bluuebunny/crossref_metadata_2025_split huggingface dataset:
Histamine‐induced inhibition of leukotriene biosynthesis in human neutrophils: involvement of the H2 receptor and cAMP
Authors: Flamand Nicolas , Plante Hendrick , Picard Serge , Laviolette Michel , Borgeat Pierre 
Published: February 2004

Histamine is generally regarded as a pro‐inflammatory mediator in diseases such as allergy and asthma. A growing number of studies, however, suggest that this autacoid is also involved in the downregulation of human polymorphonuclear leukocyte (PMN) functions and inflammatory responses through activation of the Gs‐coupled histamine H2 receptor.
We report here that histamine inhibits thapsigargin‐ and ligand (PAF and fMLP)‐induced leukotriene (LT) biosynthesis in human PMN in a dose‐dependent manner.
The suppressive effect of histamine on LT biosynthesis was abrogated by the histamine H2 receptor antagonists cimetidine, ranitidine, and tiotidine. In contrast, the histamine H1, H3, and H4 receptor antagonists used in this study were ineffective in counteracting the inhibitory effect of histamine on the biosynthesis of LT in activated human PMN.
The inhibition of LT biosynthesis by histamine was characterized by decreased arachidonic acid release and 5‐lipoxygenase translocation to the nuclear membrane.
Incubation of PMN with the cAMP‐dependent protein kinase (PKA) inhibitor N‐[2‐(p‐bromocinnamylamino)ethyl]‐5‐isoquinoline‐sulfonamide prevented the inhibitory effect of histamine on LT biosynthesis, suggesting an important role for PKA in this effect of histamine on LT biosynthesis in PMN.
These data provide the first evidences that, similarly to adenosine and prostaglandin E2, histamine is a potent suppressor of LT biosynthesis, and support the concept that histamine may play a dual role in the regulation of inflammation.

British Journal of Pharmacology (2004) 141, 552–561. doi:10.1038/sj.bjp.0705654
Effects of chlorpromazine on excitation–contraction coupling events in fast‐twitch skeletal muscle fibres of the rat
Authors: Wagner R , Fink R H A , Stephenson D G 
Published: February 2004

Single mechanically skinned fibres from the rat extensor digitorum longus muscle, which allow access to intracellular compartments, were used to examine the effects of 0.5–100 μM chlorpromazine hydrochloride (CPZ) on the major steps of the excitation–contraction (E–C) coupling to elucidate the involvement of skeletal muscle in the neuroleptic malignant syndrome (NMS).
At 1 μM, CPZ caused a 20–30% increase in the force response induced by t‐system depolarisation and a marked increase in the rate of caffeine‐induced SR Ca2+ release. At [CPZ]2.5 μM, there was an initial increase followed by a marked decrease of the t‐system depolarisation‐induced force responses, while the potentiating effect on the caffeine‐induced SR Ca2+ release remained. These effects were reversible.
CPZ had no effect on the maximum Ca2+‐activated force, but caused reversible, concentration‐dependent increases in the Ca2+ sensitivity of the contractile apparatus at [CPZ] 10 μM, with a 50% predicted shift of 0.11 pCa (−log [Ca2+]) units at 82.3 μM CPZ.
CPZ did not alter the rate of SR‐Ca2+ loading at 1 and 10 μM, but reversibly reduced it by ∼40% at 100 μM by reducing the SR Ca2+ pump. Nevertheless, the SR Ca2+ content was greater when fibres became unresponsive to t‐system‐induced depolarisation in the presence than in the absence of 100 μM CPZ.
The results show that CPZ has concentration‐dependent stimulatory and inhibitory effects on various steps of the E–C coupling, which can explain the involvement of skeletal muscle in NMS and reconcile previous divergent data on CPZ effects on muscle.

British Journal of Pharmacology (2004) 141, 624–633. doi:10.1038/sj.bjp.0705655
Studies on the mechanisms of action of picrotoxin, quercetin and pregnanolone at the GABAρ1 receptor
Authors: Goutman Juan D , Calvo Daniel J 
Published: February 2004

The mechanisms of action of antagonists of the γ‐aminobutyric acid C (GABAC) receptor picrotoxin, quercetin and pregnanolone were studied.
Ionic currents (chloride), mediated through human homomeric GABAρ1 receptors expressed in Xenopus oocytes, were recorded by two‐electrode voltage clamp.
Dose–response (D–R) curves and kinetic measurements of GABAρ1 currents were carried out in the presence or absence of antagonists. Use‐dependent actions were also evaluated.
Picrotoxin, quercetin and pregnanolone exerted noncompetitive actions.
IC50 values measured at the EC50 for GABA (1 μM) were as follows: picrotoxin 0.6±0.1 μM (Hill coefficient n=1.0±0.2); quercetin 4.4±0.4 μM (n=1.5±0.2); pregnanolone 2.1±0.5 μM (n=0.8±0.1).
These antagonists produced changes only in the slope of the linear current–voltage relationships, which was indicative of voltage‐independent effects.
The effect of picrotoxin on GABAρ1 currents was use‐dependent, strongly relied on agonist concentration and showed a slow onset and offset. The mechanism was compatible with an allosteric inhibition and receptor activation was a prerequisite for antagonism.
The effect of quercetin was use‐independent, showed relatively fast onset and offset, and resulted in a slowed time course of the GABA‐evoked currents.
The effect of pregnanolone was use‐independent, presented fast onset and a very slow washout, and did not affect current activation.
All the antagonists accelerated the time course of deactivation of the GABAρ1 currents.

British Journal of Pharmacology (2004) 141, 717–727. doi:10.1038/sj.bjp.0705657
Sildenafil (Viagra) reduces arrhythmia severity during ischaemia 24 h after oral administration in dogs
Authors: Nagy Orsolya , Hajnal Ágnes , Parratt James R , Végh Ágnes 
Published: February 2004

Sildenafil (Viagra) prolongs repolarisation in cardiac muscle, an effect that could lead to ventricular fibrillation (VF). Sildenafil (2 mg kg−1) was given by mouth to 12 mongrel dogs and, 24 h later, these dogs were anaesthetised, thoracotomised and subjected to a 25 min occlusion of the anterior descending coronary artery. Haemodynamic parameters were similar in this and the control group, but there were fewer and less serious ventricular arrhythmias during occlusion in the sildenafil group (VF 17 vs 60%; ventricular premature beats 140±52 vs 437±127% and episodes of ventricular tachycardia 4.0±3.2 vs 19.3±7.7%, all P<0.05). However, reperfusion VF and indices of ischaemia severity (epicardial ST‐segment mapping, inhomogeneity) were not modified by the drug. Sildenafil increased the QT interval, especially during ischaemia. Our conclusion is that ischaemia‐induced ventricular arrhythmias are reduced by sildenafil, but this protection is less pronounced than that following cardiac pacing or exercise.British Journal of Pharmacology (2004) 141, 549–551. doi:10.1038/sj.bjp.0705658
Regional haemodynamic effects of cyclosporine A, tacrolimus and sirolimus in conscious rats
Authors: Gardiner S M , March J E , Kemp P A , Fallgren B , Bennett T 
Published: February 2004

The observation that the immunosuppressants, cyclosporine A (CsA) and tacrolimus, have pressor effects, but sirolimus does not, has led to an hypothesis that generalised sympathoexcitation, resulting from inhibition of calcineurin by CsA and tacrolimus underlies their pressor effects, because sirolimus does not inhibit calcineurin. It is unknown if sirolimus has haemodynamic actions not accompanied by a pressor effect, and whether or not the pressor effects of CsA and tacrolimus are accompanied by similar haemodynamic changes. Therefore, the first aim of our studies was to investigate these possibilities in conscious, chronically‐instrumented, male, Sprague‐Dawley rats.
CsA (5.9 mg kg−1 bolus i.v.) caused rapid‐onset, prolonged hypertension, tachycardia and mesenteric vasoconstriction. There was a slower onset renal vasoconstriction, but no significant change in hindquarters vascular conductance; all the effects of CsA were significantly greater than those of vehicle. CsA given by infusion (over 30 min or 2 h) caused changes qualitatively similar to those above. Repeated administration of CsA over 4 days did not enhance its cardiovascular effects.
Pretreatment with the angiotensin (AT1) receptor antagonist, losartan, and the endothelin (ETA and ETB) receptor antagonist, SB 209670, reduced the pressor and mesenteric vasoconstrictor effects of CsA. Additional administration of the α‐adrenoceptor antagonist, phentolamine, completely inhibited the cardiovascular effects of CsA.
Tacrolimus (450 μg kg−1 bolus i.v.) caused similar peak pressor and tachycardic effects to CsA, but these were much slower in onset, and were maximal when there were no significant regional vasoconstrictions, indicating that the pressor effect was probably due to a rise in cardiac output. However, although propranolol reversed the tachycardic effect of tacrolimus, it did not influence the pressor response.
Sirolimus (450 μg kg−1 bolus i.v.) had no tachycardic action, and only a modest, transient pressor effect, accompanied by equally brief reductions in renal, mesenteric, and hindquarters vascular conductances.
The differences between the regional haemodynamic profiles of equipressor doses of CsA and tacrolimus, and the finding that sirolimus has significant cardiovascular actions, indicate that generalised sympathoexcitation, resulting from calcineurin inhibition (with CsA and tacrolimus), is unlikely to be the sole explanation of their pressor effects.

British Journal of Pharmacology (2004) 141, 634–643. doi:10.1038/sj.bjp.0705659
Donepezil modulates nicotinic receptors of substantia nigra dopaminergic neurones
Authors: Angelantonio Silvia Di , Bernardi Giorgio , Mercuri Nicola B 
Published: February 2004

The effects of donepezil, one of the most common cholinesterase inhibitors used for treatment of Alzheimer's disease, were studied on nicotinic receptors (nAChRs)‐mediated postsynaptic currents, in dopaminergic neurons of the substantia nigra pars compacta, using the patch‐clamp recording technique in slice preparations.
Donepezil (10–100 μM) selectively and reversibly depressed nicotine currents, induced by brief puffer pulses, through a glass micropipette positioned above the slice.
The peak amplitude fading of the responses generated by repeated test applications of low doses of nicotine was accelerated by donepezil, while it slowed the recovery of nicotine currents after a large, desensitising, dose of the same agonist.
Donepezil depressed even maximal responses to nicotine, revealing a noncompetitive mechanism of action; moreover, the inhibition of nAChRs was voltage and time independent.
Pretreatment with vesamicol or methamidophos did not prevent the reduction of nicotine‐induced currents. The data indicated direct effect on nAChR, independent from the activity of donepezil as cholinesterase inhibitor.

British Journal of Pharmacology (2004) 141, 644–652. doi:10.1038/sj.bjp.0705660
Role of cyclic GMP on inhibition by nitric oxide donors of human eosinophil chemotaxis in vitro
Authors: Thomazzi Sara M , Moreira Juliana , Marcondes Sisi , Nucci Gilberto De , Antunes Edson 
Published: February 2004

This study was designed to investigate the effects of the nitric oxide (NO) donors sodium nitroprusside (SNP), 3‐morpholinosydnonimine (SIN‐1) and S‐nitroso‐N‐acetylpenicillamine (SNAP) on N‐formyl‐L‐methionyl‐L‐leucyl‐phenylalanine (fMLP, 1 × 10−7 M)‐induced human eosinophil chemotaxis, cyclic guanosine‐3′,5′‐monophosphate (cGMP) levels, protein nitration and cytotoxicity.
Human eosinophils were exposed to SNP, SIN‐1 and SNAP (0.001–1.0 mM) for either short (10 min) or prolonged (90 min) time periods. Exposition of eosinophils with these NO donors significantly inhibited the eosinophil chemotaxis irrespective of whether cells were exposed to these agents for 10 or 90 min. No marked differences were detected among them regarding the profile of chemotaxis inhibition.
Exposition of eosinophils to SNP, SIN‐1 and SNAP (0.001–1.0 mM) markedly elevated the cGMP levels above basal levels, but the 90‐min exposition resulted in significantly higher levels compared with the 10‐min protocols (5.3±0.6 and 2.6±0.2 nM 1.5 × 106 cells−1, respectively). The cGMP levels achieved with SNAP were greater than SNP and SIN‐1.
The NO donors did not induce cell toxicity in any experimental condition used. Additionally, eosinophils exposed to SNP, SIN‐1 and SNAP (1.0 mM each) either for 10 or 90 min did not show any tyrosine nitration in conditions where a strong nitration of bovine serum albumin was observed.
Our findings show that inhibitory effects of fMLP‐induced human eosinophil chemotaxis by NO donors at short or prolonged exposition time were accompanied by significant elevations of cGMP levels. However, additional elevations of cGMP levels do not change the functional profile (chemotaxis inhibition) of stimulated eosinophils.

British Journal of Pharmacology (2004) 141, 653–660. doi:10.1038/sj.bjp.0705661
Neuroprotective effects of M826, a reversible caspase‐3 inhibitor, in the rat malonate model of Huntington's disease
Authors: Toulmond Sylvie , Tang Keith , Bureau Yves , Ashdown Helen , Degen Sarah , O'Donnell Ruth , Tam John , Han Yongxin , Colucci John , Giroux André , Zhu Yanxia , Boucher Mathieu , Pikounis Bill , Xanthoudakis Steven , Roy Sophie , Rigby Michael , Zamboni Robert , Robertson George S , Ng Gordon Y K , Nicholson Donald W , Flückiger Jean‐Pierre 
Published: February 2004

Caspases, key enzymes in the apoptosis pathway, have been detected in the brain of HD patients and in animal models of the disease. In the present study, we investigated the neuroprotective properties of a new, reversible, caspase‐3‐specific inhibitor, M826 (3‐({(2S)‐2‐[5‐tert‐butyl‐3‐{[(4‐methyl‐1,2,5‐oxadiazol‐3‐yl)methyl]amino}‐2‐oxopyrazin‐1(2H)‐yl]butanoyl}amino)‐5‐[hexyl(methyl)amino]‐4‐oxopentanoic acid), in a rat malonate model of HD.
Pharmacokinetic and autoradiography studies after intrastriatal (i.str.) injection of 1.5 nmol of M826 or its tritiated analogue [3H]M826 indicated that the compound diffused within the entire striatum. The elimination half‐life (T1/2) of M826 in the rat striatum was 3 h.
I.str. injection of 1.5 nmol of M826 10 min after malonate infusion induced a significant reduction (66%) in the number of neurones expressing active caspase‐3 in the ipsilateral striatum.
Inhibition of active caspase‐3 translated into a significant but moderate reduction (39%) of the lesion volume, and of cell death (24%), 24 h after injury. The efficacy of M826 at inhibiting cell death was comparable to that of the noncompetitive NMDA receptor antagonist MK801.
These data provide in vivo proof‐of‐concept of the neuroprotective effects of reversible caspase‐3 inhibitors in a model of malonate‐induced striatal injury in the adult rat.

British Journal of Pharmacology (2004) 141, 689–697. doi:10.1038/sj.bjp.0705662
Endothelins contribute towards nociception induced by antigen in ovalbumin‐sensitised mice
Authors: Piovezan Anna P , D'Orléans‐Juste Pedro , Frighetto Monica , Souza Glória E P , Henriques Maria G M O , Rae Giles A 
Published: February 2004

The contribution of endogenous endothelins to nociceptive responses elicited by ovalbumin (OVA) in the hind‐paw of mice sensitised to this antigen (50 μg OVA+5 mg Al(OH)3, s.c., 14 days beforehand) was investigated.
Sensitised mice exhibited greater nocifensive responsiveness to intraplantar (i.pl.) OVA (total licking time over first 30 min: 85.2±14.6 s at 0.3 μg; 152.6±35.6 s at 1 μg) than nonsensitised animals (29.3±7.4 s at 1 μg). Nocifensive responses of sensitised mice to 0.3 μg OVA were inhibited by morphine (3 mg kg−1, s.c.) or local depletion of mast cells (four daily i.pl. injections of compound 48/80).
Pretreatment with i.v. bosentan (mixed ETA/ETB receptor antagonist; 52 μmol kg−1) or A‐122722.5 (selective ETA receptor antagonist; 6 μmol kg−1) reduced OVA‐induced licking from 124.8±20.6 s to 45.7±13.0 s and 64.2±12.1 s, respectively, whereas A‐192621.1 (selective ETB receptor antagonist; 25 μmol kg−1) enhanced them to 259.2±39.6 s.
Local i.pl. pretreatment with BQ‐123 or BQ‐788 (selective ETA or ETB receptor antagonists, respectively, each at 3 nmol) reduced OVA‐induced licking (from 106.2±15.2 to 57.0±9.4 s and from 118.6±10.5 to 76.8±14.7 s, respectively). Sarafotoxin S6c (selective ETB receptor agonist, 30 pmol, i.pl., 30 min after OVA) induced nocifensive responses in OVA‐sensitised, but not in nonsensitised, animals.
Compound 48/80 (0.3 μg, i.pl.) induced nocifensive responses per se and potentiated those induced by i.pl. capsaicin (0.1 μg). Treatment with BQ‐123 (3 nmol, i.pl.) reduced only the hyperalgesic effect of compound 48/80, whereas BQ‐788 (3 nmol) was ineffective.
Thus, immune‐mediated Type I hypersensitivity reactions elicit mast cell‐ and endothelin‐dependent nociception in the mouse hind‐paw, which are mediated locally by both ETA and ETB receptors. The nocifensive response to antigen is amenable to blockade by systemic treatment with dual ETA/ETB or selective ETA receptor antagonists, but is sharply potentiated by systemic selective ETB receptor antagonist treatment. The apparently distinct roles played by ETB receptors in this phenomenon at local and other sites remain to be characterised.

British Journal of Pharmacology (2004) 141, 755–763. doi:10.1038/sj.bjp.0705663
Cyclosporin A enhances colchicine‐induced apoptosis in rat cerebellar granule neurons
Authors: Canudas Anna Maria , Jordà Elvira G , Verdaguer Ester , Jiménez Andrés , Sureda Francesc Xavier , Rimbau Víctor , Camins Antoni , Pallàs Mercè 
Published: February 2004

Cyclosporin A (CsA, 1–50 μM), an immunosuppressive drug with known neurotoxic effects, did not decrease the viability of primary cultures of rat cerebellar granule neurons (CGN) or induce apoptotic features. However, CsA specifically enhanced the cytotoxicity and apoptosis induced by colchicine (1 μM).
Flavopiridol, an inhibitor of cyclin‐dependent kinases (CDKs), prevented the neurotoxic effects of colchicine plus CsA. At 0.1–5 μM, it also showed antiapoptotic effects, as revealed by propidium iodide staining, flow cytometry and counting of cell nuclei.
Roscovitine (25–50 μM), a selective cdk1, 2 and 5 inhibitor, showed an antiapoptotic effect against colchicine‐ and colchicine plus CsA‐induced apoptosis.
CsA increased the expression of cdk5 and cdk5/p25 mediated by colchicine, a CDK involved in neuronal apoptosis. After treatment of CGN with colchicine plus CsA, the changes in the p25/p35 ratio pointed to cdk5 activation.
Immunohistochemical results showed a nuclear localization of cdk5 after neurotoxic treatment, which was prevented by cdk inhibitors. Thus, we propose a new mechanism of modulation of CsA neurotoxicity mediated by cdk5.

British Journal of Pharmacology (2004) 141, 661–669. doi:10.1038/sj.bjp.0705664
Noradrenaline inhibits pacemaker currents through stimulation of β1‐adrenoceptors in cultured interstitial cells of Cajal from murine small intestine
Authors: Jun Jae Yeoul , Choi Seok , Yeum Cheol Ho , Chang In Youb , Park Chan Kuk , Kim Man Yoo , Kong In Deok , So Insuk , Kim Ki Whan , You Ho Jin 
Published: February 2004

Interstitial cells of Cajal (ICCs) are pacemaker cells that activate the periodic spontaneous inward currents (pacemaker currents) responsible for the production of slow waves in gastrointestinal smooth muscle. The effects of noradrenaline on the pacemaker currents in cultured ICCs from murine small intestine were investigated by using whole‐cell patch‐clamp techniques at 30°C.
Under current clamping, ICCs had a mean resting membrane potential of −58±5 mV and produced electrical slow waves. Under voltage clamping, ICCs produced pacemaker currents with a mean amplitude of −410±57 pA and a mean frequency of 16±2 cycles min−1.
Under voltage clamping, noradrenaline inhibited the amplitude and frequency of pacemaker currents and increased resting currents in the outward direction in a dose‐dependent manner. These effects were reduced by intracellular GDPβS.
Noradrenaline‐induced effects were blocked by propranolol (β‐adrenoceptor antagonist). However, neither prazosin (α1‐adrenoceptor antagonist) nor yohimbine (α2‐adrenoceptor antagonist) blocked the noradrenaline‐induced effects. Phenylephrine (α1‐adrenoceptor agonist) had no effect on the pacemaker currents, whereas isoprenaline (β‐adrenoceptor agonist) mimicked the effect of noradrenaline. Atenolol (β1‐adrenoceptor antagonist) blocked the noradrenaline‐induced effects, but butoxamine (β2‐adrenoceptor antagonist) did not. In addition, BRL37344 (β3‐adrenoceptor agonist) had no effect on pacemaker currents.
9‐(Tetrahydro‐2‐furanyl)‐9H‐purine‐6‐amine (SQ‐22536; adenylate cyclase inhibitor) and a myristoylated protein kinase A inhibitor did not inhibit the noradrenaline‐induced effects and 8‐bromo‐cAMP had no effects on pacemaker currents. 8‐Bromo‐cGMP and SNAP inhibited pacemaker currents and these effects of SNAP were blocked by 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ; a guanylate cyclase inhibitor). However, ODQ did not block the noradrenaline‐induced effects.
Neither tetraethylammonium (a voltage‐dependent K+ channel blocker), apamin (a Ca2+‐dependent K+ channel blocker) nor glibenclamide (an ATP‐sensitive K+ channel blocker) blocked the noradrenaline‐induced effects.
The results suggest that noradrenaline‐induced stimulation of β1‐adrenoceptors in the ICCs inhibits pacemaker currents, and that this is mediated by the activation of G‐protein. Neither adenylate cyclase, guanylate cyclase nor a K+ channel‐dependent pathway are involved in this effect of noradrenaline.

British Journal of Pharmacology (2004) 141, 670–677. doi:10.1038/sj.bjp.0705665
Predicting the distribution of four species of raptors (Aves: Accipitridae) in southern Spain: statistical models work better than existing maps
Authors: Bustamante Javier , Seoane Javier 
Published: February 2004

AbstractAim  To test the effectiveness of statistical models based on explanatory environmental variables vs. existing distribution information (maps and breeding atlas), for predicting the distribution of four species of raptors (family Accipitridae): common buzzard Buteo buteo (Linnaeus, 1758), short‐toed eagle Circaetus gallicus (Gmelin, 1788), booted eagle Hieraaetus pennatus (Gmelin, 1788) and black kite Milvus migrans (Boddaert, 1783).Location  Andalusia, southern Spain.Methods  Generalized linear models of 10 × 10 km squares surveyed for the presence/absence of the species by road census. Statistical models use as predictors variables derived from topography, vegetation and land‐use, and the geographical coordinates (to take account of possible spatial trends). Predictions from the models are compared with current distribution maps from the national breeding atlas and leading reference works.Results  The maps derived from statistical models for all four species were more predictive than the previously published range maps and the recent national breeding atlas. The best models incorporated both topographic and vegetation and land‐use variables. Further, in three of the four species the inclusion of spatial coordinates to account for neighbourhood effects improved these models. Models for the common buzzard and black kite were highly predictive and easy to interpret from an ecological point of view, while models for short‐toed eagle and, particularly, booted eagle were not so easy to interpret, but still predicted better than previous distribution information.Main conclusions  It is possible to build accurate predictive models for raptor distribution with a limited field survey using as predictors environmental variables derived from digital maps. These models integrated in a geographical information system produced distribution maps that were more accurate than previously published ones for the study species in the study area. Our study is an example of a methodology that could be used for many taxa and areas to improve unreliable distribution information.