bluuebunny/crossref_metadata_2025_split huggingface dataset:
Platelets, neutrophils, and vasoconstriction after arterial injury by angioplasty in pigs: effects of MK‐886, a leukotriene biosynthesis inhibitor
Authors: Provost Patrick , Borgeat Pierre , Merhi Yahye 
Published: January 2005

Leukotrienes constitute a class of potent bioactive mediators known to play a pivotal role in inflammation. Since their biosynthesis has been shown to be enhanced by platelet‐neutrophil interactions, leukotrienes may be involved in these interactions and the arterial response to injury. Therefore, we investigated the effects of the selective leukotriene biosynthesis inhibitor 3‐[1‐(4‐chlorobenzyl)‐3‐t‐butyl‐thio‐5‐isopropylindol‐2‐yl]‐2,2‐dimethylpropanoic acid (MK‐886) on the acute thrombotic and vasomotor responses after arterial injury by angioplasty.
Carotid arterial injury was produced by balloon dilatation in control (molecusol vehicle; n=10) and treated (MK‐886, 10 mg kg−1, i.v.; n=9) pigs. The acute thrombotic reaction following deep arterial wall injury was quantified with 51Cr labelled platelets and 111In labelled neutrophils, and the vasomotor response was determined angiographically.
Platelet deposition at the site of deep arterial wall injury averaged 56.4±11.0×106 platelets cm−2 in the control group, and was significantly reduced to 18.2±3.8×106 platelets cm−2 (P<0.005) by treatment with MK‐886. Neutrophil deposition was also decreased by MK‐886, from 242.8±36.8 to 120.9±20.3×103 neutrophils cm−2 (P<0.01). MK‐886‐treated animals had a significant decrease in the postangioplasty vasoconstrictive response at the site of endothelial injury distally, from 37.5±3.1% in the control group to 13.5±2.5% (P<0.001).
The effects of MK‐886 were associated with a profound inhibition of ex vivo leukotriene B4 (LTB4) synthesis in blood stimulated by the calcium ionophore A23187 and a significant reduction of neutrophil aggregation in whole blood (P<0.01), whereas neutrophil superoxide anion production, serum thromboxane B2 and platelet aggregation in whole blood were not influenced.
The relevant effects of MK‐886 are primarily related to inhibition of neutrophil function and suggest an important modulatory role for leukotrienes in the pathophysiological response associated with platelet and neutrophil interactions following arterial injury in vivo.

British Journal of Pharmacology (1998) 123, 251–258; doi:10.1038/sj.bjp.0701611
Effect of L‐buthionine‐(S,R)‐sulphoximine, an inhibitor of γ‐glutamylcysteine synthetase on peroxynitrite‐ and endotoxic shock‐induced vascular failure
Authors: Cuzzocrea Salvatore , Zingarelli Basilia , O'Connor Michael , Salzman Andrew L. , Szabó Csaba 
Published: January 2005

Peroxynitrite, a cytotoxic oxidant formed from the reaction of nitric oxide (NO) and superoxide is a mediator of cellular injury in ischaemia/reperfusion injury, shock and inflammation. Here we investigated whether L‐buthionine‐(S,R)‐sulphoximine (BSO), an inhibitor of γ‐glutamylcysteine synthetase, alters endothelial and vascular smooth muscle injury in response to peroxynitrite in vitro and during endotoxic shock in vivo.
In human umbilical vein endothelial cells and in rat aortic smooth muscle cells, BSO (1 mM, for 24 h) enhanced, whereas glutathione (3 mM) or glutathione ethyl ester (3 mM) attenuated the peroxynitrite (100–1000 μM)‐induced suppression of mitochondrial respiration (measured by the conversion of 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) to formazan), formation of nitrotyrosine (detected by Western blotting), protein oxidation (measured by detection of 2,4 dinitrophenylhydrazine‐reactive carbonyls), and DNA single strand breakage and activation of the nuclear enzyme poly (ADP‐ribose) synthetase (PARS) (measured by the incorporation of radiolabelled NAD+ into nuclear proteins and by the alkaline unwinding assay, respectively). Glutathione ethyl ester treatment reduced the BSO‐induced enhancement of peroxynitrite‐induced cytotoxicity.
In rat isolated thoracic aortic rings, BSO treatment (in vivo, at 1 g kg−1 intraperitoneally (i.p.) for 24 h) enhanced, whereas pretreatment with glutathione (in vitro, 3 mM) attenuated the peroxynitrite‐induced reduction of the contractions to noradrenaline, and the peroxynitrite‐induced impairment of the endothelium‐dependent relaxations to acetylcholine.
In BSO‐pretreated rats, treatment with bacterial lipopolysaccharide (LPS, 15 mg kg−1, i.p., for 6 h) caused a more pronounced vascular hyporeactivity and endothelial dysfunction ex vivo. BSO pretreatment also increased the degree of nitrotyrosine staining (detected by imunohistochemistry) in the aorta after LPS treatment.
In conclusion, our results demonstrate that L‐buthionine‐(S,R)‐sulphoximine, an inhibitor of γ‐glutamylcysteine synthetase enhances peroxynitrite‐ and endotoxic shock‐induced vascular failure. Based on these findings, we suggest that endogenous glutathione plays an important protective role against peroxynitrite‐ and LPS‐induced vascular injury.

British Journal of Pharmacology (1998) 123, 525–537; doi:10.1038/sj.bjp.0701612
Pharmacology of (S)‐homoquisqualic acid and (S)‐2‐amino‐5‐phosphonopentanoic acid [(S)‐AP5] at cloned metabotropic glutamate receptors
Authors: Bräuner‐Osborne Hans , Krogsgaard‐Larsen Povl 
Published: January 2005

In this study we have determined the pharmacological profile of (S)‐quisqualic acid, (S)‐2‐amino‐4‐phosphonobutyric acid ((S)‐AP4) and their higher homologues (S)‐homoquisqualic acid, (S)‐2‐amino‐5‐phosphonopentanoic acid ((S)‐AP5), respectively, and (R)‐AP5 at subtypes of metabotropic (S)‐glutamic acid (mGlu) receptors expressed in Chinese hamster ovary cells.
(S)‐Quisqualic acid was a potent mGlu1/mGlu5 agonist (EC50 values of 1.1 μM and 0.055 μM, respectively) showing no activity at mGlu2 and weak agonism at mGlu4 (EC50∼1000 μM).
(S)‐Homoquisqualic acid displayed competitive antagonism at mGlu1 (KB=184 μM) and full agonism at mGlu5 (EC50=36 μM) and mGlu2 (EC50=23 μM), but was inactive at mGlu4.
(S)‐AP4 was a potent and selective mGlu4 agonist (EC50=0.91 μM) being inactive at mGlu1, mGlu2 and mGlu5 both as agonist and antagonist.
(S)‐AP5 displayed very weak agonist activity at mGlu4. At the mGlu2 receptor subtype (S)‐AP5 acted as a competitive antagonist (KB=205 μM), whereas the compound was inactive at mGlu1 and mGlu5. (R)‐AP5 was inactive at all mGlu receptor subtypes tested both as agonist and antagonist.
These studies demonstrate that incorporation of an additional carbon atom into the backbone of (S)‐glutamic acid and its analogues, to give the corresponding homologues, and replacement of the terminal carboxyl groups by isosteric acidic groups have profound effects on the pharmacological profiles at mGlu receptor subtypes. Furthermore, (S)‐homoquisqualic acid has been shown to be a potentially useful tool for differentiating mGlu1 and mGlu5.

British Journal of Pharmacology (1998) 123, 269–274; doi:10.1038/sj.bjp.0701616
Role of kinins in the endothelial protective effect of ischaemic preconditioning
Authors: Bouchard Jean‐François , Chouinard Jérôme , Lamontagne Daniel 
Published: January 2005

The aim of this study was to assess whether the protective effect of ischaemic preconditioning on endothelial function in coronary arteries of the rat involves kinins.
Isolated hearts of the rat were exposed to a 30‐min low‐flow ischaemia (flow rate of 1 ml min−1) followed by 20‐min reperfusion, after which coronaries were precontracted with 0.1 μM U‐46619, and the response to the endothelium‐dependent vasodilator, 5‐hydroxytryptamine (5‐HT, 10 μM), compared to that of the endothelium‐independent vasodilator, sodium nitroprusside (SNP, 3 μM).
In untreated hearts, ischaemia‐reperfusion diminished selectively 5‐HT‐induced vasodilatation, compared with time‐matched sham hearts. The vasodilatation to SNP was unaffected after ischaemia‐reperfusion. Preconditioning (5 min of zero‐flow ischaemia followed by 10 min reperfusion) in untreated hearts preserved the vasodilatation produced by 5‐HT.
Blockade of B1 and B2 receptors with either 3 nM [Lys0, Leu8, des‐Arg9]‐bradykinin (LLDBK) or 10 nM Hoe 140 (icatibant), respectively, (started 15 min before ischaemic preconditioning or a corresponding sham period and stopped just before the 20‐min reperfusion period) had no effect on the vasodilatation produced by either 5‐HT or SNP in sham hearts. Pretreatment with Hoe 140 did not block the protective effect of ischaemic preconditioning on the 5‐HT vasodilatation. In contrast, LLDBK halved the protective effect of ischaemic preconditioning on endothelium‐dependent vasodilatation.
Perfusion with either bradykinin or des‐Arg9‐bradykinin (1 nM) 30 min before and lasting throughout the ischaemia protected the endothelium.
In conclusion, ischaemic preconditioning affords protection to the endothelial function in coronary resistance arteries of the rat partly by activation of B1 receptors. Although exogenous BK perfusion can protect the endothelium, B2 receptors do not play an important role in this protection in the rat isolated heart.

British Journal of Pharmacology (1998) 123, 413–420; doi:10.1038/sj.bjp.0701619
Effects of the enantiomers of R,S‐salbutamol on incompletely fused tetanic contractions of slow‐ and fast‐twitch skeletal muscles of the guinea‐pig
Authors: Prior Chris , Leonard Maureen B. , McCullough John R. 
Published: January 2005

The effects of racemic R,S‐salbutamol, and its individual enantiomers have been studied on incompletely fused (sub‐tetanic) contractile responses of fast‐ and slow‐contracting isolated skeletal muscles of the guinea‐pig.
R,S‐salbutamol (2–4 μM) decreased the peak force of sub‐tetani in the slow‐contracting soleus muscle and increased the peak force of sub‐tetani in the fast‐contracting peroneus longus muscle. It also increased the force of the first twitch of sub‐tetani in both muscles. The decrease in the peak force of sub‐tetani in the soleus muscle was due to defusion of the individual twitches caused by a shortening of their time course.
The effects of 4 μM of the racemate on both fast‐ and slow‐contracting muscles were mimicked by 2 μM R‐salbutamol (levalbuterol). However, 2 μM S‐salbutamol was devoid of activity in both muscles.
We concluded that all the effects of R,S‐salbutamol on guinea‐pig skeletal muscles are due to the activity of the R‐enantiomer. Thus there is a common enantiomeric profile for the skeletal muscle and bronchorelaxant activity of the compound.

British Journal of Pharmacology (1998) 123, 558–564; doi:10.1038/sj.bjp.0701627
The inhibitory effect of propranolol on ATP‐sensitive potassium channels in neonatal rat heart
Authors: Xie Lai‐Hua , Takano Makoto , Noma Akinori 
Published: January 2005

Whole cell and single channel recordings of ATP‐sensitive K+ current (IK,ATP) were carried out in ventricular myocytes isolated from neonatal rat hearts.
(±)‐Propranolol, a commonly used β‐blocker, inhibited the whole cell IK,ATP in a concentration‐dependent manner with a half‐maximal concentration (IC50) of 6.7±1.4 μM, whereas it blocked the inward rectifier K+ current (IK,1) only at much higher concentrations (IC50=102.4±20.2 μM). The inhibition was time‐ and voltage‐independent.
In the outside‐out patch configuration, (±)‐propranolol inhibited IK,ATP (IC50=9.8±2.9 μM) by decreasing the open probability of the channel without inducing additional noise in the open‐channel current or a decrease of single channel conductance. The single channel current of IK,1 was also blocked by (±)‐propranolol in the same way as IK,ATP.
(+)‐Propranolol, an optic isomer having no β‐blocking effect, inhibited IK,ATP (IC50=5.8±1.0 μM), whilst atenolol, a selective β1‐blocker had no effect. Neither GDPβS (1 mM) nor GTPγS (200 μM) included in the pipette solution modulated the inhibitory effect of (±)‐propranolol.
We concluded that the inhibitory effect of (±)‐propranolol was not via the β‐adrenergic signal transduction pathway, but by direct inhibition of IK,ATP channels.

British Journal of Pharmacology (1998) 123, 599–604; doi:10.1038/sj.bjp.0701630
Insulin‐releasing action of the novel antidiabetic agent BTS 67 582
Authors: McClenaghan Neville H. , Flatt Peter R. , Bailey Clifford J. 
Published: January 2005

BTS 67 582 (1,1‐dimethyl‐2‐(2‐morpholinophenyl)guanidine fumarate) is a novel antidiabetic agent with a short‐acting insulin‐releasing effect. This study examined its mode of action in the clonal B‐cell line BRIN‐BD11.
BTS 67 582 increased insulin release from BRIN‐BD11 cells in a concentration‐dependent manner (10−8 to 10−4 M) at both non‐stimulating (1.1 mM) and stimulating (16.7 mM) concentrations of glucose.
BTS 67 582 (10−4 M) potentiated the insulin‐releasing effect of a depolarizing concentration of K+ (30 mM), whereas the K+ channel openers pinacidil (400 μM) and diazoxide (300 μM) inhibited BTS 67 582‐induced release.
Suppression of Ca+ channel activity with verapamil (20 μM) reduced the insulin‐releasing effect of BTS 67 582 (10−4 M).
BTS 67 582 (10−4 M) potentiated insulin release induced by amino acids (10 mM), and enhanced the combined stimulant effects of glucose plus either the fatty acid palmitate (10 mM), or agents which raise intracellular cyclic AMP concentrations (25 μM forskolin and 1 mM isobutylmethylxanthine), or the cholinoceptor agonist carbachol (100 μM).
Inhibition of glucose‐stimulated insulin release by adrenaline or noradrenaline (10 μM) was partially reversed by BTS 67 582 (10−4 M).
These data suggest that the insulin‐releasing effect of BTS 67 582 involves regulation of ATP‐sensitive K+ channel activity and Ca2+ influx, and that the drug augments the stimulant effects of nutrient insulin secretagogues and agents which enhance adenylate cyclase and phospholipase C. BTS 67 582 may also exert insulin‐releasing effects independently of ATP‐sensitive K+ channel activity.

British Journal of Pharmacology (1998) 123, 400–404; doi:10.1038/sj.bjp.0701631
Ipriflavone as an inhibitor of human cytochrome P450 enzymes
Authors: Monostory Katalin , Vereczkey László , Lévai Ferenc , Szatmári István 
Published: January 2005

Reduction of theophylline metabolism and elimination were observed in a theophylline‐treated patient during ipriflavone administration. After withdrawal of ipriflavone, the serum theophylline level decreased to an extent similar to that found before administration of ipriflavone. The effects of ipriflavone and its major metabolites 7‐hydroxy‐isoflavone and 7‐(1‐carboxy‐ethoxy)‐isoflavone on cytochrome P450 activities were studied in vitro in human liver microsomes from three donors.
Ipriflavone and 7‐hydroxy‐isoflavone competitively inhibited phenacetin O‐deethylase and tolbutamide hydroxylase activity. The parent compound and its dealkylated metabolite were strong inhibitors exhibiting Ki values around 10–20 μM, while 7‐(1‐carboxy‐ethoxy)‐isoflavone had no effect on the cytochrome P450 activities investigated. 7‐Hydroxy‐isoflavone is the only one that influenced nifedipine oxidase activity. It competitively inhibited this activity with a Ki value of 129.5 μM.
The steady state concentrations of ipriflavone and 7‐hydroxy‐isoflavone in plasma of patients receiving 3×200 mg daily doses of ipriflavone for 48 weeks were found to be 0.33±0.32 μM and 1.44±0.77 μM, respectively.
The results indicate that the decrease in theophylline metabolism observed in a patient treated with ipriflavone may be due to a competitive interaction of ipriflavone or its metabolite, 7‐hydroxy‐isoflavone with CYP1A2. On the other hand, our in vitro findings predict some more interaction with CYP2C9.

British Journal of Pharmacology (1998) 123, 605–610; doi:10.1038/sj.bjp.0701633
State‐dependent NMDA receptor antagonism by Ro 8‐4304, a novel NR2B selective, non‐competitive, voltage‐independent antagonist
Authors: Kew James N C. , Trube Gerhard , Kemp John A. 
Published: January 2005

Subunit‐selective blockade of N‐methyl‐D‐aspartate (NMDA) receptors provides a potentially attractive strategy for neuroprotection in the absence of undesirable side effects. Here, we describe a novel NR2B‐selective NMDA antagonist, 4‐{3‐[4‐(4‐fluoro‐phenyl)‐3,6‐dihydro‐2H‐pyridin‐1‐yl]‐2‐hydroxy‐propoxy}‐benzamide (Ro 8‐4304), which exhibits >100 fold higher affinity for recombinant NR1001/NR2B than NR1001/NR2A receptors.
Ro 8‐4304 is a voltage‐independent, non‐competitive antagonist of NMDA receptors in rat cultured cortical neurones and exhibits a state‐dependent mode of action similar to that described for ifenprodil.
The apparent affinity of Ro 8‐4304 for the NMDA receptor increased in an NMDA concentration‐dependent manner so that Ro 8‐4304 inhibited 10 and 100 μM NMDA responses with IC50s of 2.3 and 0.36 μM, respectively. Currents elicited by 1 μM NMDA were slightly potentiated in the presence of 10 μM Ro 8‐4304, and Ro 8‐4304 binding slowed the rate of glutamate dissociation from NMDA receptors.
These results were predicted by a reaction scheme in which Ro 8‐4304 exhibits a 14 and 23 fold higher affinity for the activated and desensitized states of the NMDA receptor, respectively, relative to the agonist‐unbound resting state. Additionally, Ro 8‐4304 binding resulted in a 3–4 fold increase in receptor affinity for glutamate site agonists.
Surprisingly, whilst exhibiting a similar affinity for NR2B‐containing NMDA receptors as ifenprodil, Ro 8‐4304 exhibited markedly faster kinetics of binding and unbinding to the NMDA receptor. This spectrum of kinetic behaviour reveals a further important feature of this emerging class of NR2B‐selective compounds.

British Journal of Pharmacology (1998) 123, 463–472; doi:10.1038/sj.bjp.0701634
Cyclothiazide and AMPA receptor desensitization: analyses from studies of AMPA‐induced release of [3H]‐noradrenaline from hippocampal slices
Authors: Cowen Michael S. , Beart Philip M. 
Published: January 2005

Responses in brain produced by the activation of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA) subtype of ionotropic receptor for L‐glutamate are often rapidly desensitizing. AMPA‐induced desensitization and its characteristics, and the potentiating effect of cyclothiazide were investigated in vitro by analysing AMPA‐induced release of [3H]‐noradrenaline from prisms of rat hippocampus.
AMPA (1–1000 μM) stimulated the release of [3H]‐noradrenaline in a concentration‐dependent manner that was both calcium‐dependent and tetrodotoxin‐sensitive, and attenuated by the AMPA‐selective antagonists, NBQX (1 and 10 μM), LY 293558 (1 and 10 μM) and GYKI 52466 (10 and 30 μM).
By use of an experimental procedure with consecutive applications of AMPA (100 μM, 28 min apart), the second response was reduced, indicative of receptor desensitization, and was reversed by cyclothiazide in a concentration‐dependent manner (1–300 μM). The concentration‐response curve for AMPA‐induced release of [3H]‐noradrenaline was shifted leftwards, but the reversal by cyclothiazide of the desensitized response was partial and failed to reach the maximal response of the first stimulus.
Observations made with various schedules of cyclothiazide application indicated that the initial AMPA‐evoked response was already partially desensitized (150% potentiation by 100 μM cyclothiazide) and that the desensitization was not likely to be due to a time‐dependent diminution and was long‐lasting (second application of cyclothiazide was ineffective).
Co‐application of a number of drugs with actions on second messenger systems, in association with the second AMPA stimulus, revealed significant potentiation of the AMPA‐induced release of [3H]‐noradrenaline: forskolin (10 μM, +78%), Rp‐cAMPS (100 μM, +65%), Ro 31‐8220 (10 μM, + 163%) and thapsigargin (100 μM, +161%).
The AMPA receptor‐mediated response regulating the release of [3H]‐noradrenaline from rat hippocampal slices was desensitized and cyclothiazide acted to reverse partially the desensitization in a concentration‐dependent manner. Since the time‐course of desensitization was longer lasting than that noted in previous electrophysiological studies, multiple events may be involved in the down‐regulation of AMPA receptor activity including receptor phosphorylation and depletion of intracellular Ca2+ stores.

British Journal of Pharmacology (1998) 123, 473–480; doi:10.1038/sj.bjp.0701638
Transition of functional innervation in the developing porcine airway from nitrergic to catecholaminergic
Authors: Connellan D R. , Mitchell H W. 
Published: January 2005

We determined the distribution and chemical nature of the inhibitory neurotransmitter(s) to the airway smooth muscle (ASM) before and after birth.
Relaxation responses to electrical field stimulation (EFS) were studied in isovolumic bronchial segments from foetal (approximately 100/115 days gestation) and adult (25 kg) pigs, and in isovolumic tracheal segments from the foetus, and tracheal smooth muscle strips from the adult pig. Preparations were conditioned in low doses of atropine (10−7 M) to reduce the effects of excitatory neurotransmission and then exposed to carbachol to produce submaximal muscle tone. Some studies were also carried out on bronchial segments from 4 week old pigs.
EFS (65 V, 2 ms, 5–20 Hz for 5 s) produced a TTX‐sensitive relaxation in epithelium‐intact and epithelium‐denuded preparations. In foetal bronchial and tracheal preparations, EFS‐induced relaxation was strongly inhibited by NG‐nitro‐L‐arginine (L‐NOARG, 10−6 to 10−4 M; P<0.01–0.001). However, in the adult, only relaxations of the trachea were inhibited by L‐NOARG; bronchi were resistant to L‐NOARG and also to N‐nitro‐L‐arginine methyl ester (L‐NAME, 10−4 M). The inhibitory actions of L‐NOARG (10−6 to 10−4 M) were substantially reversed by 10−2 M L‐arginine. Experiments with bronchial segments from 4 week old pigs showed partial inhibition of relaxations by L‐NOARG.
The L‐NOARG‐insensitive relaxations recorded in the adult bronchus were blocked by propranolol (10−6 M).
The onset of relaxation to EFS was more prompt and the rate of relaxation more rapid in foetal bronchi than in adult bronchi (P<0.0005). Maximum relaxation and recovery times were the same.
Foetal and adult bronchi were relaxed by sodium nitroprusside (SNP) with similar sensitivity and maximum effect. The rate of relaxation to SNP was not different in the two ages.
In the absence of atropine and carbachol, excitatory cholinergic responses to EFS (65 V, 2 ms, 5 Hz for 20 s) were not altered by L‐NOARG (10−4 M) or L‐NAME (10−4 M) in the adult bronchus but were modestly increased by L‐NOARG in the foetal bronchus (P<0.01).
The tracheobronchial tree appears functionally innervated by nitrergic input to the smooth muscle before birth. However, at or after 4 weeks of age the inhibitory neural input to the bronchi is catecholaminergic, but it remains nitrergic in the trachea. There is also a weak nitrergic pre‐ or postsynaptic inhibition of the effects of cholinergic neurotransmission in the foetal bronchus but not in the adult.

British Journal of Pharmacology (1998) 123, 712–718; doi:10.1038/sj.bjp.0701641