bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blockade of chloride channels reveals relaxations of rat small mesenteric arteries to raised potassium
Authors: Doughty Joanne M , Boyle John P , Langton Philip D 
Published: January 2005

Raised extracellular K+ relaxes some arteries, and has been proposed as Endothelium‐Derived Hyperpolarizing Factor (EDHF). However, relaxation of rat small mesenteric arteries to K+ is highly variable. We have investigated the mechanism of K+‐induced dilatation and relaxation of pressurized arteries and arteries mounted for measurement of isometric force.
Raising [K+]o from 5.88 – 10.58 mM did not dilate or relax pressurized or isometric arteries. Relaxation to raised [K+]o was revealed in the presence of 5‐nitro‐2‐(3‐phenylpropylamino) benzoic acid (NPPB); this effect of NPPB was concentration‐dependent (IC50: 1.16 μM).
Relaxations to raised [K+]o in the presence of NPPB, were abolished by 30 μM Ba2+ or endothelial‐denudation. Acetycholine (10 μM) relaxed endothelium‐intact arteries in presence of raised [K+]o NPPB and Ba2+.
Relaxations to raised [K+]o were revealed in hyperosmotic superfusate (+60 mM sucrose). These relaxations were abolished by 30 μM Ba2+. In the presence of raised [K+]o, 60 mM sucrose and 30 μM Ba2+, 10 μM acetycholine still relaxed all arteries.
Fifty μM 18α‐glycyrrhetinic acid (18α‐GA), a gap junction inhibitor, depressed relaxations to both 10 μM acetylcholine and raised [K+]o, in the presence of 10 μM NPPB.
In summary, blockade of a volume‐sensitive Cl− conductance in small rat mesenteric arteries, using NPPB or hyperosmotic superfusion, reveals a endothelium‐dependent, Ba2+ sensitive dilatation or relaxation of rat mesenteric arteries to raised [K+]o. We conclude that inwardly rectifying potassium channels on the endothelium underlie relaxations to raised [K+]o in rat small mesenteric arteries.

British Journal of Pharmacology (2001) 132, 293–301; doi:10.1038/sj.bjp.0703769
Platelet‐derived growth factor causes endothelium‐independent relaxation of rabbit mesenteric artery via the release of a prostanoid
Authors: Yamawaki Hideyuki , Sato Koichi , Hori Masatoshi , Ozaki Hiroshi , Karaki Hideaki 
Published: January 2005

Recent evidence has indicated that the mitogen platelet‐derived growth factor (PDGF) can act acutely to regulate arterial tone. In this study we demonstrate that the BB isoform of PDGF (PDGF‐BB) can cause endothelium‐independent relaxation of rabbit isolated mesenteric arteries.
In endothelium‐denuded arteries, PDGF‐BB (40 pM–8.0 nM) caused concentration‐dependent relaxation of noradrenaline‐induced tone. The relaxation to PDGF‐BB was abolished by a cyclo‐oxygenase inhibitor, indomethacin (10 μM) and by the PDGF receptor‐associated tyrosine kinase inhibitor, tyrphostin AG1295 (50 μM), but not by NG‐monomethyl‐L‐arginine (L‐NMMA, 200 μM), an inhibitor of nitric oxide (NO) synthase.
PDGF‐BB (4.0 nM) significantly increased the release of prostacyclin (PGI2) in endothelium‐denuded arteries. Exogenously applied iloprost (1 μM), a stable analogue of PGI2, relaxed the endothelium‐denuded artery. PDGF‐BB (4.0 nM) significantly increased the cyclic AMP content.
In the absence of Ca2+, PDGF‐BB (4.0 nM) failed to relax the artery, and the release of PGI2 was almost completely suppressed. In addition, the release of PGI2 by PDGF‐BB (4.0 nM) was significantly reduced in the presence of endothelium. The effect of endothelium was eliminated by L‐NMMA (200 μM) and PGI2 release increased.
These data indicate that in rabbit mesenteric arteries, PDGF‐BB can evoke endothelium‐independent relaxation by stimulating the synthesis of PGI2. The PDGF‐BB‐induced prostaglandin synthesis is dependent on both Ca2+ and tyrosine phosphorylation of the PDGF receptor, and is attenuated by endothelium‐derived NO.

British Journal of Pharmacology (2000) 131, 1546–1552; doi:10.1038/sj.bjp.0703771
Protective effects of a new stable, highly active SOD mimetic, M40401 in splanchnic artery occlusion and reperfusion
Authors: Cuzzocrea Salvatore , Mazzon Emanuela , Dugo Laura , Caputi Achille P , Aston Karl , Riley Dennis P , Salvemini Daniela 
Published: January 2005

Splanchnic artery occlusion shock (SAO) causes an enhanced formation of reactive oxygen species (ROS), which contribute to the pathophysiology of shock. Here we have investigated the effects of M40401, a new S,S‐dimethyl substituted biscyclohexylpyridine Mn‐based superoxide dismutase mimetic (SODm, kcat=1.2×10+9 M−1 s−1 at pH=7.4), in rats subjected to SAO shock.
Treatment of rats with M40401 (applied at 0.25, 2.5 or 25 μg kg−1, 15 min prior to reperfusion), attenuated the mean arterial blood and the migration of polymorphonuclear cells (PMNs) caused by SAO‐shock. M40401 also attenuated the ileum injury (histology) as well as the increase in the tissue levels of myeloperoxidase (MPO) and malondialdehyde (MDA) caused by SAO shock in the ileum.
Immunohistochemical analysis for nitrotyrosine revealed a positive staining in ileum from SAO‐shocked rats. The degree of staining for nitrotyrosine was markedly reduced in tissue sections obtained from SAO‐shocked rats which had received M40401. Reperfused ileum tissue sections from SAO‐shocked rats showed positive staining for P‐selectin and for anti‐intercellular adhesion molecule (ICAM‐1) in the vascular endothelial cells. M40401 treatment markedly reduced the intensity and degree of P‐selectin and ICAM‐1 in tissue sections from SAO‐shocked rats. M40401 treatment significantly improved survival.
Additionally, the very high catalytic activity of this new mimetic (comparable to the native human Cu/Zn SOD enzyme and exceeding the activity of the human Mn SOD enzyme) translates into a very low dose (∼μg kg−1) required to afford protection in this SAO model of ischemia reperfusion injury.
Taken together, our results clearly demonstrate that M40401 treatment exerts a protective effect, and part of this effect may be due to inhibition of the expression of adhesion molecules and peroxynitrite‐related pathways with subsequent reduction of neutrophil‐mediated cellular injury.

British Journal of Pharmacology (2001) 132, 19–29; doi:10.1038/sj.bjp.0703775
Leukotriene C4 enhances the contraction of porcine tracheal smooth muscle through the activation of Y‐27632, a rho kinase inhibitor, sensitive pathway
Authors: Setoguchi Hidekazu , Nishimura Junji , Hirano Katsuya , Takahashi Shosuke , Kanaide Hideo 
Published: January 2005

An unsaturated fatty acid, leukotriene C4 (LTC4), has a potent contractile effect on human airway smooth muscle, and has been implicated in the pathogenesis of human asthma. Using front‐surface fluorometry with fura‐PE3, the effect of LTC4 on the intracellular Ca2+ concentration ([Ca2+]i) and tension were investigated in porcine tracheal smooth muscle strips.
The application of LTC4 induced little or no contraction despite a small and transient increase in [Ca2+]i. In the presence of LTC4, however, the contractions evoked by high K+ depolarization or a low concentration of carbachol (CCh) were markedly enhanced without inducing any changes in the [Ca2+]i levels, thus indicating that LTC4 increases the Ca2+ responsiveness of the contractile apparatus. This LTC4‐induced increase in Ca2+ responsiveness could partly be reproduced in the permeabilized preparation of tracheal smooth muscle strips.
The LTC4‐induced enhancement of contraction was accompanied by an increase in myosin light chain (MLC) phosphorylation and was blocked by a rho kinase inhibitor (Y‐27632), but not by either a PKC inhibitor (calphostin C) or a tyrosine kinase inhibitor (genistein).
These results indicated that, in porcine tracheal smooth muscle, LTC4 enhances the contraction by increasing the Ca2+ responsiveness of the contractile apparatus in a MLC phosphorylation dependent manner, possibly through the activation of the rho‐rho kinase pathway.

British Journal of Pharmacology (2001) 132, 111–118; doi:10.1038/sj.bjp.0703780
Contralateral but not systemic administration of the κ‐opioid agonist U‐50,488H induces anti‐nociception in acute hindpaw inflammation in rats
Authors: Bileviciute‐Ljungar Indre , Spetea Mariana 
Published: January 2005

The anti‐nociceptive effects of contralateral administration of κ‐opioid agonist U‐50,488H were investigated in rats.
Inflammation was induced by unilateral injection of 1% carrageenan into the right hindpaw. Prior to carrageenan injection, U‐50,488H or saline was administered into the left hindpaw. Withdrawal responses to mechanical and heat stimulation and oedema levels were evaluated at 3, 6 and 24 h post‐carrageenan injection.
The results showed that the inflammatory effect of 1% carrageenan peaked after 6 h with bilateral decreases in withdrawal latencies and ipsilateral oedema formation.
Contralateral treatment with 0.01, 0.05, 0.3 and 2 mg of U‐50,488H attenuated nociceptive reflexes to mechanical stimulation on the inflamed side at 6 h. The anti‐nociceptive effect of contralateral treatment was dose‐dependent at 3 and 24 h. The hindpaw withdrawal latencies to heat stimulation were prolonged at 3 and 24 h after contralateral treatment with 0.3 mg U‐50,488H. No effect on inflammatory oedema formation was observed, except for a decrease at 3 h after treatment with 2 mg of U‐50,488H.
Sciatic nerve denervation on the contralateral side abolished the anti‐nociceptive effects of U‐50,488H (0.3 and 2 mg). In contrast, contralateral injection of 1 mg morphine prolonged paw latencies in denervated rats.
Both co‐administration of the peripherally selective opioid antagonist naloxone methiodide with 0.3 mg U‐50,488H, and alternatively, systemic administration of 0.3 mg U‐50,488H reversed the anti‐nociceptive effects induced by contralateral injection of U‐50,488H.
Taken together, our findings indicate that the contralateral administration of U‐50,488H attenuates nociceptive behaviour resulting from acute inflammation. The effect is mediated via peripheral neuronal κ‐opioid receptors and, possibly, spinal cord mechanisms, suggesting a new treatment approach for acute inflammatory conditions.

British Journal of Pharmacology (2001) 132, 252–258; doi:10.1038/sj.bjp.0703782
Inhibition of volume‐regulated anion channels in cultured endothelial cells by the anti‐oestrogens clomiphene and nafoxidine
Authors: Maertens Chantal , Droogmans Guy , Chakraborty Prabir , Nilius Bernd 
Published: January 2005

We have used the whole‐cell patch clamp technique to study the effect of the partial anti‐oestrogens clomiphene and nafoxidine, the pure anti‐oestrogens ICI 182,780 and RU 58,668 and the oestrogen β‐estradiol, on the volume‐regulated anion channel (VRAC) in cultured pulmonary artery endothelial (CPAE) cells.
In contrast to the pure anti‐oestrogens and β‐estradiol, clomiphene and nafoxidine potently inhibited the volume‐sensitive chloride current, ICl,swell, activated by challenging CPAE cells with a 25% hypotonic solution. For clomiphene, the estimated IC50 and Hill coefficient were 1.03±0.14 μM and 1.40±0.21 respectively. In the case of nafoxidine, these values were 1.61±0.29 μM and 1.24±0.19.
The inhibition induced by the pure enantiomers of clomiphene, zuclomiphene and enclomiphene, was not different from that of the racemic mixture, indicating that the interaction between clomiphene and VRAC is not stereoselective.
Clomiphene and nafoxidine inhibited proliferation of CPAE cells. Half‐maximal inhibition was found at 1.98±0.17 and 1.66±0.21 μM respectively, concentrations similar to those for half‐maximal block of VRAC.
In conclusion, the nonsteroidal partial anti‐oestrogens nafoxidine and clomiphene are potent inhibitors of volume‐regulated anion channels. The inhibition by clomiphene is not stereoselective and occurs at concentrations close to therapeutically relevant concentrations. Finally, both drugs inhibit the proliferation of endothelial cells.

British Journal of Pharmacology (2001) 132, 135–142; doi:10.1038/sj.bjp.0703786
Differential coupling of the human P2Y11 receptor to phospholipase C and adenylyl cyclase
Authors: Qi Ai‐Dong , Kennedy Charles , Harden T Kendall , Nicholas Robert A 
Published: January 2005

The human P2Y11 (hP2Y11) receptor was stably expressed in two cell lines, 1321N1 human astrocytoma cells (1321N1‐hP2Y11) and Chinese hamster ovary cells (CHO‐hP2Y11), and its coupling to phospholipase C and adenylyl cyclase was assessed.
In 1321N1‐hP2Y11 cells, ATP promoted inositol phosphate (IP) accumulation with low μM potency (EC50=8.5±0.1 μM), whereas it was 15 fold less potent (130±10 μM) in evoking cyclic AMP production.
In CHO‐hP2Y11 cells, ATP promoted IP accumulation with slightly higher potency (EC50=3.6±1.3 μM) than in 1321N1‐hP2Y11 cells, but it was still 15 fold less potent in promoting cyclic AMP accumulation (EC50=62.4±15.6 μM) than for IP accumulation. Comparable differences in potencies for promoting the two second messenger responses were observed with other adenosine nucleotide analogues.
In 1321N1‐hP2Y11 and CHO‐hP2Y11 cells, down regulation of PKC by chronic treatment with phorbol ester decreased ATP‐promoted cyclic AMP accumulation by 60 – 80% (P<0.001) with no change in its potency. Likewise, chelation of intracellular Ca2+ decreased ATP‐promoted cyclic AMP accumulation by ∼45% in 1321N1‐hP2Y11 cells, whereas chelation had no effect on either the efficacy or potency of ATP in CHO‐hP2Y11 cells.
We conclude that coupling of hP2Y11 receptors to adenylyl cyclase in these cell lines is much weaker than coupling to phospholipase C, and that activation of PKC and intracellular Ca2+ mobilization as consequences of inositol lipid hydrolysis potentiates the capacity of ATP to increase cyclic AMP accumulation in both 1321N1‐hP2Y11 and CHO‐hP2Y11 cells.

British Journal of Pharmacology (2001) 132, 318–326; doi:10.1038/sj.bjp.0703788
Inhibition by glucocorticoids of the mast cell‐dependent weal and flare response in human skin in vivo
Authors: Cole Zoë A , Clough Geraldine F , Church Martin K 
Published: January 2005

This study examines the relative contributions made by inhibition of mast cell degranulation, reduction of mast cell recruitment and maturation, and lowering the responsiveness of the vasculature to histamine, in the inhibition by glucocorticoids of the weal and flare in human skin.
One forearm of healthy human volunteers was treated for 24 h (n=6) or daily for 21 days (n=10) with 0.05% clobetasol propionate. The other arm served as control. Weal and flare responses were elicited by intradermal injection of 20 μl of 0.3 mM codeine. The areas of the responses were measured using scanning laser Doppler imaging. Microdialysis was used to assess histamine release. Mast cell numbers and tissue histamine content were assessed in 4‐mm punch biopsies. Histamine (20 μl of 1 μM i.d.) was used to assess the status of the vasculature.
No significant effects were seen at 24 h. At 21 days, clobetasol reduced the areas of the codeine‐induced weal and flare responses by 59 and 58% respectively (both P=0.006). Mast cell numbers were reduced by 47%, (P=0.014) and total tissue histamine content by 52% (P=0.006). Codeine‐induced histamine release was reduced by 44% (P=0.022). The weal, but not the flare, induced by histamine was significantly inhibited (P=0.019). Echography revealed a 15% thinning of the skin by clobetasol.
These results demonstrate that reduction of the weal and flare responses to codeine following clobetasol treatment, results primarily from reduced mast cell numbers and tissue histamine content rather than inhibition by corticosteroids of mast cell degranulation.

British Journal of Pharmacology (2001) 132, 286–292; doi:10.1038/sj.bjp.0703789
Pregabalin may represent a novel class of anxiolytic agents with a broad spectrum of activity
Authors: Field Mark J , Oles Ryszard J , Singh Lakhbir 
Published: January 2005

The present study examines the effect of pregabalin (previously S‐Isobutylgaba and CI‐1008) in two distinct rat models of anxiety. Pregabalin binds with high affinity and selectivity to the α2δ subunit of voltage dependent calcium channels (VDCC). Its corresponding R‐enantiomer (R‐isobutylgaba) is approximately 10 fold weaker. Pregabalin dose‐dependently induced anxiolytic‐like effects in both the rat conflict test and elevated X‐maze with respective minimum effective doses (MED) of 3 and 10 mg kg−1. In contrast, R‐isobutylgaba only showed activity at the highest dose of 100 mg kg−1 in the conflict test. These data indicate that pregabalin may possess clinical utility as a novel anxiolytic agent and demonstrates the importance of the α2δ subunit of VDCC in the mediation of anxiety related behaviours.British Journal of Pharmacology (2001) 132, 1–4; doi:10.1038/sj.bjp.0703794
Differential abilities of phorbol esters in inducing protein kinase C (PKC) down‐regulation in noradrenergic neurones
Authors: Kotsonis P , Funk L , Prountzos C , Iannazzo L , Majewski H 
Published: January 2005

The ability of several phorbol ester protein kinase C (PKC) activators (phorbol 12, 13‐dibutyrate, PDB; phorbol 12, 13‐diacetate, PDA; and 12‐deoxyphorbol 13‐acetate, dPA) to down‐regulate PKC was studied by assessing their effects on electrical stimulation‐induced (S‐I) noradrenaline release from rat brain cortical slices and phosphorylation of the PKC neural substrate B‐50 in rat cortical synaptosomal membranes.
In cortical slices which were incubated for 20 h with vehicle, acute application of PDB, PDA and dPA (0.1 – 3.0 μM) enhanced the S‐I noradrenaline release in a concentration‐dependent manner to between 200 – 250% of control in each case. In slices incubated with PDB (1 μM for 20 h), subsequent acute application of PDB (0.1 – 3.0 μM) failed to enhance S‐I release, indicating PKC down‐regulation. However, in tissues incubated with PDA or dPA (3 μM) for 20 h, there was no reduction in the facilitatory effect of their respective phorbol esters or PDB (0.1 – 3.0 μM) when acutely applied, indicating that PKC was not down‐regulated. This was confirmed using Western blot analysis which showed that PDB (1 μM for 20 h) but not PDA (3 μM for 20 h) caused a significant reduction in PKCα.
Incubation with PDB for 20 h, followed by acute application of PDB (3 μM) failed to increase phosphorylation of B‐50 in synaptosomal membranes, indicating down‐regulation. In contrast, tissues incubated with PDA or dPA for 20 h, acute application of their respective phorbol ester (10 μM) or PDB (3 μM) induced a significant increase in B‐50 phosphorylation.
Acutely all three phorbol esters elevate noradrenaline release to about the same extent, yet PDA and dPA have lower affinities for PKC compared to PDB, suggesting unique neural effects for these agents. This inability to cause functional down‐regulation of PKC extends their unusual neural properties. Their neural potency and lack of down‐regulation may be related to their decreased lipophilicity compared to other phorbol esters.
We suggest that PKC down‐regulation appears to be related to binding affinity, where agents with high affinity, irreversibly insert PKC into artificial membrane lipid and generate Ca2+‐independent kinase activity which degrades and deplete PKC. We suggest that this mechanism may also underlie the ability of PDB to down‐regulate PKC in nerve terminals, in contrast to PDA and dPA.

British Journal of Pharmacology (2001) 132, 489–499; doi:10.1038/sj.bjp.0703813
Neural mechanisms underlying migrating motor complex formation in mouse isolated colon
Authors: Brierley Stuart M , Nichols Kim , Grasby Dallas J , Waterman Sally A 
Published: January 2005

Little is known about the intrinsic enteric reflex pathways associated with migrating motor complex (MMC) formation. Acetylcholine (ACh) mediates the rapid component of the MMC, however a non‐cholinergic component also exists. The present study investigated the possible role of endogenous tachykinins (TKs) in the formation of colonic MMCs and the relative roles of excitatory and inhibitory pathways.
MMCs were recorded from the circular muscle at four sites (proximal, proximal‐mid, mid‐distal and distal) along the mouse colon using force transducers.
The tachykinin (NK1 and NK2) receptor antagonists SR‐140 333 (250 nM) and SR‐48 968 (250 nM) reduced the amplitude of MMCs at all recording sites, preferentially abolishing the long duration contraction. Residual MMCs were abolished by the subsequent addition of atropine (1 μM).
The neuronal nitric oxide synthase inhibitor, Nωnitro‐L‐arginine (L‐NOARG, 100 μM), increased MMC amplitude in the distal region, whilst reducing the amplitude in the proximal region. In preparations where MMCs did not migrate to the distal colon, addition of L‐NOARG resulted in the formation of MMCs. Subsequent addition of apamin (250 nM) or suramin (100 μM) further increased MMC amplitude in the distal region, whilst suramin increased MMC amplitude in the mid‐distal region. Apamin but not suramin reduced MMC amplitude in the proximal region. Subsequent addition of SR‐140 333 and SR‐48 968 reduced MMC amplitude at all sites. Residual MMCs were abolished by atropine (1 μM).
In conclusion, TKs, ACh, nitric oxide (NO) and ATP are involved in the neural mechanisms underlying the formation of MMCs in the mouse colon. Tachykinins mediate the long duration component of the MMC via NK1 and NK2 receptors. Inhibitory pathways may be involved in determining whether MMCs are formed.

British Journal of Pharmacology (2001) 132, 507–517; doi:10.1038/sj.bjp.0703814
Activity of adenosine diphosphates and triphosphates on a P2YT‐type receptor in brain capillary endothelial cells
Authors: Simon J , Vigne P , Eklund K M , Michel A D , Carruthers A M , Humphrey P P A , Frelin C , Barnard E A 
Published: January 2005

A P2Y (nucleotide) receptor activity in a clonal population (B10) of rat brain capillary endothelial cells is coupled to inhibition of adenylyl cyclase and has functional similarities to the P2YT (previously designated ‘P2T’) receptor for ADP of blood platelets. However, the only P2Y receptor which was detectable in a previous study of B10 cells by mRNA analysis was the P2Y1 receptor, which elsewhere shows no transduction via cyclic nucleotides. We have sought here to clarify these issues.
The inhibition of forskolin‐stimulated adenylyl cyclase induced by purified nucleotides was measured on B10 cells. The EC50 value for 2‐methylthioADP (2‐MeSADP) was 2.2 nM and, surprisingly, 2‐MeSATP was an almost equally strong agonist (EC50=3.5 nM). ATP and 2‐ClATP were weak partial agonists (EC50=26 μM and 10 μM respectively) and under appropriate conditions could antagonise the activity on 2‐MeSADP.
A known selective antagonist of the platelet P2YT receptor, 2‐propylthioadenosine‐5′‐(β,γ)‐difluoromethylene) triphosphonate (AR‐C 66096), was a competitive antagonist of this B10 cell receptor, with pKB=7.6. That ligand is inactive at the P2Y1 receptor in the same cells. Conversely, the competitive P2Y1 receptor antagonists, the 3′, 5′‐ and 2′, 5′‐adenosine bis‐monophosphates, are, instead, weak agonists at the adenylyl cyclase‐inhibitory receptor.
The inhibition of adenylyl cyclase by 2‐MeSADP was completely abolished by pertussis toxin.
In summary, these brain endothelial cells possess a P2YT‐type receptor in addition to the P2Y1 receptor. The two have similarities in agonist profiles but are clearly distinguishable by antagonists and by their second messenger activations. The possible relationships between the B10 and platelet P2YT receptors are discussed.

British Journal of Pharmacology (2001) 132, 173–182; doi:10.1038/sj.bjp.0703816