bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential agonist activity of somatostatin and L‐362855 at human recombinant sst4 receptors
Authors: Smalley K S M , Feniuk W , Humphrey P P A 
Published: January 2005

The operational characteristics of somatostatin (SRIF) sst4 receptors are poorly understood. In this study, we have characterized human recombinant sst4 receptors expressed in CHO cells (CHOsst4) by radioligand binding and microphysiometry.
Increasing concentrations SRIF or other SRIF receptor ligands inhibited specific [125I]‐Tyr11‐SRIF binding in CHOsst4 cell membranes with respective pIC50 values of SRIF (8.82), L‐362855 (7.40), BIM‐23027 (<5.5) and MK‐678 (<5.5).
These ligands displayed agonist activity, producing concentration‐dependent increases in rates of extracellular acidification (EAR) with pEC50 values of SRIF (9.6) and L‐362855 (8.0), respectively. BIM‐23027 and MK‐678 were at least 1000 times weaker than SRIF. The SRIF maximum was about 40% of that observed with L‐362855.
In the presence of SRIF (0.1–1 nM), concentration‐effect curves to L‐362855 were displaced to the right with a progressive reduction in the L‐362855 maximum.
When cells were only exposed to a single maximally effective concentration of SRIF or L‐362855, there was no difference in the magnitude of the agonist‐induced increase in EAR. However, a second agonist challenge, 30 min later showed that responses to SRIF but not L‐362855 were markedly desensitized.
When concentration‐effect curves to SRIF and L‐362855 were obtained by combining data from cells exposed to only a single agonist concentration, SRIF (pEC50 9.2) was approximately 20 times more potent than L‐362855 (pEC50 8.0) but the maxima were the same. Responses to both SRIF and L‐362855 were abolished by pertussis toxin.
SRIF and L‐362855‐induced increases in EAR were inhibited by N‐ethyl isopropyl amiloride (10 μM) but were not modified by inhibitors of PKC (Go‐6976), MAP kinase (PD‐98059), tyrosine kinase (genistein) or tyrosine phosphatase (sodium orthovanadate).
The results suggest that SRIF‐induced increases in EAR in CHOsst4 cells involved activation of the Na+/H+ antiporter and were mediated via Gi/Go G proteins. Responses to SRIF, but not L‐362855, were subject to marked desensitization which may be a consequence of differential activation of receptor‐effector coupling pathways.

British Journal of Pharmacology (1998) 125, 833–841; doi:10.1038/sj.bjp.0702133
Infarct size‐reducing effect of heat stress and α1 adrenoceptors in rats
Authors: Joyeux Marie , Godin‐Ribuot Diane , Patel Asha , Demenge Pierre , Yellon Derek M , Ribuot Christophe 
Published: January 2005

Noradrenaline (NA), which is abundantly released during heat stress (HS), is known to induce both delayed cardioprotection and heat stress protein (HSP) 72 expression by the mediation of α1 adrenoceptors. Therefore, we have investigated the implication of α1 adrenoceptors in HS‐induced resistance to myocardial infarction, in the isolated rat heart model.
Rats were pretreated with prazosin (1 mg kg−1, i.p., Praz) or 5‐methylurapidil (3 mg kg−1, i.v, 5MU) or chloroethylclonidine (3 mg kg−1, i.v., CEC) or vehicle (V) in order to selectively antagonize α1, α1A and α1B adrenoceptors. They were then either heat stressed (42°C for 15 min) or sham anaesthetized. Twenty‐four hours later, their hearts were isolated, retrogradely perfused, and subjected to a 30 min occlusion of the left coronary artery followed by 120 min of reperfusion.
Infarct‐to‐risk ratio was significantly reduced in HS+V (15.4±1.8%) compared to Sham+V (35.7±1.3%) hearts. This effect was abolished in Praz‐treated (29.1±1.6% in HS+Praz vs 34.1±4.0% in Sham+Praz), 5MU‐treated (34.5±2.2% in HS+5MU vs 31.2±2.0% in Sham+5MU) and CEC‐treated (33.4±3.0% in HS+CEC vs 32.4±1.3% in Sham+CEC) groups. Western blot analysis of myocardial HSP72 showed an HS‐induced increase of this protein, which was not modified by Praz, 5MU and CEC pretreatments.
We conclude that both α1A and α1B adrenoceptor subtypes appear to play a role in the heat stress‐induced cardioprotection, independently of the HSP72 level. Further investigations are required to elucidate the precise role of HSPs in this adaptative response.

British Journal of Pharmacology (1998) 125, 645–650; doi:10.1038/sj.bjp.0702137
Influence of receptor number on the stimulation by salmeterol of gene transcription in CHO‐K1 cells transfected with the human β2‐adrenoceptor
Authors: McDonnell J , Latif M L , Rees E S , Bevan N J , Hill S J 
Published: January 2005

The β2‐agonist salmeterol is a potent relaxant of airway smooth muscle with a long duration of action. Previous studies of cyclic AMP accumulation, however, have indicated that salmeterol is a low efficacy β2‐agonist when compared to isoprenaline. Here we have compared the properties of salmeterol and isoprenaline as stimulants of gene transcription in CHO‐K1 cells transfected with the human β2‐adrenoceptor to different levels (50 and 310 fmol mg protein−1).
Gene transcription was monitored using a secreted placental alkaline phosphate (SPAP) reporter gene under the transcriptional control of six cyclic AMP response element (CRE) sequences.
In the lower expressing cells (CHO‐β2/6), salmeterol produced a maximal cyclic AMP response that was only 22% that of that obtained with isoprenaline. In contrast in the higher expressing cells (CHO‐β2/4), the two maxima were of similar magnitude.
Salmeterol was a more potent stimulant of gene transcription, producing the same maximal response as isoprenaline in both cell lines. Furthermore, in the CHO‐β2/4 cells, Salmeterol was 50 fold more potent as a stimulant of SPAP secretion than of cyclic AMP accumulation. In contrast, isoprenaline was 24 fold less sensitive as a stimulant of SPAP secretion than of cyclic AMP accumulation. In the presence of serum (10%), the effects of both salmeterol and isoprenaline on gene transcription were augmented.
These data suggest that the low efficacy and/or long duration of action of salmeterol, favours a potent stimulation of gene transcription when compared to more efficacious but shorter‐lived agonists such as isoprenaline.

British Journal of Pharmacology (1998) 125, 717–726; doi:10.1038/sj.bjp.0702139
Weaning‐induced development of δ‐opioid receptors in rat brain: differential effects of guanine nucleotides and sodium upon ligand‐receptor recognition
Authors: Kelly M. D. W. , Hill R. G. , Borsodi A , Toth G , Kitchen I 
Published: January 2005

We have previously shown that weaning at day 21 increases δ‐opioid receptor binding in the brain at day 25, which might be due to stimulation of the development of a δ‐opioid receptor subtype or activation of G‐protein coupling processes.
We have addressed the possibility that weaning stimulates coupling of the δ‐receptor by homogenate binding studies with four agonist and one antagonist radioligand in the presence of a GTP analogue and Na+ in brain tissue from weaned and non‐weaned animals.
Saturation studies with three agonist ligands ([3H]‐deltorphin I, [3H]‐S‐Atc‐Ile5,6deltorphin I and [3H]‐R‐Atc‐Ile5,6deltorphin II) showed higher levels of maximal binding in brains from 25‐day weaned than in brains from non‐weaned rats. The magnitude of the effects of GMPPNP and Na+ in decreasing this binding was ligand dependant and in each case was significantly more marked in brains from weaned animals. GMPPNP and Na+ were completely without effect on Bmax for, [3H]‐S‐Atc‐Ile5,6deltorphin I and [3H]‐R‐Atc‐Ile5,6deltorphin II in brains from non‐weaned rats.
[3H]‐Ile5,6deltorphin II and [3H]‐naltrindole showed no differences in labelling between weaned and non‐weaned groups and both groups responded similarly to the effects of GMPPNP and Na+ treatment.
GMPPNP and Na+ had small effects on binding affinity (KD) for some of the agonist radioligands which were similar in both weaned and non‐weaned groups.
Weaning induced increases in binding of δ‐receptors in 25‐day rats can be explained in terms of the way δ‐agonist radioligands recognize the receptor environment.

British Journal of Pharmacology (1998) 125, 979–986; doi:10.1038/sj.bjp.0702142
Effects of prenatal exposure to low concentrations of carbon monoxide on sexual behaviour and mesolimbic dopaminergic function in rat offspring
Authors: Cagiano Raffaele , Ancona Donata , Cassano Tommaso , Tattoli Maria , Trabace Luigia , Cuomo Vincenzo 
Published: January 2005

Inhalation of low concentrations of carbon monoxide (CO) by pregnant rats (75 and 150 p.p.m. from day 0 to day 20 of gestation) leads to changes in mesolimbic dopaminergic transmission associated with an impairment of sexual behaviour in male offspring.
Eighty day old males exposed in utero to CO (150 p.p.m.) exhibited a significant increase in mount/intromission latency as well as a significant decrease in mount/intromission frequency. A significant decrease in ejaculation frequency was also found in CO (150 p.p.m.)‐exposed animals.
The acute administration of amphetamine, at a dose (0.5 mg kg−1 s.c.) stimulating copulatory activity in control rats, failed to reduce mount/intromission latency and did not increase mount frequency in 80‐day offspring exposed to CO (150 p.p.m.) during gestation.
These behavioural alterations were paralleled by neurochemical changes (in vivo microdialysis) showing that prenatal CO exposure, at concentrations (150 p.p.m.) that did not affect basal extracellular levels of dopamine in the nucleus accumbens, blunted the amphetamine (0.5 mg kg−1 s.c.)‐induced increase in dopamine release in 80‐day old male rats.
No significant changes in either behavioural or neurochemical parameters were observed in 10‐month old rats exposed prenatally to CO.
Since the alterations in sexual behaviour and dopaminergic transmission have been produced by prenatal exposure to CO levels resulting in maternal blood carboxyhaemoglobin concentrations equivalent to those maintained by human cigarette smokers, the present data further point out the large risk that the smoking mother poses for her offspring.

British Journal of Pharmacology (1998) 125, 909–915; doi:10.1038/sj.bjp.0702143
Systemic anti‐inflammatory effect induced by counter‐irritation through a local release of somatostatin from nociceptors
Authors: Szolcsányi János , Pintér Erika , Helyes Zsuzsanna , Oroszi Gábor , Németh József 
Published: January 2005

Neurogenic plasma extravasation evoked by topical application of 1% vv−1 mustard oil on the skin of the acutely denervated rat hindleg (primary reaction) inhibited the development of a subsequent oil‐induced plasma extravasation induced in the skin of the contralateral hindleg by 49.3±7.06% (n=9) and in the conjunctival mucosa due to 0.1% wv−1 capsaicin instillation by 33.5±10.05% (n=6). The primary reaction also inhibited the non‐neurogenic hindpaw oedema evoked by s.c. injection of 5% wv−1 dextran into the chronically denervated hindpaw by 48.0±4.6% (n=5).
Capsaicin injection (100 μg ml−1 in 50 μl, s.c.) into the acutely denervated hindleg caused 56.5±4.0% (n=5) inhibition in the intensity of plasma extravasation elicited by 1% vv−1 mustard oil smearing on the contralateral side. After chronic denervation, subplantar injection of 5% wv−1 dextran elicited a non‐neurogenic inflammatory response with intensive tissue oedema without causing any systemic anti‐inflammatory effect. Bilateral adrenalectomy did not inhibit the mustard oil‐induced anti‐inflammatory effect in the contralateral hindleg.
Pretreating the rats with polyclonal somatostatin antiserum (0.5 ml rat−1, i.v.) or with the somatostatin depleting agent cysteamine (280 mg kg−1, s.c.) prevented the inhibitory action of mustard oil‐induced inflammation on subsequent neurogenic plasma extravasation and strongly diminished the inhibition of non‐neurogenic oedema formation evoked by dextran.
Exogenous somatostatin (10 μg kg−1, i.p.) caused a 30.3±8.3% (n=6) inhibition of plasma extravasation caused by mustard oil smearing on the acutely denervated hindleg and this inhibitory effect was abolished by somatostatin antiserum (0.5 ml rat−1, i.v.). The plasma level of somatostatin‐like immunoreactivity (SST‐LI) increased by 40.03±6.8% (n=6) 10 min after topical application of 1% vv−1 mustard oil on the acutely denervated hindpaws compared to the paraffin oil treated control group. Chronic denervation of the hindlegs or cysteamine (280 mg kg−1, s.c.) pretreatment prevented the mustard oil‐induced elevation of SST‐LI in plasma.
It is concluded that chemical excitation of the capsaicin‐sensitive sensory receptors not only induces local neurogenic plasma extravasation but also inhibits the development of a subsequent inflammatory reaction at remote sites of the body in the rat. A role for somatostatin in this systemic anti‐inflammatory effect is suggested.

British Journal of Pharmacology (1998) 125, 916–922; doi:10.1038/sj.bjp.0702144
Heat stress‐induced B1 receptor synthesis in the rat: an ex vivo study
Authors: Lagneux Caroline , Innocenti‐Francillard Patricia , Godin‐Ribuot Diane , Bader Mickael , Ribuot Christophe 
Published: January 2005

This ex vivo study was performed to characterize B1 receptor induction in rats submitted to heat stress. Changes in aortic isometric tension were recorded after a 90 min in vitro incubation with [des‐Arg9]‐bradykinin. B1 receptor mRNA were detected in aorta and heart using RT–PCR technique.
Aortic rings from sham rats did not respond to [des‐Arg9]‐bradykinin. In contrast, this agonist induced a concentration‐dependent relaxation of aortic rings from rats submitted to lipopolysaccharide (LPS) treatment or to heat stress 24 h earlier.
The concentration‐dependent relaxation induced by [des‐Arg9]‐bradykinin on aortic rings from heat‐stressed rats was abolished by [des‐Arg10]‐HOE 140, a selective B1 receptor antagonist.
In endothelium denuded aortic rings from heat‐stress rats, [des‐Arg9]‐bradykinin induced a concentration‐dependent constriction.
Pretreatment of intact aortic rings from heat‐stress rats with the cyclo‐oxygenase inhibitor, diclofenac (1 μM) did not prevent the concentration‐dependent relaxation in response to [des‐Arg9]‐bradykinin. In contrast, NO synthase inhibition with Nω‐nitro‐L‐arginine methyl ester (30 μM) totally prevented the vasorelaxant response.
B1 receptor mRNA were not detected in aorta and heart from sham animals but were present in tissue from heat‐stressed and LPS‐treated rats.
In conclusion, our results suggest that heat stress induces a transcriptional activation of the B1 receptor gene. The induction of B1 receptors leads to an endothelium‐ and NO‐dependent vasorelaxant response to [des‐Arg9]‐bradykinin.

British Journal of Pharmacology (1998) 125, 812–816; doi:10.1038/sj.bjp.0702146
Effects of sulphonylureas on the volume‐sensitive anion channel in rat pancreatic β‐cells
Authors: Best L , Benington S 
Published: January 2005

The volume‐sensitive anion conductance in rat pancreatic β‐cells was studied directly using the conventional whole‐cell and perforated patch recording techniques, and indirectly by measuring 3H‐taurine efflux from pre‐loaded, perifused islets.
Using the conventional whole‐cell recording configuration, activation of the outwardly‐rectifying, DIDS‐sensitive conductance was induced by glibenclamide (10 μM) but not by tolbutamide (100 μM) nor by meglitinide (20 μM). A high concentration of glibenclamide (100 μM) caused a voltage‐and time‐dependent inhibition of the conductance. Tolbutamide had a modest inhibitory effect on swelling‐induced inward currents.
In perforated patch recordings, glibenclamide, tolbutamide and meglitinide were all without effect on the conductance, although activation could be induced under these conditions by exposure to a hypotonic bath solution.
The rate of efflux of 3H‐taurine, a marker for activity of the volume‐sensitive anion channel, from preloaded, perifused islets was markedly stimulated by exposure to a hypotonic solution. However, glibenclamide and tolbutamide were both without effect.
Electrical activity of β‐cells in response to glibenclamide or tolbutamide was not inhibited by 4,4′‐dithiocyanatostilbene‐2,2′‐disulphonic acid (DIDS), an inhibitor of the volume‐sensitive anion channel.
It is concluded that activity of the volume‐sensitive anion conductance in rat pancreatic β‐cells is not modulated by the sulphonylurea receptor. The activation of the conductance by glibenclamide in whole‐cell recordings could be the result of a non‐specific interaction of the drug with plasma membrane lipids.

British Journal of Pharmacology (1998) 125, 874–878; doi:10.1038/sj.bjp.0702148
Contrasting effects of an aminobisphosphonate, a potent inhibitor of bone resorption, on lipopolysaccharide‐induced production of interleukin‐1 and tumour necrosis factor α in mice
Authors: Sugawara Shunji , Shibazaki Masahiko , Takada Haruhiko , Kosugi Hiroshi , Endo Yasuo 
Published: January 2005

Aminobisphosphonates (aminoBPs), potent inhibitors of bone resorption, have been reported to induce inflammatory reactions such as fever and an increase in acute phase proteins in human patients, and to induce the histamine‐forming enzyme, histidine decarboxylase, in mice. In the present study, we examined the effect of aminoBP, 4‐amino‐1‐hydroxybutylidene‐1,1‐bisphosphonic acid (AHBuBP), on the production of the pro‐inflammatory cytokines, IL‐1 and TNFα, in mice.
Intraperitoneal injection of AHBuBP did not itself produce detectable levels of IL‐1 (α and β) and TNFα in the serum. However, the elevation of serum IL‐1 induced by lipopolysaccharide (LPS) was greatly augmented in mice injected with AHBuBP 3 days before the LPS injection, whereas the LPS‐induced elevation of serum TNFα was almost completely abolished.
Spleen and bone marrow cells taken from mice injected with AHBuBP produced IL‐1β in vitro spontaneously, and the production was augmented following the addition of LPS. Cells that accumulated in the peritoneal cavity in response to AHBuBP produced a particularly large amount of IL‐1β. However, AHBuBP treatment of mice did not lead to an impairment of the in vitro production of TNFα by these three types of cells.
Liposomes encapsulating dichloromethylene bisphosphonate (a non‐amino BP) selectively deplete phagocytic macrophages. When an intraperitoneal injection of these liposomes was given 2 days after an injection of AHBuBP, there was a marked decrease in the LPS‐induced elevation of serum IL‐1 (α and β) (LPS being injected 3 days after the injection of AHBuBP).
These results indicate that AHBuBP has contrasting effects on the in vivo LPS‐induced production of IL‐1 and TNFα in mice, enhancing the production of IL‐1 by phagocytic macrophages and suppressing the production of TNFα, although underling mechanisms remain to be clarified.

British Journal of Pharmacology (1998) 125, 735–740; doi:10.1038/sj.bjp.0702151
Genotypic and phenotypic analysis of the polymorphic thiopurine S‐methyltransferase gene (TPMT) in a European population
Authors: Spire‐Vayron de la Moureyre Catherine , Debuysere Hervé , Mastain Bruno , Vinner Elizabeth , Marez Delphine , Lo Guidice Jean‐Marc , Chevalier Dany , Brique Serge , Motte Kokou , Colombel Jean‐Frédéric , Turck Dominique , Noel Christian , Flipo René‐Marc , Pol Annie , Lhermitte Michel , Lafitte Jean‐Jacques , Libersa Christian , Broly Franck 
Published: January 2005

Characterization of allelic variants of the TPMT gene (TPMT) responsible for changes in TPMT activity, and elucidation of the mechanism by which these alleles act, are required because of the clinical importance of this polymorphism for patients receiving thiopurine drugs.
We defined the mutational and allelic spectrum of TPMT in a group of 191 Europeans. Using PCR–SSCP, we screened for mutation the entire coding sequence, the exon‐intron boundaries, the promoter region and the 3′‐flanking region of the gene. Six mutations were detected throughout the ten exons and seven TPMT alleles were characterized. Four of them, TPMT*2, *3A, *3C and *7, harbouring the known mutations, G238C, G460A, A719G or T681G, were nonfunctional and accounted for 0.5, 5.7, 0.8 and 0.3% of the allele totality, respectively.
Within the promoter region, six alleles corresponding to a variable number of tandem repeats (VNTR), were identified. VNTR*V4 and *V5a which harbour four or five repeats of a 17–18 bp unit, were the most frequent (55% and 34%, respectively). The other VNTR alleles, having from five to eight repeats, were rarer.
The TPMT phenotype was correctly predicted by genotyping for 87% of individuals. A clear negative correlation between the total number of repeats from both alleles and the TPMT activity level was observed, indicating that VNTRs contribute to interindividual variations of TPMT activity. Therefore, additional analysis of the promoter region of TPMT can improve the phenotype prediction rate by genotyping.

British Journal of Pharmacology (1998) 125, 879–887; doi:10.1038/sj.bjp.0702152
Properties of neuronal nicotinic acetylcholine receptor mutants from humans suffering from autosomal dominant nocturnal frontal lobe epilepsy
Authors: Bertrand S , Weiland S , Berkovic S F , Steinlein O K , Bertrand D 
Published: January 2005

Physiological and pharmacological properties of the human neuronal α4β2 nicotinic AChR and mutants found in patients suffering from autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) were studied.
Investigations of nicotinic AChRs reconstituted in Xenopus oocytes with the control or mutated α4 subunits revealed that both mutation S248F as well as the Leucine insertion (776ins3) result in major but different changes in the physiological and pharmacological properties of the receptors.
Mutation S248F causes a decrease in apparent affinity to ACh of about 7 fold. In addition, this receptor already desensitizes during exposure to agonist concentration 3000 times lower than the control.
776ins3 provokes a 10 fold increase of apparent ACh affinity, an increase in the IC50 caused by prolonged ACh exposures and a slowing down of the response decay.
At saturating ACh concentration cells expressing the S248F mutant display average currents that are about five times smaller than control.
When measured at very low concentration, agonist sensitivities of the control and mutated receptors to ACh, nicotine and epibatidine exhibit differences that match those observed for higher agonist concentrations.
Mutation 776ins3 increases the apparent efficacy to cytisine.
Data presented herein suggest that mutation S248F mainly affects the desensitization properties of the receptor while the leucine insertion (776ins3) increases the probability of transition to the active state. Although these mutations differentially affect the receptor properties they both result in reduced permeability to calcium and enhanced desensitization sensitivity that might account for the ADNFLE phenotype.

British Journal of Pharmacology (1998) 125, 751–760; doi:10.1038/sj.bjp.0702154