bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered active but not passive properties of mesenteric resistance arteries from the vitamin E‐deprived rat
Authors: Davidge Sandra T , Gandley Robin E , McLaughlin Margaret K 
Published: January 2005

We tested the hypothesis that lowering antioxidant protection through dietary vitamin E deprivation would alter active and passive mechanical properties in resistance arteries of the rat. Specifically, we hypothesized that vascular tone in isolated mesenteric arteries of the vitamin E‐deprived rats would be altered due to impaired endothelial influences of nitric oxide and/or prostaglandins.
Lumen diameter and wall thickness were measured in pressurized arteries (≈amp;250 μm diameter) from control (n=9) and vitamin E deprived (n=9) Sprague‐Dawley female rats by use of a dimension analysing system.
Treatment with a cyclo‐oxygenase inhibitor (meclofenamate) did not affect the basal vascular tone in either group. Treatment with a nitric oxide synthase inhibitor (NG‐methyl‐L‐arginine) caused a significant increase in basal tone only in the vitamin E‐deprived rats (% tone: 6.2±1.1 vs 1.2±0.3%; P<0.05). When tone was induced to 25% of the initial diameter with phenylephrine, treatment with the nitric oxide synthase inhibitor resulted in a greater potentiated tone in the vitamin E‐deprived rats compared to the controls (26.5±2.7 vs 16.4±3.4%; P<0.05); suggesting a greater nitric oxide affect in the vessels from the vitamin E‐deprived rats. Meclofenamate treatment in the induced tone arteries significantly relaxed (−17.4±4.0%; P<0.05) only the arteries from the vitamin E‐deprived rats, indicating that a vasoconstrictor was modifying tone. The passive characteristics of distensibility and stress‐strain relationship were not different between the two groups of rats.
In summary, vitamin E deprivation in the rat enhanced the modulation of vascular tone by both the nitric oxide and cyclo‐oxygenase pathways but did not alter passive characteristics of mesenteric arteries.

British Journal of Pharmacology (1998) 123, 275–280; doi:10.1038/sj.bjp.0701639
A new selective antagonist of the nociceptin receptor
Authors: Guerrini Remo , Calo Girolamo , Rizzi Anna , Bigoni Raffaella , Bianchi Clementina , Salvadori Severo , Regoli Domenico 
Published: January 2005

[Phe1Ψ(CH2‐NH)Gly2]NC(1‐13)NH2 has been tested in the electrically stimulated guinea pig ileum and mouse vas deferens, two nociceptin sensitive preparations. The new compound showed per se little or no effect in the two tissues, but it displaced to the right the concentration‐response curves of nociceptin in a concentration‐dependent manner. Schild analyses of the data indicated a competitive type of antagonism and pA2 values of 7.02 and 6.75 in the guinea‐pig ileum and the mouse vas deferens, respectively. At 10 μM [Phe1Ψ(CH2‐NH)Gly2]NC(1‐13)NH2 does not modify either the inhibitory effect of deltorphin I (the selective δ opioid receptor agonist) in the mouse vas deferens or that of dermorphine (the selective μ opioid receptor agonist) in the guinea‐pig ileum. The present findings indicate that [Phe1Ψ(CH2‐NH)Gly2]NC(1‐13)NH2 is a selective antagonist of the nociceptin receptor.British Journal of Pharmacology (1998) 123, 163–165; doi:10.1038/sj.bjp.0701640
Effects of pyrethroid molecules on rat nerves in vitro: potential to reverse temperature‐sensitive conduction block of demyelinated peripheral axons
Authors: Lees George 
Published: January 2005

Prolongation of action potentials by cooling or pharmacological treatment can restore conduction in demyelinated axons. We have assessed the ability of pyrethroids (in vitro) to modify action potential kinetics and to reverse conduction block in lesioned peripheral nerve.
Fast Na+ currents were isolated in mammalian neuroblastoma (NIE115). Pyrethroids (4 μM) concurrently slowed inactivation and produced a spectrum of pronounced tail currents: s‐bioallethrin (duration 12.2±7 ms), permethrin (24.2±3 ms) and deltamethrin (2230±100 ms).
Deltamethrin (5 μM) effected a slowly developing depression of compound action potential (CAP) amplitude in peroneal nerve trunks (P<0.05). Permethrin produced no net effect on CAP amplitude, area or repolarization time.
s‐Bioallethrin (5 μM) enhanced CAP area, time for 90% repolarization and induced regenerative activity in a subpopulation of axons.
Tibial nerve trunks were demyelinated by lysolecithin (2 μl) injection: 6–14 days later, slowly‐conducting axons in the CAP (and peri‐axonal microelectrode recordings) were selectively blocked by warming to 37°C.
At 37°C, s‐bioallethrin (45 min, 5 μM) produced much greater after‐potentials in lesioned nerves than in uninjected controls: area (P<0.05) and relative amplitude ratios (P<0.0001) were significantly altered.
In 3 of 4 cells (single‐unit recording), s‐bioallethrin restored conduction through axons exhibiting temperature‐dependent block by raising blocking temperature (by 1.5 to >3°C) and reducing refractory period.
s‐Bioallethrin induced temperature‐dependent regenerative activity only in a sub‐population of axons even after prolonged superfusion (>1 h).
It was concluded that pyrethroids differentially alter Na+ current kinetics and action potential kinetics. The effects of s‐bioallethrin are consistent with reversal of conduction block by demyelinated axons but regenerative/ectopic firing even in normal cells is likely to underpin its acknowledged neurotoxic actions and severely limit the clinical potential of this and related molecules.

British Journal of Pharmacology (1998) 123, 487–496; doi:10.1038/sj.bjp.0701644
Structural basis for specificity and potency of xanthine derivatives as activators of the CFTR chloride channel
Authors: Chappe V. , Mettey Y. , Vierfond J M. , Hanrahan J W. , Gola M. , Verrier B. , Becq F. 
Published: January 2005

On the basis of their structure, we compared the ability of 35 xanthine derivatives to activate the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel stably expressed in chinese hamster ovary (CHO) cells using the cell‐attached patch clamp and iodide efflux techniques.
Activation of CFTR channels was obtained with 3‐mono, 1,3‐di or 1,3,7‐tri‐substituted alkyl xanthine derivatives (enprofylline, theophylline, aminophylline, IBMX, DPMX and pentoxifylline). By contrast, xanthine derivatives substituted at the C8‐ or N9‐position failed to open CFTR channels.
The CFTR chloride channel activity was blocked by glibenclamide (100 μM) but not by DIDS (100 μM).
Activation of CFTR by xanthines was not mimicked by the calcium ionophore A23187, adenosine, UTP, ATP or the specific phosphodiesterase inhibitors rolipram, Ro 20‐1724 and milrinone. In addition, we found no correlation between the effect of xanthines on CFTR and on the cellular cyclic AMP or ATP levels.
We then synthesized a series of 3,7‐dimethyl‐1‐alkyl xanthine derivatives; among them, 3,7‐dimethyl‐1‐propyl xanthine and 3,7‐dimethyl‐1‐isobutyl xanthine both activated CFTR channels without increasing the intracellular cyclic AMP level, while the structurally related 3,7‐dimethyl‐1‐(2‐propenyl) xanthine and 3,7‐dimethyl‐1‐(oxiranyl methyl) xanthine were inactive.
Our findings delineate a novel function for xanthine compounds and identify the molecular features that enable xanthine activation of CFTR. These results may be useful in the development of new molecules for studying the pharmacology of chloride channels.

British Journal of Pharmacology (1998) 123, 683–693; doi:10.1038/sj.bjp.0701648
Relaxant effects of NKH477, a new water‐soluble forskolin derivative, on guinea‐pig tracheal smooth muscle: the role of Ca2+‐activated K+ channels
Authors: Satake K. , Takagi K. , Kodama I. , Honjo H. , Toyama J. , Shibata S. 
Published: January 2005

Mechanisms underlying the bronchorelaxant action of NKH477, a newly developed water‐soluble forskolin derivative, were investigated in guinea‐pig isolated tracheal smooth muscle.
In muscles precontracted with 3 μM histamine, NKH477 (1 nM–1 μM) caused a concentration‐dependent decrease of isometric tension, resulting in a complete relaxation at 300 nM. The EC50 for the relaxation was 32.6±4.3 nM (n=6).
In the presence of 30 or 90 nM iberiotoxin (IbTX), a selective blocker of the large‐conductance Ca2+‐activated K+ (BKCa) channel, the relaxing action of NKH477 on the histamine‐induced contraction was inhibited, giving rise to a parallel shift of the concentration‐response curves; the EC50 of NKH477 was increased to 131.4±20.4 nM at 30 nM IbTX (n=4), and 125.3±12.2 nM at 90 nM IbTX (n=4).
Pretreatment of muscles with 30 mM tetraethylammonium (TEA) caused a similar rightward shift of the concentration‐response curve to NKH477 with an increase of the EC50 to 139.8±18.4 nM (n=5). In contrast, the relaxing action of NKH477 was unaffected by 10 μM glibenclamide, an ATP‐sensitive K+ channel blocker, or by 100 nM apamin, a blocker of small conductance Ca2+‐activated K+ channels.
In muscles pretreated with 1 μM nifedipine, a blocker of the voltage‐dependent Ca2+ channel (VDC), 30–90 nM IbTX did not affect the relaxant effects of NKH477 on the histamine‐induced contraction.
In muscles precontracted by a K+‐rich (40 mM) solution, NKH477 caused only minimal relaxation (19.8±1.7%, n=4) even at the highest concentration (1 μM).
In experiments to measure the ratio of fura‐2 fluorescence signals (R340/380) as an index of the intracellular Ca2+ concentration ([Ca2+]i), the application of 100 nM NKH477 or 200 nM isoprenaline to the preparation precontracted by 3 μM histamine resulted in a decrease in [Ca2+]i in association with a decrease in tension. The reduction of [Ca2+]i and tension by NKH477 was 47.0±5.6% and 62.8±7.0%, respectively (n=5), and that with isoprenaline 60.6±7.4% and 67.4±6.4%, respectively (n=5). These effects of NKH477 and isoprenaline on [Ca2+]i and tension were inhibited by 30 nM IbTX. The inhibitory action of IbTX was abolished in the presence of 1 μM nifedipine.
These results suggest that the bronchorelaxant action of NKH477 may result, at least in part, from activation of BKCa channels, which may cause a hyperpolarization of smooth muscle cell membranes and a secondary decrease in Ca2+ influx through VDCs, leading to a decrease in [Ca2+]i.

British Journal of Pharmacology (1998) 123, 753–761; doi:10.1038/sj.bjp.0701655
Comparison of relaxin receptors in rat isolated atria and uterus by use of synthetic and native relaxin analogues
Authors: Tan Y Y. , Wade J D. , Tregear G W. , Summers R J. 
Published: January 2005

The receptors for relaxin in the rat atria and uterus were investigated and compared by use of a series of synthetic and native relaxin analogues. The assays used were the positive chronotropic and inotropic effects in rat spontaneously beating, isolated right atrium and electrically driven left atrium and the relaxation of K+ precontracted uterine smooth muscle.
Relaxin analogues with an intact A‐ and B‐chain were active in producing powerful chronotropic and inotropic effects in the rat isolated atria at nanomolar concentrations. Single‐chain analogues and structural homologues of relaxin such as human insulin and sheep insulin‐like growth factor I had no agonist action and did not antagonize the effect of the B29 form of human gene 2 relaxin.
Shortening the B‐chain carboxyl terminal of human gene 1 (B2–29) relaxin to B2–26 reduced the activity of the peptide and removal of another 2 amino acid residues (B2–24) abolished the activity. This suggests that the B‐chain length may be important for determination of the activity of relaxin. More detailed studies are needed to determine the effect of progressive amino acid removal on the structure and the bioactivity of relaxin.
Porcine prorelaxin was as active as porcine relaxin on a molar basis, suggesting that the presence of the intact C‐peptide did not affect the binding of the prorelaxin to the receptor to produce functional responses.
Relaxin caused relaxation of uterine longitudinal and circular smooth muscle precontracted with 40 mM K+. The pEC50 values for human gene 2 and porcine relaxins were lower than those in the atrial assay, but rat relaxin had similar pEC50 values in both atrial and uterine assays. Rat relaxin was significantly less potent than either human gene 2 or porcine relaxin in the atrial assay, but in the uterine assay they were equipotent. The results suggest that the relaxin receptor or the signalling pathway in rat atria may differ from that in the uterus.

British Journal of Pharmacology (1998) 123, 762–770; doi:10.1038/sj.bjp.0701659
Stimulation of nitric oxide release from rat spinal cord by prostaglandin E2
Authors: Sakai Masato , Minami Toshiaki , Hara Naoki , Nishihara Isao , Kitade Hiroaki , Kamiyama Yasuo , Okuda Kazuyuki , Takahashi Hakuo , Mori Hidemaro , Ito Seiji 
Published: January 2005

We recently demonstrated that intrathecal administration of prostaglandin E2 (PGE2) and PGF2α induced allodynia through a pathway that includes the glutamate receptor and nitric oxide (NO)‐generating systems from pharmacological studies. In order to clarify the involvement of NO in prostaglandin‐induced allodynia, we measured NO released from rat spinal cord slices by a chemiluminescence method.
PGE2 stimulated NO release from both dorsal and ventral regions all along the spinal cord. PGE2 stimulated the release within 10 min and increased it in a time‐dependent manner.
The PGE2‐induced NO release was observed at 100 nM–10 μM. PGF2α stimulated the release at concentrations higher than 1 μM, but PGD2 (up to 10 μM) did not enhance it.
17‐Phenyl‐ω‐trinor PGE2 (EP1>EP3) and sulprostone (EP1<EP3) were as potent as PGE2, but PGE1 was less potent, in stimulating NO release. While M&B 28767 (EP3) did not enhance the release, butaprost (EP2) stimulated it at 1 μM. The PGE2‐evoked release was blocked by ONO‐NT‐012, a bifunctional EP1 antagonist/EP3 agonist.
The PGE2‐evoked release was Ca2+‐dependent and blocked by MK‐801 (NMDA receptor antagonist) and L‐NAME (NO synthase inhibitor). The release was also inhibited by PGD2 and dibutyryl‐cyclic AMP.
The present study demonstrated that PGE2 stimulates NO release in the rat spinal cord by activation of NMDA receptors through the EP1 receptor, and supports our previous findings that the NO‐generating system is involved in the PGE2‐induced allodynia.

British Journal of Pharmacology (1998) 123, 890–894; doi:10.1038/sj.bjp.0701661
Suppression of nitric oxide formation by tyrosine kinase inhibitors in murine N9 microglia
Authors: Lockhart B P. , Cressey K C. , Lepagnol J M. 
Published: January 2005

Microglial cells represent the first line of defence in the brain against infection and damage. However, under conditions of chronic inflammation and neurodegeneration, excessive activation of microglia can contribute to the neurodegenerative process by releasing a cornucopia of potentially cytotoxic substances including the cytotoxic free radical nitric oxide (NO). Although the cell signalling events implicated in NO formation in peripheral macrophages are well defined, events occurring in the phenotypically homologous cerebral microglial cell are not yet fully characterized.
In the present study, a cloned murine microglial cell line (N9), stimulated with combined lipopolysaccharide/interferon‐γ (LPS/IFN) incubation, was shown to produce a significant increase in NO formation, as measured by medium nitrite levels, during 8–72 h exposure.
LPS/IFN‐stimulated NO production was partially inhibited with the nitric oxide synthase (NOS) competitive antagonists; Nω‐nitro‐L‐arginine methyl ester and Nω‐nitro‐L‐arginine. The ability of the selective inducible (iNOS) inhibitor, aminoguanidine, but not the selective ‘neuronal‐type’ constitutive (cNOS) inhibitor 7‐nitroindazole, to inhibit NO production suggested a primary role of iNOS in this response and was confirmed by immunolabelling of activated cells with a specific iNOS antibody.
A series of tyrosine kinase inhibitors, herbimycin A, genestein, tyrphostins, AG‐126, AG‐556 and the tyrosine phosphatase inhibitors, sodium orthovanadate and phenylarsine oxide, significantly attenuated LPS/IFN‐mediated NO production. The serine/threonine kinase inhibitors, staursporine (protein kinase C), H‐9 (cyclic GMP/cyclic AMP‐dependent kinase) or serine/threonine phosphatase inhibitors, cyclosporin A (phosphatase 2B) and okadaic acid (phosphatase 1/2A), reduced NO formation by an apparent cytostatic mechanism, as determined by cellular reduction of 3‐(4,5‐dimethylthiazol‐2‐yi)‐2,5‐diphenyl‐tetrazolium bromide (MTT).
The present results suggest that the co‐ordinated activation of protein tyrosine kinases/phosphatases, and proximal signalling events implicating the interplay between serine‐threonine kinases/phosphatases, is intricately linked with inflammatory mediated mechanisms of iNOS activation in microglial cells by regulating the activation of the transcription factor NFκB.

British Journal of Pharmacology (1998) 123, 879–889; doi:10.1038/sj.bjp.0701664
Inhibitory action of insulin‐sensitizing agents on calcium channels in smooth muscle cells from resistance arteries of guinea‐pig
Authors: Nakamura Yoshito , Ohya Yusuke , Onaka Uran , Fujii Koji , Abe Isao , Fujishima Masatoshi 
Published: January 2005

The actions of troglitazone, pioglitazone, metformin and bezafibrate, agents that improve insulin‐resistance, on voltage‐dependent Ca2+ channels in arterial smooth muscle cells were examined by use of the conventional and nystatin‐perforated whole‐cell clamp methods. Single cells were freshly isolated from resistance mesenteric arteries of guinea‐pigs. The actions of these agents on 77 mM K+‐induced contraction of the isolated arteries were also examined with the use of isometric tension recording.
The thiazolidinedione derivatives, troglitazone and pioglitazone, inhibited whole‐cell Ca2+ currents in a dose‐dependent manner with dissociation constants of 3.0 μM and 44.9 μM and Hill coefficients of 0.61 and 0.68, respectively. These two agents inhibited the 77 mM K+‐induced contraction with similar potencies as those inhibiting the Ca2+ currents. Metformin and bezafibrate had no apparent effects on the Ca2+ current or high K+‐induced contraction.
The inhibitory action of troglitazone on Ca2+ currents was not affected by the command potential, the holding potential, or the stimulation frequency, suggesting that its mode of the action differs from that of known organic Ca2+ channel antagonists.
The inhibitory action of troglitazone on Ca2+ currents was not affected by the addition of insulin to, or the removal of glucose from, the solutions.
In conclusion, the thiazolidinedione derivatives directly inhibited the voltage‐dependent Ca2+ channels in a different manner from that of organic Ca2+ channel antagonists. This inhibitory action on Ca2+ channels was not a common feature of insulin‐sensitizing agents.

British Journal of Pharmacology (1998) 123, 675–682; doi:10.1038/sj.bjp.0701669
Inhibition of glycosphingolipid synthesis by threo‐1‐phenyl‐2‐decanoylamino‐3‐morpholino‐1‐propanol (PDMP) and the modulation of IL‐1β‐stimulated expression of inducible nitric oxide synthase in rat aortic smooth muscle cells
Authors: Weber Artur‐Aron , Seul Claudia , Harth Volker , Ko Yon , Seewald Stefan , Vetter Hans , Sachinidis Agapios 
Published: January 2005

The composition of glycosphingolipids is altered in atherosclerotic tissue. In order to study the possible modulation of interleukin‐1β (IL‐1β)‐induced expression of inducible nitric oxide synthase (iNOS) by endogenously synthesized glycosphingolipids, we investigated rat aortic vascular smooth muscle cells (VSMC) grown in the presence of the inhibitor of glycosphingolipid synthesis, threo‐1‐phenyl‐2‐decanoylamino‐3‐morpholino‐1‐propanol (PDMP).
Depletion of glycosphingolipids by PDMP (20–30 μM) was demonstrated by thin‐layer chromatography of D‐[1−14C]‐galactose‐ or L‐[‐U14C]‐serine‐labelled glycosphingolipids. Nitrite generation was measured by the diaminonaphthalene assay, nitric oxide was determined by the oxyhaemoglobin technique and iNOS protein was detected by immunocytochemistry.
In VSMC grown in the presence of PDMP, the glycosphingolipid content was reduced by 30–50%. In PDMP‐treated VSMC, IL‐1β (3 u ml−1)‐stimulated release of nitrite (135±4 nmol mg−1 protein 48 h−1) was significantly increased as compared to IL‐1β‐stimulated control cells (40±3 nmol mg−1 protein 48 h−1; n=6, P<0.001). Similarly, IL‐1β (3 u ml−1, 36 h)‐stimulated release of nitric oxide was higher in PDMP‐treated VSMC (6.1±0.5 nmol mg−1 protein h−1) as compared to untreated cells (2.0±0.6 nmol mg−1 protein h−1; n=3, P<0.01). These findings were confirmed by the demonstration of increased expression of iNOS protein (14.9±1.2% vs 6.4±0.2%; n=4, P<0.001), as shown by immunocytochemistry.
Evidence is presented that endogenous glycosphingolipids are important modulators of cytokine‐induced iNOS expression. In view of an altered glycosphingolipid profile in atherosclerotic arteries, these mechanisms might be of relevance for the pathogenesis of atherosclerosis and restenosis subsequent to vessel injury.

British Journal of Pharmacology (1998) 123, 906–910; doi:10.1038/sj.bjp.0701674
Histamine‐induced biphasic macromolecular leakage in the microcirculation of the conscious hamster: evidence for a delayed nitric oxide‐dependent leakage
Authors: Gimeno G , Carpentier P H. , Desquand‐Billiald S , Hanf R , Finet M 
Published: January 2005

Late effects (up to 3 h) of intravenously‐injected histamine on FITC‐dextran extravasation were investigated in the conscious hamster, by use of computer‐assisted image analysis of fluorescence distribution in a microscopic window of dorsal skin fold preparations. This analysis allowed measurement of local (skin) and general (all organs) extravasations caused by a bolus injection of histamine (1 mg kg−1, i.v.)
Histamine doses higher than 0.01 mg kg−1 caused biphasic local and general extravasations. Initial phases developed fully within 15 min (for local) and 60 min (for general) and were followed by late phases beginning 90 min after histamine injection. Although the initial and late phases of histamine‐induced extravasations had differential apparent reactivities to the autacoid, all the effects of histamine on the microcirculation (1 mg kg−1) were inhibited by pyrilamine (1 mg kg−1, i.v.) but not by cimetidine (1 mg kg−1, i.v.).
Pretreatment with NG‐monomethyl‐L‐arginine (L‐NMMA, 30 mg kg−1, i.v.) or NG‐nitro‐L‐arginine methyl ester (L‐NAME, 100 mg kg−1, i.v.) did not affect the initial phases but did prevent the late phases of local and general extravasations triggered by 1 mg kg−1 histamine. The inhibitory effects of L‐NAME were reversed by L‐arginine (30 mg kg−1) but not by D‐arginine (30 mg kg−1) according to the enantioselectivity of nitric oxide synthase (NOS). A late NO‐mediated venular dilatation occurred in response to plasma histamine.
A low dose of aminoguanidine (1 mg kg−1, i.v.), a selective inhibitor of the inducible isoform of NOS (iNOS), mimicked the inhibitory effects of L‐NAME on the late phases of histamine‐induced macromolecular extravasations and venular dilatation.
Pretreatment with dexamethasone (1 mg kg−1, i.v.) prevented both the initial and late phases of histamine‐induced extravasations. Fucoidan (1 or 25 mg kg−1, i.v.) prevented the late phases without affecting initial phases, consistent with a role for leukocytes adhesion in the development of the late NO‐mediated effects of histamine.
We conclude that intravenous injection of histamine triggers a biphasic inflammatory cascade via initial activation of H1 receptors which induces a late NO‐mediated PMN‐dependent extravasation process.

British Journal of Pharmacology (1998) 123, 943–951; doi:10.1038/sj.bjp.0701676