bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cholecystokinin‐8 enhances nerve growth factor synthesis and promotes recovery of capsaicin‐induced sensory deficit
Authors: Manni Luigi , Lundeberg Thomas , Tirassa Paola , Aloe Luigi 
Published: January 2005

Alterations of nerve growth factor (NGF) expression have been demonstrated during peripheral nerve disease and the impaired expression or synthesis and transportation of NGF has been correlated with the pathogenesis of several peripheral neuropathies. Since exogenous NGF administration seems to cause undesired side‐effects, therapeutical strategies based on the regulation of endogenous synthesis of NGF could prove useful in the clinical treatment of these disorders.
The aim of the present study was to analyse the effects of exogenous peripheral administration of the neuropeptide cholecystokinin‐8 (CCK‐8) on endogenous NGF synthesis, NGF mRNA and distribution of peripheral neuropeptides which are known to be regulated by this neurotrophin.
To address these questions we studied the effects of capsaicin (CAPS) before and after the administration of CCK‐8 on NGF levels, NGF mRNA expression and localization, and the concentration of substance P (SP) and calcitonin gene‐related peptide (CGRP) in peripheral tissue
These studies demonstrate that administration of the CCK‐8 induces an increase of NGF protein and mRNA in peripheral tissue. NGF level in paw skin of CAPS/CCK‐8‐treated mice is 3 fold higher than in controls (1241±110 pg gr−1 of tissue wet weight versus 414±110 pg gr−1 of controls) and nearly 6 fold higher than in CAPS‐treated mice (1241±110 pg gr−1 versus 248±27 pg gr−1). The increase of NGF is correlated with the recovery of impaired nocifensive behaviour and with an overexpression of SP and CGRP.
The evidence that CCK‐8 promotes the recovery of sensory deficits suggests a potential clinical use for this neuropeptide in peripheral neuropathies.

British Journal of Pharmacology (2000) 129, 744–750; doi:10.1038/sj.bjp.0703088
Non‐prostanoid prostacyclin mimetics as neuronal stimulants in the rat: comparison of vagus nerve and NANC innervation of the colon
Authors: Rudd John A , Qian Yue‐ming , Tsui Kenneth K C , Jones Robert L 
Published: January 2005

The spontaneous activity of the rat isolated colon is suppressed by prostacyclin analogues such as cicaprost (IC50=4.0 nM). Activation of prostanoid IP1‐receptors located on NANC inhibitory neurones is involved. However, several non‐prostanoids, which show medium to high IP1 agonist potency on platelet and vascular preparations, exhibit very weak inhibitory activity on the colon. The aim of the study was to investigate this discrepancy.
Firstly, we have demonstrated the very high depolarizing potency of cicaprost on the rat isolated vagus nerve (EC50=0.23 nM). Iloprost, taprostene and carbacyclin were 7.9, 66, and 81 fold less potent than cicaprost, indicating the presence of IP1 as opposed to IP2‐receptors. Three non‐prostanoid prostacyclin mimetics, BMY 45778, BMY 42393 and ONO‐1301, although much less potent than cicaprost (195, 990 and 1660 fold respectively), behaved as full agonists on the vagus nerve.
On re‐investigating the rat colon, we found that BMY 45778 (0.1–3 μM), BMY 42393 (3 μM) and ONO‐1301 (3 μM) behaved as specific IP1 partial agonists, but their actions required 30–60 min to reach steady‐state and only slowly reversed on washing. This profile contrasted sharply with the rapid and readily reversible contractions elicited by a related non‐prostanoid ONO‐AP‐324, which is an EP3‐receptor agonist.
The full versus partial agonism of the non‐prostanoid prostacyclin mimetics may be explained by the markedly different IP1 agonist sensitivities of the two rat neuronal preparations. However, the slow kinetics of the non‐prostanoids on the NANC system of the colon remain unexplained, and must be taken into account when characterizing neuronal IP‐receptors.

British Journal of Pharmacology (2000) 129, 782–790; doi:10.1038/sj.bjp.0703090
Changes in the cytosolic Ca2+ concentration and Ca2+‐sensitivity of the contractile apparatus during angiotensin II‐induced desensitization in the rabbit femoral artery
Authors: Ushio‐Fukai Masuko , Yamamoto Hiromichi , Toyofuku Kazuki , Nishimura Junji , Hirano Katsuya , Kanaide Hideo 
Published: January 2005

To investigate the underlying mechanism for the angiotensin II‐induced desensitization of the contractile response during the prolonged stimulation of the vascular smooth muscle, we determined the effects of angiotensin‐II on (1) cytosolic Ca2+ concentration ([Ca2+]i) and tension using fura‐2‐loaded medial strips of the rabbit femoral artery, (2) 45Ca2+ influx in ring preparations, and (3) Ca2+‐sensitivity of the contractile apparatus in α‐toxin permeabilized preparations.
In the presence of extracellular Ca2+, high concentrations of angiotensin‐II elicited biphasic increases in [Ca2+]i and tension, which consisted of initial transient and subsequent lower and sustained phases.
The 45Ca2+ influx initially increased after the application of 10−6 M angiotensin‐II, and thereafter gradually decreased. At 20 min after the application, there was a discrepancy between the level of [Ca2+]i and the extent of 45Ca2+ influx.
The relationships between [Ca2+]i and tension suggested that the angiotensin‐II‐induced increase in the Ca2+‐sensitivity of the contractile apparatus was maintained during the desensitization of smooth muscle contraction.
When 10−6 M angiotensin‐II was applied during the sustained phase of contraction induced by 118 mm K+‐depolarization, at 10 min after the application, the [Ca2+]i levels were significantly lower and the tension levels were significantly higher than those prior to the application of angiotensin‐II.
In conclusion, the decrease in [Ca2+]i, which is partially due to the inhibition of the Ca2+ influx, is mainly responsible for the desensitization evoked by high concentrations of angiotensin‐II, and angiotensin‐II seems to activate additional mechanisms which inhibit Ca2+ signaling during prolonged stimulation.

British Journal of Pharmacology (2000) 129, 425–436; doi:10.1038/sj.bjp.0703092
The mechanism of the decrease in cytosolic Ca2+ concentrations induced by angiotensin II in the high K+‐depolarized rabbit femoral artery
Authors: Ushio‐Fukai Masuko , Yamamoto Hiromichi , Nishimura Junji , Hirano Katsuya , Kanaide Hideo 
Published: January 2005

Using front‐surface fluorometry of fura‐2‐loaded strips, and measuring the transmembrane 45Ca2+ fluxes of ring preparations of the rabbit femoral artery, the mechanism underlying a sustained decrease in the cytosolic Ca2+ concentration ([Ca2+]i) induced by angiotensin II (AT‐II) was investigated.
The application of AT‐II during steady‐state 118 mM K+‐induced contractions caused a sustained decrease in [Ca2+]i following a rapid and transient increase in [Ca2+]i, while the tension was transiently enhanced.
When the intracellular Ca2+ stores were depleted by thapsigargin, the initial rapid and transient increase in [Ca2+]i was abolished, however, neither the sustained decrease in [Ca2+]i nor the enhancement of tension were affected.
Depolarization with 118 mM K+ physiological salt solution containing 1.25 mM Ba2+ induced a sustained increase in both the cytosolic Ba2+ concentration ([Ba2+]i) level and tension. However, the application of 10−6 M AT‐II during sustained Ba2+‐contractions was found to have no effect on [Ba2+]i, but it did enhance tension.
After thapsigargin treatment, AT‐II neither decreased nor increased the enhanced Ca2+ efflux rate induced by 118 mM K+‐depolarization, whereas AT‐II did increase the enhanced 45Ca2+ influx and the 45Ca2+ net uptake induced by 118 mM K+‐depolarization.
Pretreatment with calphostin‐C, partially, but significantly inhibited the decrease in [Ca2+]i induced by AT‐II.
These findings therefore suggest that AT‐II stimulates Ca2+ sequestration into the thapsigargin‐insensitive Ca2+ stores, and thus induces a decrease in [Ca2+]i in the high external K+‐stimulated rabbit femoral artery.

British Journal of Pharmacology (2000) 129, 437–447; doi:10.1038/sj.bjp.0703093
Involvement of kinins in hyperresponsiveness induced by platelet activating factor in the human nasal airway
Authors: Turner P J , Dear J W , Foreman J C 
Published: January 2005

The aim of this study was to investigate the role of kinins in the development of nasal hyperresponsiveness induced by platelet activating factor (PAF) in normal human subjects.
Intranasal administration of PAF, 60 μg, induced an increased responsiveness to histamine, 200 μg per nostril, 6 h later. This effect was abolished by pretreatment with the bradykinin B2 receptor antagonists icatibant and [1‐adamantaneacetyl‐D‐Arg0,Hyp3,β‐(2‐thienyl)‐Ala5,8,D‐Phe7]‐bradykinin ([Ad]‐BK), both at 200 μg, every 2 h following PAF administration.
In a separate experiment, utilizing the same protocol, nasal lavage was used to measure the release of mediators into the nasal cavity following treatment with PAF. PAF increased the levels of eosinophil cationic protein (ECP) and kinin detected in the lavage samples, compared with a saline control. The levels of these mediators were reduced by pretreatment with either icatibant or [Ad]‐BK.
Administration of lyso‐PAF, 60 μg intranasally, did not cause a rise in kinin or ECP levels in nasal lavage fluid.
Exogenous bradykinin, 500 μg, or a saline control, applied topically to the nasal mucosa every 30 min for 2 h, failed to cause hyperresponsiveness to histamine.
We conclude that bradykinin itself does not cause hyperresponsiveness, but is involved in the hyperresponsiveness induced by PAF in the human nasal airway.

British Journal of Pharmacology (2000) 129, 525–532; doi:10.1038/sj.bjp.0703095
Differential response to chloroethylclonidine in blood vessels of normotensive and spontaneously hypertensive rats: role of α1D‐ and α1A‐adrenoceptors in contraction
Authors: Ibarra Maximiliano , Pardo J Pablo , López‐Guerrero J Javier , Villalobos‐Molina Rafael 
Published: January 2005

The effects of chloroethylclonidine on α1‐adrenoceptor‐mediated contraction in endothelium‐denuded caudal arteries and aorta from normotensive Wistar and Wistar Kyoto (WKY), and from spontaneously hypertensive (SHR) rats were evaluated.
Chloroethylclonidine elicited concentration‐dependent contractions. Maximal contraction was similar in caudal arteries among strains (∼40% of noradrenaline effect). However, chloroethylclonidine elicited a higher contraction in aorta from SHR than from normotensive rats. In Wistar aorta chloroethylclonidine produced the smallest contractile response.
In SHR aorta, BMY 7378 and 5‐methylurapidil blocked chloroethylclonidine‐elicited contraction, while (+)‐cyclazocine did not inhibit it; while in caudal arteries, 5‐methylurapidil blocked chloroethylclonidine action; the other antagonists had no effect.
In chloroethylclonidine‐treated aorta noradrenaline elicited biphasic contraction‐response curves, indicating a high affinity (pD2, 8.5–7.5) chloroethylclonidine‐sensitive component and a low affinity (pD2, 6.3–5.2) chloroethylclonidine‐insensitive component. The high affinity component was blocked by chloroethylclonidine; while in caudal arteries noradrenaline elicited monophasic contraction‐response curves with pD2 values (6.5–5.7) similar to the low affinity component in aorta.
Chloroethylclonidine inhibition of noradrenaline response was greater in aorta than in caudal arteries. Chloroethylclonidine increased the EC50 values of noradrenaline ∼1000 fold in aorta and ∼10 fold in caudal arteries.
In SHR aorta BMY 7378 protected α1D‐adrenoceptors and in caudal arteries 5‐methylurapidil protected α1A‐adrenoceptors from chloroethylclonidine alkylation, allowing noradrenaline to elicit contraction.
These results show marked strain‐dependent differences in the ability of chloroethylclonidine to contract aorta; moreover, chloroethylclonidine stimulates α1D‐adrenoceptors in aorta and α1A‐adrenoceptors in caudal arteries. The higher contraction observed in aorta from SHR and WKY suggests an augmented number of α1D‐adrenoceptors in these strains.

British Journal of Pharmacology (2000) 129, 653–660; doi:10.1038/sj.bjp.0703097
The effects of heparin and related molecules upon the adhesion of human polymorphonuclear leucocytes to vascular endothelium in vitro
Authors: Lever Rebecca , Hoult J Robin S , Page Clive P 
Published: January 2005

The effects of an unfractionated heparin preparation (Multiparin), a low molecular weight heparin preparation (Fragmin) and a selectively O‐desulphated derivative of heparin lacking anticoagulant activity, have been investigated for their effects on the adhesion of human polymorphonuclear leucocytes (PMNs) to cultured human umbilical vein endothelial cells (HUVECs) in vitro. The effect of poly‐L‐glutamic acid, a large, polyanionic molecule was also studied.
Unfractionated heparin (50–1000 U ml−1), the O‐desulphated derivative (0.3–6 mg ml−1) and the low molecular weight heparin (50 U–1000 U ml−1) all inhibited significantly the adhesion of 51Cr labelled PMNs to HUVECs stimulated with interleukin‐1β (IL‐1β; 10 U ml−1), bacterial lipopolysaccharide (LPS; 2.5 μg ml−1) or tumour necrosis factor‐α (TNF‐α; 125 U ml−1) for 6 h, whereas poly‐L‐glutamic acid had no effect. In addition, the three heparin preparations in the same concentration range inhibited significantly the adhesion of f‐met‐leu‐phe‐stimulated PMNs to resting HUVECs.
The effects of unfractionated heparin upon the expression of adhesion molecules intercellular adhesion molecule‐1 (ICAM‐1) and E‐selection were also investigated, as were the effects of unfractionated heparin upon adhesion of human PMNs to previously stimulated HUVECs. Heparin had little effect upon levels of expression of these adhesion molecules on stimulated HUVECs. However, a profound effect upon PMN adhesion to previously stimulated HUVECs was demonstrated using the same preparation, suggesting that inhibition of adhesion molecule expression is not a major component of the described inhibitory effects of heparin.
Pre‐incubation of PMNs with heparin followed by washing inhibited their adhesion to HUVECs, under different conditions of cellular activation, implying that heparin can bind to these cells and exert its anti‐adhesive effects even when not directly present in the system.
These observations would suggest that both heparin and a low molecular weight heparin are capable of inhibiting adhesion of human PMNs to endothelial cells, an effect not dependent solely upon the polyanionic nature of these molecules, nor dependent upon their ability to act as anticoagulants.

British Journal of Pharmacology (2000) 129, 533–540; doi:10.1038/sj.bjp.0703099
Isolation of the serotoninergic 5‐HT4(e) receptor from human heart and comparative analysis of its pharmacological profile in C6‐glial and CHO cell lines
Authors: Mialet Jeanne , Berque‐Bestel Isabelle , Eftekhari Pierre , Gastineau Monique , Giner Mireille , Dahmoune Yamina , Donzeau‐Gouge Patrick , Hoebeke Johan , Langlois Michel , Sicsic Sames , Fischmeister Rodolphe , Lezoualc'h Frank 
Published: January 2005

RT–PCR technique was used to clone the human 5‐HT4(e) receptor (h5‐HT4(e)) from heart atrium. We showed that this h5‐HT4(e) receptor splice variant is restricted to brain and heart atrium.
Recombinant h5‐HT4(e) receptor was stably expressed in CHO and C6‐glial cell lines at 347 and 88 fmol mg−1 protein, respectively. Expression of h5‐HT4(e) receptors at the cell membrane was confirmed by immunoblotting.
The receptor binding profile, determined by competition with [3H]‐GR113808 of a number of 5‐HT4 ligands, was consistent with that previously reported for other 5‐HT4 receptor isoforms. Surprisingly, we found that the rank order of potencies (EC50) of 5‐HT4 agonists obtained from adenylyl cyclase functional assays was inversely correlated to their rank order of affinities (Ki) obtained from binding assays. Furthermore, EC50 values for 5‐HT, renzapride and cisapride were 2 fold lower in C6‐glial cells than in CHO cells.
ML10302 and renzapride behaved like partial agonists on the h5‐HT4(e) receptor. These results are in agreement with the reported low efficacy of the these two compounds on L‐type Ca2+ currents and myocyte contractility in human atrium.
A constitutive activity of the h5‐HT4(e) receptor was observed in CHO cells in the absence of any 5‐HT4 ligand and two 5‐HT4 antagonists, GR113808 and ML10375, behaved as inverse agonists.
These data show that the h5‐HT4(e) receptor has a pharmacological profile which is close to the native h5‐HT4 receptor in human atrium with a functional potency which is dependent on the cellular context in which the receptor is expressed.

British Journal of Pharmacology (2000) 129, 771–781; doi:10.1038/sj.bjp.0703101
Chlorotoxin does not inhibit volume‐regulated, calcium‐activated and cyclic AMP‐activated chloride channels
Authors: Maertens Chantal , Wei Lin , Tytgat Jan , Droogmans Guy , Nilius Bernd 
Published: January 2005

It was the aim of this study to look for a high‐affinity and selective polypeptide toxin, which could serve as a probe for the volume‐regulated anion channel (VRAC) or the calcium‐activated chloride channel (CaCC). We have partially purified chlorotoxin, including new and homologous short chain insectotoxins, from the crude venom of Leiurus quinquestriatus quinquestriatus (Lqq) by means of gel filtration chromatography. Material eluting between 280 and 420 min, corresponding to fractions 15–21, was lyophilized and tested on VRAC and CaCC, using the whole‐cell patch‐clamp technique. We have also tested the commercially available chlorotoxin on VRAC, CaCC, the cystic fibrosis transmembrane conductance regulator (CFTR) and on the glioma specific chloride channel (GCC).
VRAC and the correspondent current, ICl,swell, was activated in Cultured Pulmonary Artery Endothelial (CPAE) cells by a 25% hypotonic solution. Neither of the fractions 16–21 significantly inhibited ICl,swell (n=4–5). Ca2+‐activated Cl− currents, ICl,Ca, activated by loading T84 cells via the patch pipette with 1 μM free Ca2+, were not inhibited by any of the tested fractions (15–21), (n=2–5).
Chlorotoxin (625 nM) did neither effect ICl,swell nor ICl,Ca (n=4–5). The CFTR channel, transiently transfected in COS cells and activated by a cocktail containing IBMX and forskolin, was not affected by 1.2 μM chlorotoxin (n=5). In addition, it did not affect currents through GCC.
We conclude that submicromolar concentrations of chlorotoxin do not block volume‐regulated, Ca2+‐activated and CFTR chloride channels and that it can not be classified as a general chloride channel toxin.

British Journal of Pharmacology (2000) 129, 791–801; doi:10.1038/sj.bjp.0703102
Wound collagen deposition in rats: effects of an NO‐NSAID and a selective COX‐2 inhibitor
Authors: Muscará Marcelo N , McKnight Webb , Asfaha Samuel , Wallace John L 
Published: January 2005

Selective cyclo‐oxygenase (COX)‐2 inhibitors and nitric oxide‐releasing nonsteroidal anti‐inflammatory drugs (NSAIDs) exhibit reduced toxicity in the gastrointestinal tract, but may affect wound healing in other tissues. In this study, we have compared the effects of a selective COX‐2 inhibitor (celecoxib), a nitric‐oxide releasing derivative of naproxen (HCT‐3012) and naproxen in a model of wound collagen deposition in the rat.
Polyvinyl alcohol sponges were implanted subcutaneously in rats. The rats were treated daily for 5 days with the test drugs at equieffective anti‐inflammatory doses.
Naproxen (10 mg kg−1) significantly decreased (45%) collagen deposition at the wound site relative to the vehicle‐treated control group. In contrast, HCT‐3012 (14.5 mg kg−1) significantly increased (62%) collagen deposition, while celecoxib (10 mg kg−1) had no effect.
Naproxen and HCT‐3012 suppressed prostaglandin (PG) E2 levels at the wound site and whole blood thromboxane synthesis to similar degrees. Celecoxib had no significant effect on wound fluid PGE2 levels, but slightly reduced whole blood thromboxane synthesis (by 17%).
COX‐1 mRNA and protein were expressed in the wound exudate, the skin surrounding the wound and in normal skin. In contrast, COX‐2 mRNA, but not protein, was expressed in wound and normal skin.
These results demonstrate that HCT‐3012 can significantly enhance collagen deposition at a wound site, despite inhibiting prostaglandin synthesis to the same extent as the parent drug. Nitric oxide‐releasing NSAIDs may represent a safer alternative to standard NSAIDs for use as anti‐inflammatory and analgesic agents by post‐surgery patients.

British Journal of Pharmacology (2000) 129, 681–686; doi:10.1038/sj.bjp.0703112
Preservation of mitochondrial function by diazoxide during sustained ischaemia in the rat heart
Authors: Iwai Takeshi , Tanonaka Kouichi , Koshimizu Miki , Takeo Satoshi 
Published: January 2005

A possible mechanism for the action of the KATP channel opener diazoxide on the improvement of energy metabolism of ischaemic/reperfused hearts was examined.
Isolated, perfused rat hearts were subjected to 40 min ischaemia followed by 60 min reperfusion. Diazoxide at concentrations of 3 to 30 μM was present in the perfusion buffer for the last 15 min of pre‐ischaemia.
Treatment of the perfused heart with diazoxide enhanced the post‐ischaemic recovery of rate‐pressure product, attenuated the post‐ischaemic rise in left ventricular end‐diastolic pressure, and suppressed the release of creatine kinase and purine nucleosides and bases from the reperfused heart. Treatment of the heart with diazoxide also restored myocardial ATP and creatine phosphate and attenuated the decrease in mitochondrial oxygen consumption rate after reperfusion. This attenuation was maintained at the end of ischaemia as well as at the end of reperfusion.
In another set of experiments, myocardial skinned bundles were incubated for 30 min under hypoxic conditions in the presence and absence of diazoxide, and then the mitochondrial oxygen consumption rate was determined. Hypoxia induced a decrease in the mitochondrial oxygen consumption rate of the skinned bundles to approximately 40% of the pre‐hypoxic value. In contrast, treatment of the bundles with 30 μM diazoxide preserved the normal mitochondrial oxygen consumption rate during hypoxia. This effect was abolished concentration‐dependently by the combined treatment with either the KATP channel blocker glibenclamide or 5‐hydroxydecanoate.
These results suggest that diazoxide is capable of attenuating ischaemia/reperfusion injury of isolated perfused hearts due to preservation of mitochondrial function during ischaemia.

British Journal of Pharmacology (2000) 129, 1219–1227; doi:10.1038/sj.bjp.0703148
Peroxisome proliferator‐activated receptors in the cardiovascular system
Authors: Bishop‐Bailey David 
Published: January 2005

Peroxisome proliferator‐activated receptor (PPAR)s are a family of three nuclear hormone receptors, PPARα, ‐δ, and ‐γ, which are members of the steriod receptor superfamily. The first member of the family (PPARα) was originally discovered as the mediator by which a number of xenobiotic drugs cause peroxisome proliferation in the liver. Defined functions for all these receptors, until recently, mainly concerned their ability to regulate energy balance, with PPARα being involved in β‐oxidation pathways, and PPARγ in the differentiation of adipocytes. Little is known about the functions of PPARδ, though it is the most ubiquitously expressed. Since their discovery, PPARs have been shown to be expressed in monocytes/macrophages, the heart, vascular smooth muscle cells, endothelial cells, and in atherosclerotic lesions. Furthermore, PPARs can be activated by a vast number of compounds including synthetic drugs, of the clofibrate, and anti‐diabetic thiazoldinedione classes, polyunsaturated fatty acids, and a number of eicosanoids, including prostaglandins, lipoxygenase products, and oxidized low density lipoprotein. This review will aim to introduce the field of PPAR nuclear hormone receptors, and discuss the discovery and actions of PPARs in the cardiovascular system, as well as the source of potential ligands.British Journal of Pharmacology (2000) 129, 823–834; doi:10.1038/sj.bjp.0703149