bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of inflammation and inflammatory mediators on nociceptive behaviour induced by ATP analogues in the rat
Authors: Hamilton Sara G , Wade Alex , McMahon Stephen B 
Published: January 2005

We have studied the behavioural effects of intraplantar injections of adenosine 5′‐triphosphate (ATP) and related compounds in freely moving rats and investigated whether these nociceptive effects are augmented in the presence of inflammatory mediators.
We find that in normal animals ATP and analogues produce dose‐dependent nocifensive behaviour (seen as bursts of elevation of the treated hindpaw), and localized thermal hyperalgesia. The rank order of potency was: α,β‐methyleneadenosine 5′‐triphosphate (α,β‐methylene ATP) >2‐methylthioadenosine triphosphate (2‐methylthio ATP)>ATP. After neonatal treatment with capsaicin, to destroy small calibre primary sensory neurones, nocifensive behaviour was largely absent.
The effects of ATP analogues were assessed in three models of peripheral sensitization: 2 h after dilute intraplantar carrageenan (0.25% w v−1); 24 h after irradiation of the hindpaw with ultraviolet (U.V.) B; immediately following prostaglandin E2 (PGE2) treatment. In all models the effect of α,β‐methylene ATP was greatly augmented. After carrageenan, significant hindpaw‐lifting behaviour activity was induced by injection of only 0.05 nmol of α,β‐methylene ATP, some 100 times less than necessary in normal skin.
Our data suggest that it is much more likely that endogenous levels of ATP will reach levels capable of exciting nociceptors in inflamed versus normal skin. Our data also suggest the involvement of P2X3 receptor subunits in ATP‐induced nociception.

British Journal of Pharmacology (1999) 126, 326–332; doi:10.1038/sj.bjp.0702258
Studies of the role of endothelium‐dependent nitric oxide release in the sustained vasodilator effects of corticotrophin releasing factor and sauvagine
Authors: Barker Diana M , Corder Roger 
Published: January 2005

The mechanisms of the sustained vasodilator actions of corticotrophin‐releasing factor (CRF) and sauvagine (SVG) were studied using rings of endothelium de‐nuded rat thoracic aorta (RTA) and the isolated perfused rat superior mesenteric arterial vasculature (SMA).
SVG was ∼amp;50 fold more potent than CRF on RTA (EC40: 0.9±0.2 and 44±9 nM respectively, P<0.05), and ∼amp;10 fold more active in the perfused SMA (ED40: 0.05±0.02 and 0.6±0.1 nmol respectively, P<0.05). Single bolus injections of CRF (100 pmol) or SVG (15 pmol) in the perfused SMA caused reductions in perfusion pressure of 23±1 and 24±2% that lasted more than 20 min.
Removal of the endothelium in the perfused SMA with deoxycholic acid attenuated the vasodilatation and revealed two phases to the response; a short lasting direct action, and a sustained phase which was fully inhibited.
Inhibition of nitric oxide synthase with L‐NAME (100 μM) L‐NMMA (100 μM) or 2‐ethyl‐2‐thiopseudourea (ETPU, 100 μM) had similar effects on the vasodilator responses to CRF as removal of the endothelium, suggesting a pivotal role for nitric oxide. However the selective guanylate cyclase inhibitor 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ, 10 μM) did not affect the response to CRF.
High potassium (60 mM) completely inhibited the vasodilator response to CRF in the perfused SMA, indicating a role for K+ channels in this response.
Compared to other vasodilator agents acting via the release of NO, the actions of CRF and SVG are strikingly long‐lasting, suggesting a novel mechanism of prolonged activation of nitric oxide synthase.

British Journal of Pharmacology (1999) 126, 317–325; doi:10.1038/sj.bjp.0702261
The cyclo‐oxygenase‐dependent regulation of rabbit vein contraction: evidence for a prostaglandin E2‐mediated relaxation
Authors: Rouaud Céline , Delaforge Marcel , Anger‐Leroy Marielle , Le Filliatre Gaël , Finet Michel , Hanf Rémy 
Published: January 2005

Arachidonic acid (0.01–1μM) induced relaxation of precontracted rings of rabbit saphenous vein, which was counteracted by contraction at concentrations higher than 1μM. Concentrations higher than 1μM were required to induce dose‐dependent contraction of vena cava and thoracic aorta from the same animals.
Pretreatment with a TP receptor antagonist (GR32191B or SQ29548, 3μM) potentiated the relaxant effect in the saphenous vein, revealed a vasorelaxant component in the vena cava response and did not affect the response of the aorta.
Removal of the endothelium from the venous rings, caused a 10 fold rightward shift in the concentration‐relaxation curves to arachidonic acid. Whether or not the endothelium was present, the arachidonic acid‐induced relaxations were prevented by indomethacin (10μM) pretreatment.
In the saphenous vein, PGE2 was respectively a 50 and 100 fold more potent relaxant prostaglandin than PGI2 and PGD2. Pretreatment with the EP4 receptor antagonist, AH23848B, shifted the concentration‐relaxation curves of this tissue to arachidonic acid in a dose‐dependent manner.
In the presence of 1μM arachidonic acid, venous rings produced 8–10 fold more PGE2 than did aorta whereas 6keto‐PGF1α and TXB2 productions remained comparable.
Intact rings of saphenous vein relaxed in response to A23187. Pretreatment with L‐NAME (100μM) or indomethacin (10μM) reduced this response by 50% whereas concomitant pretreatment totally suppressed it. After endothelium removal, the remaining relaxing response to A23187 was prevented by indomethacin but not affected by L‐NAME.
We conclude that stimulation of the cyclo‐oxygenase pathway by arachidonic acid induced endothelium‐dependent, PGE2/EP4 mediated relaxation of the rabbit saphenous vein. This process might participate in the A23187‐induced relaxation of the saphenous vein and account for a relaxing component in the response of the vena cava to arachidonic acid. It was not observed in thoracic aorta because of the lack of a vasodilatory receptor and/or the poorer ability of this tissue than veins to produce PGE2.

British Journal of Pharmacology (1999) 126, 35–44; doi:10.1038/sj.bjp.0702265
Enantioselective inhibition of the biotransformation and pharmacological actions of isoidide dinitrate by diphenyleneiodonium sulphate
Authors: Ratz Jodan D , McGuire John J , Bennett Brian M 
Published: January 2005

We have shown previously that the D‐ and L‐ enantiomers of isoidide dinitrate (D‐IIDN and L‐IIDN) exhibit a potency difference for relaxation and cyclic GMP accumulation in isolated rat aorta and that this is related to preferential biotransformation of the more potent enantiomer (D‐IIDN). The objective of the current study was to examine the effect of the flavoprotein inhibitor, diphenyleneiodonium sulphate (DPI), on the enantioselectivity of IIDN action.
In isolated rat aortic strip preparations, exposure to 0.3 μM DPI resulted in a 3.6 fold increase in the EC50 value for D‐IIDN‐induced relaxation, but had no effect on L‐IIDN‐induced relaxation.
Incubation of aortic strips with 2 μM D‐ or L‐IIDN for 5 min resulted in significantly more D‐isoidide mononitrate formed (5.0±1.5 pmol mg  protein−1) than L‐isoidide mononitrate (2.1±0.7 pmol mg protein−1) and this difference was abolished by pretreatment of tissues with 0.3 μM DPI. DPI had no effect on glutathione S‐transferase (GST) activity or GSH‐dependent biotransformation of D‐ or L‐IIDN in the 105,000×g supernatant fraction of rat aorta.
Consistent with both the relaxation and biotransformation data, treatment of tissues with 0.3 μM DPI significantly inhibited D‐IIDN‐induced cyclic GMP accumulation, but had no effect on L‐IIDN‐induced cyclic GMP accumulation.
In the intact animal, 2 mg kg−1 DPI significantly inhibited the pharmacokinetic and haemodynamic properties of D‐IIDN, but had no effect L‐IIDN.
These data suggest that the basis for the potency difference for relaxation by the two enantiomers is preferential biotransformation of D‐IIDN to NO, by an enzyme that is inhibited by DPI. Given that DPI binds to and inhibits NADPH‐cytochrome P450 reductase, the data are consistent with a role for the cytochromes P450‐NADPH‐cytochrome P450 reductase system in this enantioselective biotransformation process.

British Journal of Pharmacology (1999) 126, 61–68; doi:10.1038/sj.bjp.0702268
Proliferative effects of cholecystokinin in GH3 pituitary cells mediated by CCK2 receptors and potentiated by insulin
Authors: Smith Alison J , McKernan Ruth M 
Published: January 2005

Proliferative effects of CCK peptides have been examined in rat anterior pituitary GH3 cells, which express CCK2 receptors.
CCK‐8s, gastrin(1–17) and its glycine‐extended precursor G(1–17)‐Gly, previously reported to cause proliferation via putative novel sites on AR4‐2J and Swiss 3T3 cells, elicited significant dose dependent increases of similar magnitude in [3H]thymidine incorporation over 3 days in serum‐free medium of 39±10% (P<0.01, n=20), 37±8% (P<0.01, n=27) and 41±6% (P<0.01, n=36) respectively.
CCK‐8s and gastrin potentially stimulated mitogenesis (EC50 values 0.12 nM and 3.0 nM respectively), whilst G‐Gly displayed similar efficacy but markedly lower potency. L‐365,260 consistently blocked each peptide. The CCK2 receptor affinity of G‐Gly in GH3 cells was 1.09 μM (1.01;1.17, n=6) and 5.53 μM (3.71;5.99, n=4) in guinea‐pig cortex.
1 μM G‐Gly weakly stimulated Ca2+ increase, eliciting a 104±21% increase over basal Ca2+ levels, and was blocked by 1 μM L‐365,260 whilst CCK‐8s (100 nM) produced a much larger Ca2+ response (331±14%).
Insulin dose dependently enhanced proliferative effects of CCK‐8s with a maximal leftwards shift of the CCK‐8s curve at 100 ng ml−1 (17 nM) (EC50 decreased 500 fold, from 0.1 nM to 0.2 pM; P<0.0001). 10 μg ml−1 insulin was supramaximal reducing the EC50 to 5 pM (P=0.027) whilst 1 ng ml−1 insulin was ineffective. Insulin weakly displaced [125I]BHCCK binding to GH3 CCK2 receptors (IC50 3.6 μM).
Results are consistent with mediation of G‐Gly effects via CCK2 receptors in GH3 cells and reinforce the role of CCK2 receptors in control of cell growth. Effects of insulin in enhancing CCK proliferative potency may suggest that CCK2 and insulin receptors converge on common intracellular targets and indicates that mitogenic stimuli are influenced by the combination of extracellular factors present.

British Journal of Pharmacology (1999) 126, 79–86; doi:10.1038/sj.bjp.0702271
Nitric oxide limits the eicosanoid‐dependent bronchoconstriction and hypotension induced by endothelin‐1 in the guinea‐pig
Authors: Lewis Karina , Cadieux Alain , Rae Giles A , Gratton Jean‐Philippe , D'Orléans‐Juste Pedro 
Published: January 2005

This study attempts to investigate if endogenous nitric oxide (NO) can modulate the eicosanoid‐releasing properties of intravenously administered endothelin‐1 (ET‐1) in the pulmonary and circulatory systems in the guinea‐pig.
The nitric oxide synthase blocker Nω‐nitro‐L‐arginine methyl ester (L‐NAME; 300 μM; 30 min infusion) potentiated, in an L‐arginine sensitive fashion, the release of thromboxane A2 (TxA2) stimulated by ET‐1, the selective ETB receptor agonist IRL 1620 (Suc‐[Glu9,Ala11,15]‐ET‐1(8–21)) or bradykinin (BK) (5, 50 and 50 nM, respectively, 3 min infusion) in guinea‐pig isolated and perfused lungs.
In anaesthetized and ventilated guinea‐pigs intravenous injection of ET‐1 (0.1–1.0 nmol kg−1), IRL 1620 (0.2–1.6 nmol kg−1), BK (1.0–10.0 nmol kg−1) or U 46619 (0.2–5.7 nmol kg−1) each induced dose‐dependent increases in pulmonary insufflation pressure (PIP). Pretreatment with L‐NAME (5 mg kg−1) did not change basal PIP, but increased, in L‐arginine sensitive manner, the magnitude of the PIP increases (in both amplitude and duration) triggered by each of the peptides (at 0.25, 0.4 and 1.0 nmol kg−1, respectively), without modifying bronchoconstriction caused by U 46619 (0.57 nmol kg−1).
The increases in PIP induced by ET‐1, IRL 1620 (0.25 and 0.4 nmol kg−1, respectively) or U 46619 (0.57 nmol kg−1) were accompanied by rapid and transient increases of mean arterial blood pressure (MAP). Pretreatment with L‐NAME (5 mg kg−1; i.v. raised basal MAP persistently and, under this condition, subsequent administration of ET‐1 or IRL 1620, but not of U‐46619, induced hypotensive responses which were prevented by pretreatment with the cyclo‐oxygenase inhibitor indomethacin.
Thus, endogenous NO appears to modulate ET‐1‐induced bronchoconstriction and pressor effects in the guinea‐pig by limiting the peptide's ability to induce, possibly via ETB receptors, the release of TxA2 in the lungs and of vasodilatory prostanoids in the systemic circulation. Furthermore, it would seem that these eicosanoid‐dependent actions of ET‐1 in the pulmonary system and on systemic arterial resistance in this species are physiologically dissociated.

British Journal of Pharmacology (1999) 126, 93–102; doi:10.1038/sj.bjp.0702274
Effects of pyrogallol, hydroquinone and duroquinone on responses to nitrergic nerve stimulation and NO in the rat anococcygeus muscle
Authors: La Mylinh , Rand Michael J 
Published: January 2005

The hypothesis that endogenous superoxide dismutase (SOD) protects the nitrergic transmitter from inactivation by superoxide and that this explains the lack of sensitivity of the transmitter to superoxide generators was tested in the rat isolated anococcygeus muscle.
Responses to nitrergic nerve stimulation or to NO were not significantly affected by exogenous SOD or by the Cu/Zn SOD inhibitor diethyldithiocarbamic acid (DETCA).
Hydroquinone produced a concentration‐dependent reduction of responses to NO with an IC50 of 27 μM, and higher concentrations reduced relaxant responses to nitrergic nerve stimulation with an IC50 of 612 μM. The effects of hydroquinone were only slightly reversed by SOD, so it does not appear to be acting as a superoxide generator.
Pyrogallol produced a concentration‐dependent reduction in responses to NO with an IC50 value of 39 μM and this effect was reversed by SOD (100–1000 u ml−1). Pyrogallol did not affect responses to nitrergic nerve stimulation. Treatment with DETCA did not alter the differentiating action of pyrogallol.
Duroquinone produced a concentration‐dependent reduction of relaxations to NO with an IC50 value of 240 μM and 100 μM slightly decreased nitrergic relaxations. After treatment with DETCA, duroquinone produced greater reductions of relaxant responses to NO and to nitrergic stimulation, the IC50 values being 8.5 μM for NO and 40 μM for nitrergic nerve stimulation: these reductions were reversed by SOD.
The findings do not support the hypothesis that the presence of Cu/Zn SOD explains the greater susceptibility of NO than the nitrergic transmitter to the superoxide generator pyrogallol, but suggest that it may play a role in the effects of duroquinone.

British Journal of Pharmacology (1999) 126, 342–348; doi:10.1038/sj.bjp.0702277
Transcriptional down‐regulation of the rabbit pulmonary artery endothelin B receptor during phenotypic modulation
Authors: Owe‐Young R , Schyvens C G , Qasabian R A , Conigrave A D , Macdonald P S , Williamson D J 
Published: January 2005

We confirmed that endothelium‐independent contraction of the rabbit pulmonary artery (RPA) is mediated through both an endothelin A (ETAR) and endothelin B (ETB2R) receptor.
The response of endothelium‐denuded RPA rings to endothelin‐1 (ET‐1, pD2=7.84±0.03) was only partially inhibited by BQ123 (10 μM), an ETAR antagonist.
Pretreatment with 1 nM sarafotoxin S6c (S6c), an ETBR agonist, desensitized the ETB2R and significantly attenuated the response to ET‐3 (pD2=7.40±0.02 before, <6.50 after S6c).
Pretreatment with S6c had little effect on the response to ET‐1, but BQ123 (10 μM) caused a parallel shift to the right of the residual ETAR‐mediated response to ET‐1 (pD2=7.84±0.03 before S6c, 7.93±0.03 after S6c, 6.81±0.05 after BQ123).
Binding of radiolabelled ET‐1 to early passage cultures of RPA vascular smooth muscle cells (VSMC) displayed two patterns of competitive displacement characteristic of the ETAR (BQ123 pIC50=8.73±0.05) or ETB2R (S6c pIC50=10.15).
Competitive displacement experiments using membranes from late passage VSMC confirmed only the presence of the ETAR (ET‐1 pIC50=9.3, BQ123 pIC50=8.0, S6c pIC50<6.0).
The ETAR was functionally active and coupled to rises in intracellular calcium which exhibited prolonged homologous desensitization.
Using a reverse transcriptase polymerase chain reaction for the rabbit ETB2R, we demonstrated the absence of mRNA expression in phenotypically modified VSMC.
We conclude that the ETB2R expressed by VSMC which mediates contraction of RPA is rapidly down‐regulated at the transcriptional level during phenotypic modulation in vitro.

British Journal of Pharmacology (1999) 126, 103–110; doi:10.1038/sj.bjp.0702280
Effects of phrixotoxins on the Kv4 family of potassium channels and implications for the role of Ito1 in cardiac electrogenesis
Authors: Diochot Sylvie , Drici Milou‐Daniel , Moinier Danielle , Fink Michel , Lazdunski Michel 
Published: January 2005

In the present study, two new peptides, phrixotoxins PaTx1 and PaTx2 (29–31 amino acids), which potently block A‐type potassium currents, have been purified from the venom of the tarantula Phrixotrichus auratus.
Phrixotoxins specifically block Kv4.3 and Kv4.2 currents that underlie Ito1, with an 5<IC50<70 nM, by altering the gating properties of these channels.
Neither are the Shaker (Kv1), Shab (Kv2) and Shaw (Kv3) subfamilies of currents, nor HERG, KvLQT1/IsK, inhibited by phrixotoxins which appear specific of the Shal (Kv4) subfamily of currents and also block Ito1 in isolated murine cardiomyocytes.
In order to evaluate the physiological consequences of the Ito1 inhibition, mice were injected intravenously with PaTx1, which resulted in numerous transient cardiac adverse reactions including the occurrence of premature ventricular beats, ventricular tachycardia and different degrees of atrio‐ventricular block.
The analysis of the mouse electrocardiogram showed a dose‐dependent prolongation of the QT interval, chosen as a surrogate marker for their ventricular repolarization, from 249±11 to 265±8 ms (P<0.05).
It was concluded that phrixotoxins, are new and specific blockers of Kv4.3 and Kv4.2 potassium currents, and hence of Ito1 that will enable further studies of Kv4.2 and Kv4.3 channel and/or Ito1 expression.

British Journal of Pharmacology (1999) 126, 251–263; doi:10.1038/sj.bjp.0702283
The effects of specific antibody fragments on the ‘irreversible’ neurotoxicity induced by Brown snake (Pseudonaja) venom
Authors: Jones R G A , Lee L , Landon J 
Published: January 2005

Brown snake (Pseudonaja) venom has been reported to produce ‘irreversible’ post synaptic neurotoxicity (Harris & Maltin, 1981; Barnett et al., 1980).
A murine phrenic nerve/diaphragm preparation was used to study the neurotoxic effects of this venom and pre‐ and post‐synaptic components were distinguished by varying the temperature and frequency of nerve stimulation. There were no myotoxic effects and the neurotoxicity proved irreversible by washing alone.
The effects of a new Fab based ovine antivenom have been investigated and proved able to produce a complete, rapid (<1 h) reversal of the neurotoxicity induced by Brown snake venom. A reversal was also possible when the antivenom addition was delayed for a further 60 min.
We believe that this is the first time such a reversal has been shown.

British Journal of Pharmacology (1999) 126, 581–584; doi:10.1038/sj.bjp.0702286
Neuroregulation by vasoactive intestinal peptide (VIP) of mucus secretion in ferret trachea: activation of BKCa channels and inhibition of neurotransmitter release
Authors: Liu Yu‐Chih , Patel Hema J , Khawaja Aamir M , Belvisi Maria G , Rogers Duncan F 
Published: January 2005

The aims of this study were to determine: (1) whether vasoactive intestinal peptide (VIP) regulates cholinergic and ‘sensory‐efferent’ (tachykininergic) 35SO4 labelled mucus output in ferret trachea in vitro, using a VIP antibody, (2) the class of potassium (K+) channel involved in VIP‐regulation of cholinergic neural secretion using glibenclamide (an ATP‐sensitive K+ (KATP) channel inhibitor), iberiotoxin (a large conductance calcium activated K+ (BKca) channel blocker), and apamin (a small conductance Kca (SKca) channel blocker), and (3) the effect of VIP on cholinergic neurotransmission using [3H]‐choline overflow as a marker for acetylcholine (ACh) release.
Exogenous VIP (1 and 10 μM) alone increased 35SO4 output by up to 53% above baseline, but suppressed (by up to 80% at 1 μM) cholinergic and tachykininergic neural secretion without altering secretion induced by ACh or substance P (1 μM each). Endogenous VIP accounted for the minor increase in non‐adrenergic, non‐cholinergic (NANC), non‐tachykininergic neural secretion, which was compatible with the secretory response of exogenous VIP.
Iberiotoxin (3 μM), but not apamin (1 μM) or glibenclamide (0.1 μM), reversed the inhibition by VIP (10 nM) of cholinergic neural secretion.
Both endogenous VIP (by use of the VIP antibody; 1 : 500 dilution) and exogenous VIP (0.1 μM), the latter by 34%, inhibited ACh release from cholinergic nerve terminals and this suppression was completely reversed by iberiotoxin (0.1 μM).
We conclude that, in ferret trachea in vitro, endogenous VIP has dual activity whereby its small direct stimulatory action on mucus secretion is secondary to its marked regulation of cholinergic and tachykininergic neurogenic mucus secretion. Regulation is via inhibition of neurotransmitter release, consequent upon opening of BKCa channels. In the context of neurogenic mucus secretion, we propose that VIP joins NO as a neurotransmitter of i‐NANC nerves in ferret trachea.

British Journal of Pharmacology (1999) 126, 147–158; doi:10.1038/sj.bjp.0702288
Effect of acute and long‐term treatment with 17‐β‐estradiol on the vasomotor responses in the rat aorta
Authors: Andersen Heidi L , Weis Jan U , Fjalland Bjarne , Korsgaard Niels 
Published: January 2005

This study sought to evaluate whether the effects of acute and long‐term treatment with 17‐β‐estradiol on the vasomotor responses in rat aortic rings are mediated through the same mechanism.
Ovariectomized rats were treated daily with either 17‐β‐estradiol‐3‐benzoate (100 μg kg−1) or vehicle for 1 week.
The effect of long‐term 17‐β‐estradiol treatment on the responses to cumulative doses of phenylephrine, 5‐HT, calcium, potassium and 17‐β‐estradiol was determined in aortic rings. In the same rings, the effect of acute exposure to 17‐β‐estradiol (5 and 10 μM) on the dose response curves for phenylephrine, 5‐HT, calcium, potassium and acetylcholine were estimated. The measurements were made in rings with and without intact endothelium. The tone‐related basal release of nitric oxide (NO) was measured in rings with intact endothelium.
Long‐term 17‐β‐estradiol treatment reduced the maximum developed contraction to all contracting agents studied. This effect was abolished in endothelium denuded vessels. Acute 17‐β‐estradiol treatment also reduced maximal contraction. This effect, however, was independent of the endothelium.
Long‐term 17‐β‐estradiol treatment significantly increased the ability of the rings to dilate in response to acetylcholine whereas acute exposure to 17‐β‐estradiol had no effect. The tone‐related release of NO was significantly increased after long‐term exposure to 17‐β‐estradiol.
In conclusion, this study indicate that the acute and long‐term effects of 17‐β‐estradiol in the rat aorta are mediated through different mechanisms. The long‐term effect is mediated through the endothelium most likely by increasing NO release. In contrast, the acute effect of 17‐β‐estradiol seems to be through an effect on the vascular smooth muscle cells.

British Journal of Pharmacology (1999) 126, 159–168; doi:10.1038/sj.bjp.0702289