receptor was studied in the presence of a range of agonists.Key results:Binding of [35S]GTPγS was dissociable in the absence of agonist and dissociation was accelerated both in rate and extent by dopamine, an effect which was blocked by the dopamine D2 receptor antagonist raclopride and by suramin, which inhibits receptor/G protein interaction. A range of agonists of varying efficacy increased the rate of dissociation of [35S]GTPγS binding, with the more efficacious agonists resulting in faster dissociation. Agonists were able to dissociate about 70% of the pre‐bound [35S]GTPγS, leaving a component which may not be accessible to the agonist‐bound receptor. The dissociable component of the [35S]GTPγS binding was reduced with longer association times and increased [35S]GTPγS concentrations.Conclusions and implications:These data are consistent with [35S]GTPγS binding being initially to receptor‐linked G proteins and then to G proteins which have separated from the agonist bound receptor. Under the conditions used typically for [35S]GTPγS binding assays, therefore, much of the agonist‐receptor complex remains in proximity to G proteins after they have been activated by agonist.British Journal of Pharmacology (2007) 151, 125–133. doi:10.1038/sj.bjp.0707197
Modulation of angiogenesis by dithiolethione‐modified NSAIDs and valproic acid
Authors: Isenberg J S , Jia Y , Field L , Ridnour L A , Sparatore A , Del Soldato P , Sowers A L , Yeh G C , Moody T W , Wink D A , Ramchandran R , Roberts D D 
Published: March 2007

Background and purpose:Angiogenesis involves multiple signaling pathways that must be considered when developing agents to modulate pathological angiogenesis. Because both cyclooxygenase inhibitors and dithioles have demonstrated anti‐angiogenic properties, we investigated the activities of a new class of anti‐inflammatory drugs containing dithiolethione moieties (S‐NSAIDs) and S‐valproate.Experimental approach:Anti‐angiogenic activities of S‐NSAIDS, S‐valproate, and the respective parent compounds were assessed using umbilical vein endothelial cells, muscle and tumor tissue explant angiogenesis assays, and developmental angiogenesis in Fli:EGFP transgenic zebrafish embryos.Key results:Dithiolethione derivatives of diclofenac, valproate, and sulindac inhibited endothelial cell proliferation and induced Ser78 phosphorylation of hsp27, a known molecular target of anti‐angiogenic signaling. The parent drugs lacked this activity, but dithiolethiones were active at comparable concentrations. Although dithiolethiones can potentially release hydrogen sulphide, NaSH did not reproduce some activities of the S‐NSAIDs, indicating that the dithioles regulate angiogenesis through mechanisms other than release of H2S. In contrast to the parent drugs, S‐NSAIDs, S‐valproate, NaSH, and dithiolethiones were potent inhibitors of angiogenic responses in muscle and HT29 tumor explants assessed by 3‐dimensional collagen matrix assays. Dithiolethiones and valproic acid were also potent inhibitors of developmental angiogenesis in zebrafish embryos, but the S‐NSAIDs, remarkably, lacked this activity.Conclusions and implication:S‐NSAIDs and S‐valproate have potent anti‐angiogenic activities mediated by their dithiole moieties. The novel properties of S‐NSAIDs and S‐valproate to inhibit pathological versus developmental angiogenesis suggest that these agents may have a role in cancer treatment.British Journal of Pharmacology (2007) 151, 142–151. doi:10.1038/sj.bjp.0707198
Interactions between NO, CO and an endothelium‐derived hyperpolarizing factor (EDHF) in maintaining patency of the ductus arteriosus in the mouse
Authors: Baragatti B , Brizzi F , Barogi S , Laubach V E , Sodini D , Shesely E G , Regan R F , Coceani F 
Published: March 2007

Background and purpose:Prenatal patency of ductus arteriosus is maintained by prostaglandin (PG) E2, possibly along with nitric oxide (NO) and carbon monoxide (CO), and cyclooxygenase (COX) deletion upregulates NO. Here, we have examined enzyme source and action of NO for ductus patency and whether NO and CO are upregulated by deletion of, respectively, heme oxygenase 2 (HO‐2) and COX1 or COX2.Experimental approach:Experiments were performedin vitroandin vivowith wild‐type and gene‐deleted, near‐term mouse fetuses.Key results:NG‐nitro‐L‐arginine methyl ester (L‐NAME) contracted the isolated ductus and its effect was reduced by eNOS, but not iNOS, deletion. L‐NAME contraction was not modified by HO‐2 deletion. Zinc protoporphyrin (ZnPP) also contracted the ductus, an action unaffected by deletion of either COX isoform. Bradykinin (BK) relaxed indomethacin‐contracted ductus similarly in wild‐type and eNOS−/− or iNOS−/−. BK relaxation was suppressed by either L‐NAME or ZnPP. However, it reappeared with combined L‐NAME and ZnPP to subside again with K+increase or K+channel inhibition.In vivo, the ductus was patent in wild‐type and NOS‐deleted fetuses. Likewise, no genotype–related difference was noted in postnatal closure.Conclusions and implications:NO, formed mainly via eNOS, regulates ductal tone. NO and CO cooperatively mediate BK‐induced relaxation in the absence of PGE2. However, in the absence of PGE2, NO and CO, BK induces a relaxant substance behaving as an endothelium‐derived hyperpolarizing factor. Ductus patency is, therefore, sustained by a cohort of agents with PGE2and NO being preferentially coupled for reciprocal compensation.British Journal of Pharmacology(2007)151, 54–62. doi:10.1038/sj.bjp.0707211