bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of the receptors involved in the 5‐HT‐induced excitation of canine antral longitudinal muscle
Authors: Prins N H , Akkermans L M A , Lefebvre R A , Schuurkes J A J 
Published: January 2005

We aimed to characterize the 5‐HT receptors involved in the 5‐HT‐induced effect on electrically induced contractions of dog antrum longitudinal muscle in vitro.
In the presence of L‐NOARG (0.1 mM), electrical field stimulation (EFS) induced atropine‐ and tetrodotoxin‐sensitive contractions. Tetrodotoxin or atropine left any agonist tested ineffective. These EFS‐induced contractions were on average enhanced by 5‐HT (0.3 μM), however, pronounced variation in the response to 5‐HT was observed. There were non‐significant trends of the selective 5‐HT3 receptor antagonist granisetron (1 μM), and methysergide (1 μM; preventing interactions of 5‐HT with 5‐HT1, 5‐HT2, 5‐ht5, 5‐HT6 and 5‐HT7 receptors) to increase the response to 5‐HT. The selective 5‐HT4 receptor antagonist GR 113808 (0.1 μM) displayed a non‐significant trend to inhibit the 5‐HT‐induced increase.
Combination experiments with methysergide (1 μM), granisetron (1 μM) and GR 113808 (0.1 μM) revealed that the 5‐HT (0.3 μM)‐induced response consisted of (1) an excitatory component blocked by GR 113808, (2) excitatory and inhibitory components both blocked by methysergide.
The selective 5‐HT4 receptor agonist prucalopride (0.3 μM) increased EFS‐induced contractions, an effect prevented by GR 113808 (0.1 μM).
The increase of EFS‐induced contractions by the preferential 5‐HT2 receptor agonist α‐Me‐5‐HT (0.3 μM) was antagonized by 5‐HT2B receptor antagonists.
The 5‐HT1/5‐HT7 receptor agonist 5‐carboxamidotryptamine (5‐CT; 0.3 μM) inhibited EFS‐induced contractions. This was prevented by methysergide (1 μM), the 5‐HT7 receptor antagonist mesulergine (0.3 μM) and the selective 5‐HT7 receptor antagonist SB‐269970 (0.3 μM).
In the presence of GR 113808 (0.1 μM), α‐Me‐5‐HT (1 μM) increased EFS‐induced contractions. The 5‐HT (0.3 μM)‐induced inhibition of the stimulation by α‐Me‐5‐HT was prevented by SB‐269970 (0.3 μM).
In conclusion, dog antral longitudinal muscle is endowed with (1) excitatory neuronal 5‐HT4 receptors and 5‐HT2B receptors and (2) inhibitory smooth muscle 5‐HT7 receptors.

British Journal of Pharmacology (2001) 134, 1351–1359; doi:10.1038/sj.bjp.0704376
Parathyroid hormone‐related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets
Authors: Clemens Thomas L , Cormier Sarah , Eichinger Anne , Endlich Karlhans , Fiaschi‐Taesch Nathalie , Fischer Evelyne , Friedman Peter A , Karaplis Andrew C , Massfelder Thierry , Rossert Jérôme , Schlüter Klaus‐Dieter , Silve Caroline , Stewart Andrew F , Takane Karen , Helwig Jean‐Jacques 
Published: January 2005

The cloning of the so‐called ‘parathyroid hormone‐related protein’ (PTHrP) in 1987 was the result of a long quest for the factor which, by mimicking the actions of PTH in bone and kidney, is responsible for the hypercalcemic paraneoplastic syndrome, humoral calcemia of malignancy. PTHrP is distinct from PTH in a number of ways. First, PTHrP is the product of a separate gene. Second, with the exception of a short N‐terminal region, the structure of PTHrP is not closely related to that of PTH. Third, in contrast to PTH, PTHrP is a paracrine factor expressed throughout the body. Finally, most of the functions of PTHrP have nothing in common with those of PTH. PTHrP is a poly‐hormone which comprises a family of distinct peptide hormones arising from post‐translational endoproteolytic cleavage of the initial PTHrP translation products. Mature N‐terminal, mid‐region and C‐terminal secretory forms of PTHrP are thus generated, each of them having their own physiologic functions and probably their own receptors. The type 1 PTHrP receptor, binding both PTH(1‐34) and PTHrP(1‐36), is the only cloned receptor so far. PTHrP is a PTH‐like calciotropic hormone, a myorelaxant, a growth factor and a developmental regulatory molecule. The present review reports recent aspects of PTHrP pharmacology and physiology, including: (a) the identification of new peptides and receptors of the PTH/PTHrP system; (b) the recently discovered nuclear functions of PTHrP and the role of PTHrP as an intracrine regulator of cell growth and cell death; (c) the physiological and developmental actions of PTHrP in the cardiovascular and the renal glomerulo‐vascular systems; (d) the role of PTHrP as a regulator of pancreatic beta cell growth and functions, and, (e) the interactions of PTHrP and calcium‐sensing receptors for the control of the growth of placental trophoblasts. These new advances have contributed to a better understanding of the pathophysiological role of PTHrP, and will help to identify its therapeutic potential in a number of diseases.British Journal of Pharmacology (2001) 134, 1113–1136; doi:10.1038/sj.bjp.0704378
N[3‐(4′‐fluorophenyl)‐3‐(4′‐phenylphenoxy)propyl]sarcosine (NFPS) is a selective persistent inhibitor of glycine transport
Authors: Aubrey Karin R , Vandenberg Robert J 
Published: January 2005

The regulation of glycine concentrations within excitatory synapses is poorly understood and it has been proposed that the GLYT1 subtypes of glycine transporters play a critical role in determining resting concentrations of glycine. Selective GLYT1 inhibitors may provide pharmacological tools to probe the dynamics of synaptic glycine concentrations, which may influence the activation properties of NMDA receptor activity.
We have characterized the selectivity and mechanism of action of the glycine transport inhibitor N[3‐(4′‐fluorophenyl)‐3‐(4′‐phenylphenoxy)propyl]sarcosine (NFPS). The glycine transporters, GLYT1a, b and c and GLYT2a were expressed in Xenopus laevis oocytes and two electrode voltage clamp techniques and radiolabelled 3H‐glycine flux measurements were used to characterize the effects of NFPS on glycine transport.
NFPS inhibits glycine transport by the GLYT1a, b and c subtypes of glycine transporters, but has no effect on the GLYT2a subtype of transporter. We show that NFPS does not attain its specificity via an interaction with the Na+, Cl− or glycine site, nor does it act at an intracellular site. NFPS inhibition of glycine transport is time and concentration dependent and inhibition of transport by NFPS persists after washout of NFPS from the bath solution, which suggests that inhibition by NFPS is long lasting.

British Journal of Pharmacology (2001) 134, 1429–1436; doi:10.1038/sj.bjp.0704381
HIV‐1 coat protein gp120 stimulates interleukin‐1β secretion from human neuroblastoma cells: evidence for a role in the mechanism of cell death
Authors: Corasaniti Maria Tiziana , Bilotta Anna , Strongoli Maria Concetta , Navarra Michele , Bagetta Giacinto , Renzo Gianfranco Di 
Published: January 2005

The role of the pro‐inflammatory cytokine interleukin‐1β (IL‐1β) in the mechanism of cell death induced by the human immunodeficiency virus type 1 (HIV‐1) recombinant coat glycoprotein, gp120 IIIB, has been studied in the human CHP100 neuroblastoma cell line maintained in culture.
Death of neuroblastoma cells typically elicited by 10 pM gp120 or by human recombinant IL‐1β (10 ng ml−1) has been minimized by the antagonist of IL‐1 receptor, i.e. IL‐1ra (0.5 and 50 ng ml−1, respectively), an endogenous molecule that antagonizes most of the biological actions of IL‐1β, or by an antibody (5 and 50 ng ml−1) which blocks the human IL‐1 receptor type I (IL‐1RI).
ELISA experiments have established that gp120 enhances immunoreactive IL‐1β levels in the culture medium and this is prevented by exposure to the IL‐1 converting enzyme (ICE) inhibitor t‐butoxycarbonyl‐L‐aspartic acid benzyl ester‐chloromethylketone [Boc‐Asp(OBzl)‐CMK] used at a concentration (2.5 μM) which significantly (P<0.001) reduces cell death.
Death of CHP100 cells induced by gp120 is also prevented by acetyl‐Tyr‐Val‐Ala‐Asp‐chloromethylketone (Ac‐YVAD‐CMK; 10 – 100 μM), a second inhibitor of ICE, supporting the concept that the viral protein stimulates the conversion of the 31 kDa pro‐IL‐1β in to the 17 kDa mature cytokine which is then secreted to cause death.
In conclusion, our present data demonstrate that gp120 stimulates the secretion of IL‐1β which then triggers CHP100 neuroblastoma cell death via stimulation of IL‐1 receptor type I.

British Journal of Pharmacology (2001) 134, 1344–1350; doi:10.1038/sj.bjp.0704382
Effect of chronic clonidine treatment on transmitter release from sympathetic varicosities of the guinea‐pig vas deferens
Authors: Knight David , Cunnane Tom C , Lavidis Nickolas A 
Published: January 2005

Previous studies have demonstrated that chronic pre‐synaptic inhibition of transmitter release by morphine evokes a counter‐adaptive response in the sympathetic nerve terminals that manifests itself as an increase in transmitter release during acute withdrawal. In the present study we examined the possibility that other pre‐synaptically acting drugs such as clonidine also evoke a counter‐adaptive response in the sympathetic nerve terminals.
In chronically saline treated (CST) preparations, clonidine (0.5 μM) completely abolished evoked transmitter release from sympathetic varicosities bathed in an extracellular calcium concentration ([Ca2+]o) of 2 mM. The inhibitory effect of clonidine was reduced by increasing [Ca2+]o from 2 to 4 mM and the stimulation frequency from 0.1 to 1 Hz.
The nerve terminal impulse (NTI) was not affected by concentrations of clonidine that completely abolished evoked transmitter release.
Sympathetic varicosities developed a tolerance to clonidine (0.5 μM) following 7 – 9 days of chronic exposure to clonidine.
Acute withdrawal of preparations following chronic clonidine treatment (CCT) resulted in a significant (P<0.005) enhancement of neurotransmitter release (3.75 times) above control levels observed in CST preparations.
The present findings demonstrate an enhancement of neurotransmitter release from sympathetic varicosities following acute withdrawal from chronic clonidine treatment.

British Journal of Pharmacology (2001) 134, 1480–1486; doi:10.1038/sj.bjp.0704383
Vasoconstrictor activity of novel endothelin peptide, ET‐1(1 – 31), in human mammary and coronary arteries in vitro
Authors: Maguire Janet J , Kuc Rhoda E , Davenport Anthony P 
Published: January 2005

The ability of the putative chymase product of big endothelin‐1 (big ET‐1), ET‐1(1 – 31), to constrict isolated endothelium‐denuded preparations of human coronary and internal mammary artery was determined.
pD2 values in coronary and mammary artery respectively were 8.21±0.12 (n=14) and 8.55±0.11 (n=12) for ET‐1, 6.74±0.11 (n=16) and 7.10±0.08 (n=16) for ET‐1(1 – 31) and 6.92±0.10 (n=15) and 7.23±0.11 (n=12) for big ET‐1. ET‐1(1 – 31) was significantly less potent than ET‐1 (P<0.001, Student's t‐test) and equipotent with big ET‐1.
Vasoconstrictor responses to 100 – 700 nM ET‐1(1 – 31) were significantly (P<0.05, Student's paired t‐test) attenuated by the ETA antagonist PD156707 (100 nM).
There was no effect of the ECE inhibitor PD159790 (30 μM), the ECE/NEP inhibitor phosphoramidon (100 μM) or the serine protease inhibitor chymostatin (100 μM) on ET‐1(1 – 31) responses in either artery.
Radioimmunoassay detected significant levels of mature ET in the bathing medium of coronary (1.6±0.5 nM, n=14) and mammary (2.1±0.6 nM, n=14) arteries, suggesting that conversion of ET‐1(1 – 31) to ET‐1 contributed to the observed vasoconstriction.
ET‐1(1 – 31) competed for specific [125I]‐ET‐1 binding to ETA and ETB receptors in human left ventricle with a pooled KD of 71.6±7.0 nM (n=3).
Therefore, in human arteries the novel peptide ET‐1(1 – 31) mediated vasoconstriction via activation of the ETA receptor. The conversion of ET‐1(1 – 31) to ET‐1, by an as yet unidentified protease, must contribute wholly or partly to the observed constrictor response. Chymase generated ET‐1(1 – 31) may therefore represent an alternative precursor for ET‐1 production in the human vasculature.

British Journal of Pharmacology (2001) 134, 1360–1366; doi:10.1038/sj.bjp.0704384
The interaction between ethanol and pregnanolone at induction of anaesthesia investigated with a threshold method in male rats
Authors: Wang Ming‐De , Zhu Di , Bäckström Torbjörn , Wahlström Göran 
Published: January 2005

An anaesthesia threshold was used to investigate the pharmacodynamic and pharmacokinetic interactions between ethanol and pregnanolone in male rats.The criterion to determine threshold doses of pregnanolone was the first burst suppression of 1 s in the EEG. Ethanol (0.5, 1.0, 1.5 and 2.0 g kg−1) was injected i.p. 15 min before pregnanolone infusion. Trunk blood, serum, cortex, cerebellum, hippocampus, striatum, brain stem, fat and muscle tissues obtained at criterion were used to determine ethanol (blood) and pregnanolone.Ethanol reduced threshold doses in a dose dependent linear manner. A similar reduction of pregnanolone tissue concentrations was only found in brain stem and striatum. Deviations consisted of larger decreases in serum, cerebellum and hippocampus after 0.5 g kg−1ethanol and in cerebellum, cortex and hippocampus after 2.0 g kg−1of ethanol. Positive correlations between dose and concentration of pregnanolone was recorded in brain stem, hippocampus, cerebellum and cortex. A kinetic component influenced the concentration in cortex. There was a correlation between dose and serum concentration of pregnanolone only after ethanol. In the muscle 0.5 g kg−1ethanol had no influence on pregnanolone concentration.The linear, additive pharmacodynamic interaction could involve the GABA ionophore. A pharmacokinetic interaction was found in cortex. The retained high uptake of pregnanolone in muscle (after 0.5 g kg−1) corresponded to losses in other tissues (including serum). The reduced uptake of pregnanolone in cerebellum, cortex and hippocampus (after 2.0 g kg−1) was not due to a corresponding change in serum concentration. It was probably due to a reduced blood flow.British Journal of Pharmacology(2001)134, 1393–1402; doi:10.1038/sj.bjp.0704385
Commercial taxane formulations induce stomatocytosis and increase blood viscosity
Authors: Mark Michael , Walter Roland , Meredith D Osian , Reinhart Walter H 
Published: January 2005

Taxanes are antineoplastic drugs which have cardiovascular side effects of unknown mechanism. We investigated their influence on blood viscosity and erythrocyte morphology.
Whole blood was incubated in vitro with increasing concentrations of Taxol®, Taxotere®, paclitaxel (0 – 100 μM) and the vehicles Cremophor‐EL and Tween 80 (0 – 5% vol) for 1 h at 37°C. Plasma and whole blood viscosity (Haematocrit 45%) were measured and erythrocyte morphology was assessed on glutaraldehyde‐fixed cells. The same investigations were performed in seven patients before and after a Taxol®‐infusion.
Taxol® and Taxotere® induced a dose‐ and time‐dependent stomatocytic shape transformation of erythrocytes. Paclitaxel alone had no effect, but the vehicles cremophor‐EL and Tween 80, used in Taxol® and Taxotere®, respectively, induced a comparable degree of stomatocytosis. This suggests a preferential intercalation of these substances into the inner hemileaflet of the membrane lipid bilayer. Associated with this shape change a dose‐dependent increase in plasma and whole blood viscosity was observed. Neither shape nor viscosity changes were reversible upon removal of the agents. After the infusion of 130 – 300 mg Taxol® in patients a slight shift towards stomatocytosis and an increase in whole blood viscosity at high shear rate from 5.09±0.30 to 5.44±0.38 mPa.s (P<0.05) were confirmed.
Commercial taxane drug formulations induce stomatocytosis and increase blood viscosity, which is due to their formulation vehicles. These findings may contribute to the understanding of the cardiovascular side effects of these drugs.

British Journal of Pharmacology (2001) 134, 1207–1214; doi:10.1038/sj.bjp.0704387
Interleukin‐5 in growth and differentiation of blood eosinophil progenitors in asthma: effect of glucocorticoids
Authors: Kuo Han‐Pin , Wang Chun‐Hua , Lin Horng‐Chyuan , Hwang Kuo‐Shiung , Liu Shu‐Liang , Chung Kian Fan 
Published: January 2005

There are increased numbers of circulating CD34+ progenitor cells for eosinophils in patients with atopic asthma, with a further increase following allergen exposure or spontaneous worsening of asthma. We investigated the expression of IL‐5 and IL‐5Rα receptor in circulating CD34+ progenitor cells in allergic asthmatics and the effects of corticosteroids.
Using double‐staining techniques, up to 50% of CD34+ cells expressed intracellular IL‐5, and by RT – PCR, there was significant expression of IL‐5 mRNA. When cultured in a semi‐liquid methylcellulose medium, there were more eosinophil colony‐forming units grown from asthmatic non‐adherent mononuclear cell depleted of T cells in the presence of the growth factors GM‐CSF, SCF and IL‐3, but not of IL‐5.
An anti‐IL‐5Rα receptor antibody and an anti‐sense IL‐5 oligonucleotide reduced the number of eosinophil colony forming units. No IL‐5 mRNA or protein expression on T cells was observed in asthmatics or normal subjects. In the presence of growth factors including IL‐5, there were significantly greater colony numbers with eosinophilic lineage grown from either asthmatics or normal subjects.
Dexamethasone (10−6 M) suppressed IL‐5 mRNA and protein expression in CD34+ cells, and reduced eosinophil colony‐forming units in asthmatics, but not in normal subjects. Dexamethasone did not change the expression of IL‐5Rα on CD34+ cells.
We conclude that there is increased expression of IL‐5 on blood CD34+ cells of patients with asthma and that this expression may auto‐regulate eosinophilic colony formation from these progenitor cells. Corticosteroids inhibit the expression of IL‐5 in circulating CD34+ progenitor cells.

British Journal of Pharmacology (2001) 134, 1539–1547; doi:10.1038/sj.bjp.0704389
Antisense‐induced down‐regulation of thymidylate synthase and enhanced cytotoxicity of 5‐FUdR in 5‐FUdR‐resistant HeLa cells
Authors: Ferguson Peter J , DeMoor Janice M , Vincent Mark D , Koropatnick James 
Published: January 2005

Thymidylate synthase (TS) is a target for several anticancer drugs. We previously showed that an antisense oligodeoxynucleotide (ODN) directed against TS mRNA down‐regulated TS protein and enhanced cytotoxicity of TS‐targeting drugs [including 5‐fluorodeoxyuridine (5‐FUdR)] in HeLa cells. Patient tumours with increased TS expression are resistant to TS‐targeting drugs. It was hypothesized that TS mRNA and consequently TS protein could be down‐regulated in 5‐FUdR‐resistant cells that overexpress TS, sensitizing them to 5‐FUdR cytotoxicity. In this study we assessed the capacity of an anti‐TS antisense ODN to circumvent resistance dependent on TS overexpression.
Variant HeLa clones exhibiting 2 – 20 fold resistance to 5‐FUdR were selected by exposing cultured cells to drug. Clones FUdR‐5a, −25b, and −50a expressed TS protein levels 10 fold, 10 fold, and 17 fold higher (respectively) than parental cells. Cells were treated with antisense ODN 83 (a 2′‐methoxy‐ethoxylated, phosphorothioated 20‐mer, complementary to a portion of the 3′‐untranslated region of TS mRNA), or ODN 32 (a control ODN with the same base composition as ODN 83, but in randomized order). Twenty‐four and 48 h following transfection (50 – 100 nM ODN, plus polycationic liposome), TS mRNA levels (by RT – PCR) and protein levels (by radiolabelled 5‐FUdR‐monophosphate binding) were decreased by at least 60% in ODN 83‐treated cells compared with control ODN 32‐treated cells. ODN 83 enhanced the cytotoxicity of 5‐FUdR by up to 85% in both parental and 5‐FUdR‐resistant cell lines.
Antisense ODN can be used to down‐regulate TS and attenuate drug resistance in TS‐overexpressing cells.

British Journal of Pharmacology (2001) 134, 1437–1446; doi:10.1038/sj.bjp.0704394
Therapeutic potential of a novel synthetic selectin blocker, OJ‐R9188, in allergic dermatitis
Authors: Ikegami‐Kuzuhara Akemi , Yoshinaka Tsuyoshi , Ohmoto Hiroshi , Inoue Yoshimasa , Saito Tadayuki 
Published: January 2005

We investigated the ability of a newly synthesized sugar derivative, OJ‐R9188, {N‐(2‐tetradecylhexadecanoyl)‐O‐(L‐alpha‐fucofuranosyl)‐D‐seryl}‐L‐glutamic acid 1‐methylamide 5‐L‐arginine salt, to block binding of selectins to their ligands in vitro and inhibit the infiltration of leukocytes in vivo.
OJ‐R9188 prevented the binding of human E‐, P‐ and L‐selectin‐IgG fusion proteins to immobilized sialyl Lewisx (sLex)‐pentasaccharide glycolipid, with IC50 values of 4.3, 1.3, and 1.2 μM, respectively.
In a mouse model of thioglycollate‐induced peritonitis, OJ‐R9188 at 10 mg kg−1, i.v. inhibited neutrophil accumulation in the peritoneal cavity. In the IgE‐mediated skin reaction, OJ‐R9188 at 3 and 10 mg kg−1, i.v. significantly inhibited extravasation of neutrophils and eosinophils into the inflammatory sites and at 10 mg kg−1, i.v. also inhibited infiltration caused by picryl chloride‐induced delayed‐type hypersensitivity in mice. These results suggest that OJ‐R9188 may be a useful selectin blocker, with activity against human and mouse E‐, P‐ and L‐selectins in vitro and in vivo, and that blocking selectin‐sLex binding is a promising strategy for the treatment of allergic skin diseases.

British Journal of Pharmacology (2001) 134, 1498–1504; doi:10.1038/sj.bjp.0704397
Effects of amlodipine and lacidipine on cardiac remodelling and renin production in salt‐loaded stroke‐prone hypertensive rats
Authors: Kyselovic Jan , Krenek Peter , Wibo Maurice , Godfraind Théophile 
Published: January 2005

Calcium channel blockers (CCBs) are anti‐hypertensive drugs that are usually considered to act mainly as vasodilators. We investigated the relation between the reduction of blood pressure evoked by two long‐acting CCBs and their protective effect against cardiac and renal damage in salt‐loaded stroke‐prone spontaneously hypertensive rats (SHRSP).
SHRSP were exposed to high dietary salt intake (1% NaCl in drinking solution) from 8 to 14 weeks of age, with or without amlodipine or lacidipine at three dosage regimens producing similar effects on blood pressure.
The lowest dosages of both drugs had non‐significant effects on blood pressure but inhibited the paradoxical increases in plasma renin activity (PRA) and in renin mRNA in kidney that were found in salt‐loaded SHRSP. The lowest dosage of lacidipine (but not of amlodipine) restored the physiological downregulation of renin production by high salt and reduced left ventricular hypertrophy and mRNA levels of atrial natriuretic factor and transforming growth factor‐β1.
The intermediate dosages reduced blood pressure and PRA in a comparable manner, but cardiac hypertrophy was more reduced by lacidipine than by amlodipine.
Although the highest doses exhibited a further action on blood pressure, they had no additional effect on cardiac hypertrophy, and they increased PRA and kidney levels of renin mRNA even more than in the absence of drug treatment.
We conclude that reduction of blood pressure is not the sole mechanism involved in the prevention of cardiac remodelling by CCBs, and that protection against kidney damage and excessive renin production by low and intermediate dosages of these drugs contributes to their beneficial cardiovascular effects.

British Journal of Pharmacology (2001) 134, 1516–1522; doi:10.1038/sj.bjp.0704398