bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced noradrenergic transmission in the spontaneously hypertensive rat anococcygeus muscle
Authors: Jiménez‐Altayó Francesc , Giraldo Jesús , McGrath John C , Vila Elisabet 
Published: October 2003

There is a long‐known hyper‐responsiveness of vascular adrenergic transmission in the spontaneously hypertensive rat (SHR) that is uncovered specifically in the presence of cocaine and attributed to blockade of the neuronal monoamine transporter. We have now used the rat anococcygeus muscle to investigate whether this phenomenon is generic to sympathetic transmission to smooth muscle rather than a purely vascular phenomenon. We sought the origin of the effect by successively blocking the buffering effects of the neuronal monoamine transporter, prejunctional α2‐adrenoceptors and NO from nitrergic nerves with desipramine (0.1 μM), rauwolscine (0.01 μM) and L‐NG‐nitro‐arginine (100 μM).
In the presence of desipramine, contractile responses to electrical field stimulation but not to noradrenaline (1 nM–100 μM) were greater in SHR than in Wistar–Kyoto (WKY). Neither inhibition of prejunctional α2‐adrenoceptors nor the blockade of neuronal nitric oxide synthase (nNOS) accounted for the differential enhancement of response in SHR. The enhanced effectiveness of motor neurotransmission in SHR becomes most apparent when all known major buffering mechanisms are removed.
When nitrergic responses were isolated pharmacologically (phentolamine 1 μM and guanethidine 30 μM; tone raised with carbachol 50 μM), they were not different between SHR and WKY.
Western blots showed that both nNOS and tyrosine hydroxylase are expressed to a similar extent in anococcygeus muscle from SHR and WKY, suggesting similar adrenergic and nitrergic innervations in the two strains. This suggests that enhanced motor transmission is due to increased transmitter release per varicosity rather than there being normal transmission from a greater number of sites.
We conclude that there is a generic enhancement of sympathetic transmission in SHR rather than this being a vascular phenomenon.

British Journal of Pharmacology (2003) 140, 773–779. doi:10.1038/sj.bjp.0705480
Inhibition of cardiac sodium currents by toluene exposure
Authors: Cruz Silvia L , Orta‐Salazar Gerardo , Gauthereau Marcia Y , Millan‐Perez Peña Lourdes , Salinas‐Stefanón Eduardo M 
Published: October 2003

Toluene is an industrial solvent widely used as a drug of abuse, which can produce sudden sniffing death due to cardiac arrhythmias. In this paper, we tested the hypothesis that toluene inhibits cardiac sodium channels in Xenopus laevis oocytes transfected with Nav1.5 cDNA and in isolated rat ventricular myocytes.
In oocytes, toluene inhibited sodium currents (INa+) in a concentration‐dependent manner, with an IC50 of 274 μM (confidence limits: 141–407μM). The inhibition was complete, voltage‐independent, and slowly reversible.
Toluene had no effect on: (i) the shape of the I–V curves; (ii) the reversal potential of Na+; and (iii) the steady‐state inactivation.
The slow recovery time constant from inactivation of INa+ decreased with toluene exposure, while the fast recovery time constant remained unchanged.
Block of INa+ by toluene was use‐ and frequency‐dependent.
In rat cardiac myocytes, 300 μM toluene inhibited the sodium current (INa+) by 62%; this inhibition was voltage independent.
These results suggest that toluene binds to cardiac Na+ channels in the open state and unbinds either when channels move between inactivated states or from an inactivated to a closed state.
The use‐ and frequency‐dependent block of INa+ by toluene might be responsible, at least in part, for its arrhythmogenic effect.

British Journal of Pharmacology (2003) 140, 653–660. doi:10.1038/sj.bjp.0705481
Vasoconstrictor responses, and underlying mechanisms, to isoprostanes in human and porcine bronchial arterial smooth muscle
Authors: Tazzeo Tracy , Miller John , Janssen Luke J 
Published: October 2003

We investigated the effects of five different isoprostanes (8‐isoPGE1, 8‐isoPGE2, 8‐isoPGF1α, 8‐isoPGF2αand 8‐isoPGF2β) on vasomotor tone in human and porcine bronchial arterial tissues.In the human bronchial arteries, 8‐isoPGE2and 8‐isoPGF2αevoked powerful constrictions (magnitudes several fold greater than the responses to high millimolar KCl) with negative log concentration causing 50% excitation (EC50) values of 6.8 and 6.5, respectively; 8‐isoPGE1was less potent (EC50not calculated, since a clear peak contraction was not obtained), while the other isoprostanes were largely ineffective. In the porcine arteries, on the other hand, all three F‐ring isoprostanes as well as 8‐isoPGE2evoked constrictor responses, although the peak magnitudes were approximately 50% of the KCl‐evoked response; 8‐isoPGE2and 8‐isoPGF2αwere the most potent, with negative log EC50values of 6.5.We next sought to characterize the signaling pathways underlying the vasoconstrictor responses to 8‐isoPGE2, since this was the most potent of the isoprostanes we tested. These responses were largely reversed by the thromboxane A2‐selective (TP) prostanoid receptor antagonist ICI 192605 (10−8M; 4(Z)‐6‐[(2,4,5cis)2‐(2‐chlorophenyl)‐4‐(2‐hydroxy phenyl)1,3‐dioxan‐5‐yl]hexenoic acid) as well as by the nonspecific tyrosine kinase inhibitor genistein (10−5and 10−4M), and were reversed approximately 50% by the Rho‐kinase inhibitor Y27632 (10−5M; (+)‐(R)‐trans‐4‐(1‐aminoethyl)‐N‐(pyridyl) cyclohexanecarboxamide dihydrochloride).We conclude, therefore, that 8‐isoPGE2constricts bronchial vasculature through the activation of TP receptors, which in turn trigger tyrosine kinase and Rho‐kinase activities, resulting in powerful vasoconstriction. These findings are highly relevant to lung transplantation and to exercise‐induced asthma.British Journal of Pharmacology(2003)140, 759–763. doi:10.1038/sj.bjp.0705482
Glycosylated human oxyhaemoglobin activates nuclear factor‐κB and activator protein‐1 in cultured human aortic smooth muscle
Authors: Peiró Concepción , Matesanz Nuria , Nevado Julián , Lafuente Nuria , Cercas Elena , Azcutia Verónica , Vallejo Susana , Rodríguez‐Mañas Leocadio , Sánchez‐Ferrer Carlos F 
Published: October 2003

Diabetic vessels undergo structural changes that are linked to a high incidence of cardiovascular diseases. Reactive oxygen species (ROS) mediate cell signalling in the vasculature, where they can promote cell growth and activate redox‐regulated transcription factors, like activator protein‐1 (AP‐1) or nuclear factor‐κB (NF‐κB), which are involved in remodelling and inflammation processes. Amadori adducts, formed through nonenzymatic glycosylation, can contribute to ROS formation in diabetes.
In this study, we analysed whether Amadori‐modified human oxyhaemoglobin, glycosylated at either normal (N‐Hb) or elevated (E‐Hb) levels, can induce cell growth and activate AP‐1 and NF‐κB in cultured human aortic smooth muscle cells (HASMC).
E‐Hb (1 nM–1 μM), but not N‐Hb, promoted a concentration‐dependent increase in cell size from nanomolar concentrations, although it failed to stimulate HASMC proliferation. At 10 nM, E‐Hb stimulated both AP‐1 and NF‐κB activity, as assessed by transient transfection, electromobility shift assays or immunofluorescence staining. The effects of E‐Hb resembled those of the proinflammatory cytokine tumour necrosis factor‐α (TNF‐α). E‐Hb enhanced intracellular superoxide anions content and its effects on HASMC were abolished by different ROS scavengers.
In conclusion, E‐Hb stimulates growth and activates AP‐1 and NF‐κB in human vascular smooth muscle by redox‐sensitive pathways, thus suggesting a possible direct role for Amadori adducts in diabetic vasculopathy.

British Journal of Pharmacology (2003) 140, 681–690. doi:10.1038/sj.bjp.0705483
Pharmacological characterization of a 7‐benzylidenenaltrexone‐preferring opioid receptor in porcine ileal submucosa
Authors: Townsend De Wayne , Brown David R 
Published: October 2003

In the intestine, opioids produce antidiarrhoeal and constipating actions that are mediated by enteric neurones. Through interactions with opioid receptors (ORs) on submucosal neurones, opioids suppress active ion transport evoked by transmural electrical stimulation (TES) in mucosa–submucosa sheets from the porcine ileum. In this study, we examined the pharmacological characteristics of the previously described OR, which is sensitive to theδ1‐OR antagonist 7‐benzylidenenaltrexone and modulates neurogenic transepithelial ion transport in this tissue preparation.Increases in short‐circuit current (Isc, a measure of active anion transport) evoked by TES in ileal mucosa–submucosa sheets were inhibited by opioid agonists possessing high selectivity for eitherδ‐ orμ‐ORs including [D‐Pen2,5]enkephalin (DPDPE), [D‐Ala2, Glu4]deltorphin II, and [D‐Ala2,N‐Me‐Phe4, Gly5‐ol]enkephalin (DAMGO).As determined by the Schild analysis, the actions of these agonists were competitively inhibited by 7‐benzylidenenaltrexone. The nonequilibriumμ‐OR antagonistβ‐funaltrexamine inhibited the actions of DAMGO only at a high concentration (1μM) but did not alter DPDPE or deltorphin II action. At concentrations up to 10μM, the nonequilibriumδ‐OR antagonist naltrindole 5′‐isothiocyanate did not alter the actions ofδ‐ orμ‐OR agonists.Radioligand binding analyses of neuronal homogenates from the ileal submucosa revealed that the nonselective OR ligand [3H]diprenorphine bound to two populations of specific binding sites. One of these sites possessed binding characteristics similar to theδ‐OR.In summary, neurogenic ion transport in the porcine intestine is modulated by an OR which shares pharmacological characteristics of bothμ‐ andδ‐ORs and may represent a novel receptor entity.British Journal of Pharmacology(2003)140, 691–700. doi:10.1038/sj.bjp.0705485
Vanilloid type 1 receptors (VR1) on trigeminal sensory nerve fibres play a minor role in neurogenic dural vasodilatation, and are involved in capsaicin‐induced dural dilation
Authors: Akerman S , Kaube H , Goadsby P J 
Published: October 2003

Capsaicin, the active substance in chilli peppers, activates the vanilloid type 1 receptor (VR1) rather than the vanilloid‐like receptor (VRL1) in the trigeminal ganglion and nucleus of small and medium C‐ and Aδ‐fibres.
Capsaicin induces calcitonin gene‐related peptide (CGRP) release when VR1 receptors are activated, and this can be reversed by both the VR1 receptor antagonist capsazepine and the CGRP blocker αCGRP8–37 in vitro.
In this study we used intravital microscopy to look at the possible role of the VR1 receptor in the trigeminovascular system in producing dilation of dural blood vessels. Capsazepine (3 mg kg−1) was given to study the effect of the VR1 receptor in dural vessel dilation produced by either electrical stimulation, CGRP (1 μg kg−1) or capsaicin (7 μg kg−1) bolus injection. We also looked at the effect of the CGRP blocker αCGRP8–37 (300 μg kg−1) on capsaicin‐induced dilation so that we could see if the results found in vitro could also be found in vivo.
Electrical stimulation of the dura mater produced a robust vasodilator response between 130 and 137% of baseline diameter that was no different across four repeat stimuli (F3,18=0.6, P=0.61). CGRP similarly produced a dilatation of 99–111% that was no different across four baseline infusions (F3,15=2.4, P=0.113). Capsaicin also produced a consistent dilation of between 112 and 120% of baseline across three injections (F2,10=0.6, P=0.567).
Capsazepine did not inhibit the dilation brought about by either electrical stimulation or CGRP injection, while it was able to inhibit the dilation brought about by capsaicin (t5=3.4, P<0.05). αCGRP8–37 also inhibited the capsaicin‐induced dilation (t5=7.4, P<0.05) probably inhibiting the action of released CGRP at the CGRP receptor.
The study demonstrates that capsaicin can repeatedly induce dural vessel dilation in vivo, presumably through inducing CGRP release from trigeminal sensory nerve fibres, while C‐fibres may have been desensitised. The data imply that the VR1 receptor plays only a minor role in trigeminovascular‐induced dural vessel dilation.

British Journal of Pharmacology (2003) 140, 718–724. doi:10.1038/sj.bjp.0705486
Adenosine‐induced IL‐6 expression in pituitary folliculostellate cells is mediated via A2b adenosine receptors coupled to PKC and p38 MAPK
Authors: Rees D Aled , Lewis B Mary , Lewis Mark D , Francis Karen , Scanlon Maurice F , Ham Jack 
Published: October 2003

Activation of adenosine receptors in folliculostellate (FS) cells of the pituitary gland leads to the secretion of IL‐6 and vascular endothelial growth factor (VEGF).
We investigated the action of adenosine A2 receptor agonists on IL‐6 and VEGF secretion in two murine FS cell lines (TtT/GF and Tpit/F1), and demonstrated a rank order of potency, 5′‐N‐ethylcarboxamidoadenosine (NECA)>2‐p‐(2‐carboxyethyl)phenethylamino‐5′‐N‐ethylcarboxamidoadenosine>adenosine, suggesting mediation via the A2b receptor.
NECA‐mediated IL‐6 release was inhibited by the PLC inhibitor 1‐[6‐((17β‐3‐methoxyestra‐1,3,5(10)‐tiene‐17‐yl)amino)hexyl]‐1H‐pyrrole‐2,5‐dione, the PI3 kinase inhibitor wortmannin and the PKC inhibitors bisindolylmaleimide 1 and bisindolymaleimide X1 HCl (Ro‐32‐0432).
NECA‐mediated IL‐6 release was attenuated (<50%) by the extracellular signal‐regulated kinase MAPK inhibitor 2′‐amino‐3′‐methoxyflavone, and completely (>95%) inhibited by the p38 MAPK inhibitor 4‐(4‐fluorophenyl)‐2‐(4‐methylsulphinylphenyl)‐5‐(4‐pyridyl)1H‐imidazole.
NECA stimulates p38 MAPK phosphorylation that is inhibited by Ro‐32‐0432 but not by wortmannin.
Dexamethasone inhibits NECA‐stimulated IL‐6 and VEGF secretion.
These findings indicate that adenosine can stimulate IL‐6 secretion in FS cells via the A2b receptor coupled principally to PLC/PKC and p38 MAPK; such an action may be important in the modulation of inflammatory response processes in the pituitary gland.

British Journal of Pharmacology (2003) 140, 764–772. doi:10.1038/sj.bjp.0705488
Pharmacological profile of the 5‐HT‐induced inhibition of cardioaccelerator sympathetic outflow in pithed rats: correlation with 5‐HT1 and putative 5‐ht5A/5B receptors
Authors: Sánchez‐López Araceli , Centurión David , Vázquez Erika , Arulmani Udayasankar , Saxena Pramod R , Villalón Carlos M 
Published: October 2003

Continuous infusions of 5‐hydroxytryptamine (5‐HT) inhibit the tachycardiac responses to preganglionic (C7‐T1) sympathetic stimulation in pithed rats pretreated with desipramine. The present study identified the pharmacological profile of this inhibitory action of 5‐HT.
The inhibition induced by intravenous (i.v.) continuous infusions of 5‐HT (5.6 μg kg−1 min−1) on sympathetically induced tachycardiac responses remained unaltered after i.v. treatment with saline or the antagonists GR 127935 (5‐HT1B/1D), the combination of WAY 100635 (5‐HT1A) plus GR 127935, ritanserin (5‐HT2), tropisetron (5‐HT3/4), LY215840 (5‐HT7) or a cocktail of antagonists/inhibitors consisting of yohimbine (α2), prazosin (α1), ritanserin, GR 127935, WAY 100635 and indomethacin (cyclooxygenase), but was abolished by methiothepin (5‐HT1/2/6/7 and recombinant 5‐ht5A/5B). These drugs, used in doses high enough to block their respective receptors/mechanisms, did not modify the sympathetically induced tachycardiac responses per se.
I.v. continuous infusions of the agonists 5‐carboxamidotryptamine (5‐CT; 5‐HT1/7 and recombinant 5‐ht5A/5B), CP 93,129 (r5‐HT1B), sumatriptan (5‐HT1B/1D), PNU‐142633 (5‐HT1D) and ergotamine (5‐HT1B/1D and recombinant 5‐ht5A/5B) mimicked the above sympatho‐inhibition to 5‐HT. In contrast, the agonists indorenate (5‐HT1A) and LY344864 (5‐ht1F) were inactive. Interestingly, 5‐CT‐induced cardiac sympatho‐inhibition was abolished by methiothepin, the cocktail of antagonists/inhibitors, GR 127935 or the combination of SB224289 (5‐HT1B) plus BRL15572 (5‐HT1D), but remained unchanged when SB224289 or BRL15572 were given separately.
Therefore, 5‐HT‐induced cardiac sympatho‐inhibition, being unrelated to 5‐HT2, 5‐HT3, 5‐HT4, 5‐ht6, 5‐HT7 receptors, α1/2‐adrenoceptor or prostaglandin synthesis, seems to be primarily mediated by (i) 5‐HT1 (probably 5‐HT1B/1D) receptors and (ii) a novel mechanism antagonized by methiothepin that, most likely, involves putative 5‐ht5A/5B receptors.

British Journal of Pharmacology (2003) 140, 725–735. doi:10.1038/sj.bjp.0705489
Ginsenoside Rg3 inhibits phenylephrine‐induced vascular contraction through induction of nitric oxide synthase
Authors: Kim Nak Doo , Kim Eun Mi , Kang Keon Wook , Cho Min Kyung , Choi So Yeon , Kim Sang Geon 
Published: October 2003

Ginsenoside Rg3 (Rg3) isolated from Panax ginseng relaxes vessels and exerts a cytoprotective effect. In view of the fact that nitric oxide (NO) is involved in vascular hyporeactivity and immunostimulation, the effects of total ginsenosides (GS) and Rg3 on the vascular responses and the expression of inducible nitric oxide synthase (iNOS) were investigated.
Vasocontraction of endothelium‐denuded aortic ring was induced by phenylephrine with or without GS or Rg3. The expression of iNOS was assessed by Western blot and RT–PCR analyses. NF‐κB activation was monitored by gel shift, immunoblot and immunocytochemical analyses.
Incubation of the endothelium‐denuded aortic ring with GS or Rg3 inhibited phenylephrine‐induced vasocontraction, which was abrogated by NOS inhibition. GS or Rg3 increased NO production in aortic rings, but Rb1, Rc, Re and Rg1 had no effect.
Aortic rings obtained from rats treated with GS or Rg3 responded to phenylnephrine to a lesser extent, while producing NO to a larger extent, than those from control animals. GS or Rg3 induced iNOS in vascular smooth muscle.
Rg3 induced iNOS with increase in NO production in Raw264.7 cells. Rg3 increased NF‐κB DNA binding, whose band was supershifted with anti‐p65 and anti‐p50 antibodies, and elicited p65 nuclear translocation, which was accompanied by phosphorylation and degradation of I‐κBα. PKC regulated iNOS induction by Rg3.
In conclusion, Rg3 relaxes vessels as a consequence of NO production, to which iNOS induction contributes, and iNOS induction by Rg3 accompanied NF‐κB activation, which involves phosphorylation and degradation of I‐κBα and nuclear translocation of p65.

British Journal of Pharmacology (2003) 140, 661–670. doi:10.1038/sj.bjp.0705490
Myoblast‐mediated gene transfer for therapeutic angiogenesis and arteriogenesis
Authors: Von Degenfeld Georges , Banfi Andrea , Springer Matthew L , Blau Helen M 
Published: October 2003

Therapeutic angiogenesis aims at generating new blood vessels by delivering growth factors such as VEGF and FGF. Clinical trials are underway in patients with peripheral vascular and coronary heart disease. However, increasing evidence indicates that the new vasculature needs to be stabilized to avoid deleterious effects such as edema and hemangioma formation. Moreover, a major challenge is to induce new vessels that persist following cessation of the angiogenic stimulus. Mature vessels may be generated by modulating timing and dosage of growth factor expression, or by combination of ‘growth’ factors with ‘maturation’ factors like PDGF‐BB, angiopoietin‐1 or TGF‐β. Myoblast‐mediated gene transfer has unique characteristics that make it a useful tool for studying promising novel approaches to therapeutic angiogenesis. It affords robust and long‐lasting expression, and can be considered as a relatively rapid form of ‘adult transgenesis’ in muscle. The combined insertion of different gene constructs into single myoblasts and their progeny allows the simultaneous expression of different ‘growth’ and ‘maturation’ factors within the same cell in vivo. The additional insertion of a reporter gene makes it possible to analyze the phenotype of the vessels surrounding the transgenic muscle fibers into which the myoblasts have fused. The effects of timing and duration of gene expression can be studied by using tetracycline‐inducible constructs, and dosage effects by selecting subpopulations consistently expressing distinct levels of growth factors. Finally, the autologous cell‐based approach using transduced myoblasts could be an alternative gene delivery system for therapeutic angiogenesis in patients, avoiding the toxicities seen with some viral vectors.British Journal of Pharmacology (2003) 140, 620–626. doi:10.1038/sj.bjp.0705492
Testing clinical therapeutic angiogenesis using basic fibroblast growth factor (FGF‐2)
Authors: Aviles Ronnier J , Annex Brian H , Lederman Robert J 
Published: October 2003

Therapeutic angiogenesis represents an attempt to relieve inadequate blood flow by the directed growth and proliferation of blood vessels. Neovascularization is a complex process involving multiple growth factors, receptors, extracellular matrix glycoproteins, intracellular and extracellular signaling pathways, and local and bone‐marrow‐derived constituent cells, all responding to a symphonic arrangement of temporal and spatial cues. In cardiovascular disease, patients with refractory angina and lower extremity intermittent claudication seem most amenable to early tests of therapeutic angiogenesis. Monotherapy with the recombinant protein basic fibroblast growth factor (FGF‐2) has been tested in six human trials. These have shown provisional safety, and two have provided ‘proof of concept’ for the strategy of therapeutic angiogenesis. One large randomized phase II trial failed to show significant efficacy in coronary artery disease. Another showed significant efficacy in peripheral artery disease, although the magnitude of benefit was disappointing at the dose tested. This overview details the suitable clinical trial design and further steps toward the clinical development of FGF‐2.British Journal of Pharmacology (2003) 140, 637–646. doi:10.1038/sj.bjp.0705493
Using gene expression profiling to identify the molecular basis of the synergistic actions of hepatocyte growth factor and vascular endothelial growth factor in human endothelial cells
Authors: Gerritsen Mary E , Tomlinson James E , Zlot Constance , Ziman Michael , Hwang Stuart 
Published: October 2003

Hepatocyte growth factor (HGF) and vascular endothelial cell growth factor (VEGF) are two potent endothelial mitogens with demonstrated angiogenic activities in animal models of therapeutic angiogenesis. Several recent studies suggest that these growth factors may act synergistically, although the mechanism of this interaction is not understood. Changes in the gene expression profile of human umbilical vein endothelial cells treated with HGF, VEGF or the combination of the two were analyzed with high‐density oligonucleotide arrays, representing approximately 22,000 genes. Notably, the genes significantly up‐ and downregulated by VEGF versus HGF exhibited very little overlap, indicating distinct signal transduction pathways. The combination of HGF and VEGF markedly increased the number of significantly up‐ and downregulated genes. At 4 h, the combination of the two growth factors induced a number of chemokine and cytokines and their receptors (IL‐8, IL‐6, IL‐11, CCR6, CXCR1,CXC1 and IL17RC), numerous genes involved in growth factor signal transduction (egr‐1, fosB, grb10, grb14,MAP2K3,MAP3K8, MAPKAP2,MPK3, DUSP4 and DUSP6), as well as a number of other growth factors (PDGFA, BMP2, Hb‐EGF, FGF16, heuregulin beta 1, c‐kit ligand, angiopoietin 2 and angiopoietin 4 and VEGFC). In addition, the VEGF receptors neuropilin‐1 and flt‐1 were also upregulated. At 24 h, a clear ‘cell cycle’ signature is noted, with the upregulated expression of various cell cycle control proteins and gene involved in the regulation of mitosis and mitotic spindle assembly. The receptor for HGF, c‐met, is also upregulated. These data are consistent with the hypothesis that the combination of HGF and VEGF results in the cooperative upregulation of a number of different molecular pathways leading to a more robust proliferative response, that is, growth factor(s), receptors, molecules involved in growth factor signal transduction, as well as, at later time points, upregulation of the necessary cellular proteins required for cells to escape cell cycle arrest and enter the cell cycle.British Journal of Pharmacology (2003) 140, 595–610. doi:10.1038/sj.bjp.0705494