bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potent inhibition of both the acute and delayed emetic responses to cisplatin in piglets treated with GR205171, a novel highly selective tachykinin NK1 receptor antagonist
Authors: Grélot Laurent , Dapzol Julien , Estève Eric , Frugière Alain , Bianchi Armand L , Sheldrick Robert L G , Gardner Christopher J , Ward Peter 
Published: January 2005

The effects of GR205171, a selective tachykinin NK1 receptor antagonist, were investigated on both the acute and delayed phases of cisplatin‐induced nausea‐like behaviour and vomiting in the conscious piglet.
Animals receiving cisplatin (5.5 mg kg−1, i.v.) were observed for 60 h. Fifteen min prior to cisplatin infusion (T0−15 min), eight piglets acting as controls received an intravenous injection of saline solution (1 ml kg−1), whereas experimental animals received a single i.v. administration of GR205171 (1 ml kg−1) at a dose of 0.01 (n=8), 0.03 (n=8), 0.1 (n=8), 0.3 (n=16) or 1.0 (n=13) mg kg−1. In eight additional piglets, GR205171 (1 mg kg−1) was administered 15 min before the onset of the delayed phase (T16−15 min). A further five piglets received GR205171 (1 mg kg−1) every 6 h throughout the experiment.
The latencies of the first emetic episode (EE) and nausea‐like behavioural episode (NE) increased in all experimental groups treated at T0−15 min, and the total number of both EE and NE during the 60 h was reduced in a dose‐dependent manner. In piglets treated at T0−15 min with GR205171 1 mg kg−1, eight out of 13 (62%) did not vomit throughout the experiment. Animals treated with GR205171 (1 mg kg−1) at T16−15 min exhibited an acute response to cisplatin but did not vomit during the delayed phase. The greatest inhibition of both nausea‐like behaviour and vomiting was observed in piglets receiving multiple injections of GR205171.
These results demonstrate the long‐lasting anti‐emetic effects of GR205171, and confirm the key role of substance P within the emetic reflex.

British Journal of Pharmacology (1998) 124, 1643–1650; doi:10.1038/sj.bjp.0702019
Effect of chronic hypoxia on adrenoceptor responses of ovine foetal umbilical vessels
Authors: Zhang Lubo , Hu Xiangqun , Longo Lawrence D 
Published: January 2005

The effects of chronic hypoxia on α1‐adrenoceptor‐mediated contractions were investigated in foetal umbilical vessels obtained from near‐term (∼140 day gestation) pregnant sheep maintained near sea level (∼300 m) and at high altitude (3820 m) from 30 day gestation.
Chronic hypoxia significantly decreased contractile sensitivity of the umbilical vein to noradrenaline (pD2: 6.22±0.19 vs 5.67±0.09) and reduced the maximum response by 43%. Noradrenaline‐induced contraction of the umbilical artery was abolished. In contrast, contractions to KCl were not affected by chronic hypoxia.
In umbilical vein, the apparent dissociation constant (KA) of noradrenaline to α1‐adrenoceptors was increased from 0.54±0.06 μM in control animals to 1.35±0.14 μM in chronically hypoxic animals. In accordance, radioligand binding of agonist showed high and low affinity binding sites for noradrenaline in both normoxic and chronically hypoxic tissues. Addition of GTPγS (100 μM) abolished apparent high affinity binding sites. Whereas proportional binding sites were not changed by chronic hypoxia, the apparent high affinity of noradrenaline was significantly decreased (pKi: 7.80±0.17 vs 7.20±0.16).
Chronic hypoxia significantly decreased α1‐adrenoceptor density (fmol mg protein−1) in umbilical vein (24.6±3.2 vs 12.3±3.1) and the artery (7.1±0.4 vs 3.1±0.9) with no change in [3H]‐prazosin binding affinity. There was a linear correlation of the maximum contractions to noradrenaline and α1‐adrenoceptor density.
We conclude that chronically hypoxic‐induced depression in contractions of ovine foetal umbilical vessels to noradrenaline is mediated predominantly by decreases in α1‐adrenoceptor density and the agonist binding affinity.

British Journal of Pharmacology (1998) 125, 136–142; doi:10.1038/sj.bjp.0702022
Inhibition of chemotaxis in A7r5 rat smooth muscle cells by a novel panel of inhibitors
Authors: Saxty B A , Yadollahi‐Farsani M , Kefalas P , Paul S , MacDermot J 
Published: January 2005

Arginine‐specific ADP‐ribosyltransferase (ART) activity has been implicated in white cell chemotaxis. In this study, we examined the capacity of a panel of structurally unrelated inhibitors and pseudo‐substrates of ART to inhibit chemotaxis of A7r5 rat vascular smooth muscle cells in response to PDGF‐BB.
The IC50 values for nicotinamide (12 mM) and novobiocin (165 μM) were similar to those observed for inhibition of chemotaxis by human polymorphonuclear neutrophil leucocytes (PMN), whereas vitamins K3 (IC50=22 μM) and K1 (IC50=95 μM) were less potent than previously described in PMNs. The pseudo‐substrates for the enzyme (DEA‐BAG, agmatine and arginine‐methylester) also inhibited A7r5 chemotaxis, and in addition inhibited cell adhesion at similar concentrations. Vitamin K3 was unique among the inhibitors of ART, in that it also inhibited cell adhesion.
A rat ART1 transcript was amplified by rtPCR from rat skeletal muscle, and was noted to share 94% homology with the mouse ART1 cDNA sequence. No such transcript could be detected in A7r5 cells by Northern blot analysis or rtPCR.
Evidence for ART activity on the surface of A7r5 cells was investigated using 32P‐NAD+ as substrate, and labelled membrane proteins were observed with MWt values of 116, 100, 90 and 70 kDa. Exposure of the labelled proteins to phosphodiesterase yielded 32P‐AMP, and hydrolysis with NaOH yielded 32P‐NAD+. These results indicated that the labelled proteins were adducts with NAD+, and not the products of ART activity. The absence of ART catalytic activity in A7r5 cells was confirmed in protocols designed to show ADP‐ribosylation of agmatine.
We conclude that the chemotactic activity of A7r5 cells is independent of ART activity, and the mechanism whereby the novel panel of inhibitors reduced cell migration remains undefined.

British Journal of Pharmacology (1998) 125, 152–158; doi:10.1038/sj.bjp.0702027
Investigation on the mechanisms involved in the central protective effect of amylin on gastric ulcers in rats
Authors: Guidobono F , Pagani F , Ticozzi C , Sibilia V , Netti C 
Published: January 2005

The mechanisms involved in the protective effect of amylin (administered into the brain ventricle, i.c.v.) on gastric ulcers induced by the oral administration of ethanol 50% (EtOH, 1 ml/rat) or indomethacin (indomethacin, 20 mg kg−1, at a dosing volume of 5 ml) were investigated in rats.
The possible involvement of endogenous nitric oxide (NO) in the beneficial effect of amylin against EtOH‐induced ulcers was examined. The inhibitor of NO‐synthesis, NG‐nitro‐L‐arginine methyl ester (L‐NAME, 70 mg kg−1, s.c.) was injected 30 min before amylin (2.2 μg/rat, i.c.v.) followed by EtOH after a further 30 min. Rats were sacrified 1 h after EtOH. L‐NAME completely removed the protective effect of amylin.
The interaction between amylin and gastric nonprotein sulfhydryl groups was studied. The rats were treated with N‐ethyl‐maleimide (NEM, 25 mg kg−1, s.c.) 30 min before amylin (2.2 μg/rat, i.c.v.) followed by EtOH 30 min after or by indomethacin 5 min after amylin. Rats were sacrified 1 h or 6 h respectively after EtOH or indomethacin. NEM counteracted the protective effect of amylin against EtOH‐induced ulcers but not against those provoked by indomethacin.
To determine whether amylin was able to promote ulcer healing, the peptide was injected 5 min after EtOH or 1 h after indomethacin. In the case of EtOH, the beneficial effect of amylin was lost whereas it was still effective on indomethacin‐induced ulcers.
The results indicate that: the mechanisms involved in the antiulcer effects of amylin are different in these two types of gastric lesions probably because of the different etiopathology of various types of ulcers. Endogenous NO and nonprotein sulfhydryl groups are involved in the mucosal protective effects of amylin on EtOH and not on indomethacin‐induced ulcers. Furthermore the effectiveness of amylin against indomethacin‐induced lesions when administered after the ulcerogenic process has started suggests that amylin is involved not only in the protection but also in the healing mechanisms in this type of ulcer.

British Journal of Pharmacology (1998) 125, 23–28; doi:10.1038/sj.bjp.0702029
Antithrombotic activity of a monoclonal antibody inducing the substrate form of plasminogen activator inhibitor type 1 in rat models of venous and arterial thrombosis
Authors: Berry C N , Lunven C , Lechaire I , Girardot C , O'Connor S E 
Published: January 2005

Elevated plasminogen activator inhibitor 1 (PAI‐1) is a risk factor for thrombosis, and inhibitors of the interaction between PAI‐1 and tissue plasminogen activator (t‐PA) have antithrombotic and pro‐thrombolytic activity in animals. We describe the antithrombotic effects in the rat of a monoclonal antibody (MA33H1) which converts PAI‐1 to a non‐inhibitory substrate.
The activity of MA33H1 against rat PAI‐1 was confirmed using two‐chain t‐PA and a chromogenic substrate. MA33H1 was evaluated in rat venous (thromboplastin+stasis in the abdominal vena cava) and arterial (electric current applied to a carotid artery) thrombosis models. The effects on tail‐transection bleeding time were studied.
MA33H1 at 100 ng ml−1 inhibited both human (44.1%) and rat PAI‐1 (49.7%). This effect was concentration‐dependent. Its effect on human PAI‐1 was not significantly inhibited by 1 μg ml−1 fibrin or a ≈7 fold molar excess of vitronectin (1 nM). Inhibition of rat PAI‐1 was unchanged by fibrin, but vitronectin reduced inhibition from 0.5 nM.
In the venous thrombosis model, MA33H1 significantly reduced thrombus weights by 38 and 58.6% at 50 and 100 μg kg−1 min−1 i.v. respectively. This effect was inhibited by tranexamic acid. In the arterial model, MA33H1 significantly increased the delay to occlusive thrombus formation by 58 and 142% at 50 and 100 μg kg−1 min−1 i.v., and did not affect bleeding time at 300 μg kg−1 min−1 i.v.
Thus, a monoclonal antibody which transforms PAI‐1 to a t‐PA substrate prevents thrombus formation in the rat with no effect on bleeding time at a higher dose.

British Journal of Pharmacology (1998) 125, 29–34; doi:10.1038/sj.bjp.0702030
Structural determinants for binding to CGRP receptors expressed by human SK‐N‐MC and Col 29 cells: studies with chimeric and other peptides
Authors: Poyner David R , Soomets Ursel , Howitt Stephen G , Langel Ulo 
Published: January 2005

Structure‐activity relationships for the binding of human α‐calcitonin gene‐related peptide 8–37 (hαCGRP8–37) have been investigated at the CGRP receptors expressed by human SK‐N‐MC (neuroblastoma) and Col 29 (colonic epithelia) cells by radioligand binding assays and functional assays (hαCGRP stimulation of adenylate cyclase).
On SK‐N‐MC cells the potency order was hαCGRP8–37>hαCGRP19–37=AC187>rat amylin8–37> hα[Tyr0]‐CGRP28–37 (apparent pKBs of 7.49±0.25, 5.89±0.20, 6.18±0.19, 5.85±0.19 and 5.25±0.07). The SK‐N‐MC receptor appeared CGRP1‐like.
On Col 29 cells, only hαCGRP8–37 of the above compounds was able to antagonize the actions of hαCGRP (apparent pKB=6.48±0.28). Its receptor appeared CGRP2‐like.
hα[Ala11,18]‐CGRP8–37, where the amphipathic nature of the N‐terminal α‐helix has been reduced, bound to SK‐N‐MC cells a 100 fold less strongly than hαCGRP8–37.
On SK‐N‐MC cells, hαCGRP8–18, 28–37 (M433) and mastoparan‐hαCGRP28–37 (M432) had apparent pKBs of 6.64±0.16 and 6.42±0.26, suggesting that residues 19–27 play a minor role in binding. The physico‐chemical properties of residues 8–18 may be more important than any specific side‐chain interactions.
M433 was almost as potent as hαCGRP8–37 on Col 29 cells (apparent pKB=6.17±0.20). Other antagonists were inactive.

British Journal of Pharmacology (1998) 124, 1659–1666; doi:10.1038/sj.bjp.0702032
A discriminant block among K+ channel types by phenytoin in neuroblastoma cells
Authors: Nobile M , Lagostena L 
Published: January 2005

The action of the anticonvulsant drug phenytoin on K+ channels was investigated in neuroblastoma cells (N2A) by using the single‐channel patch‐clamp technique.
N2A cells expressed three types of delayed rectifier K+ channels, which were found to have a conductance of 10–20 pS in a `physiological' K+ gradient. When added to the external solution at concentrations ranging between 1 and 200 μM, phenytoin decreased single channel activity, whereas the unitary current amplitude was unaffected in all three types of channels.
The open probability of the biggest channel decreased, according to an exponential distribution of open and closed times, from 40% in control conditions to 10% in the presence of 50 μM phenytoin (Vm=40 mv). The reduction in the open‐channel probability was concentration‐dependent with a IC50=27.2±0.9 μM.
A transient type of K+ channel was identified that was affected by cumulative inactivation and had a conductance of a mean value equal to 26 pS. Finally, a voltage‐and Ca2+‐dependent K+ channel with a unitary conductance of 95 pS was recorded. Both the channel's amplitude and kinetics were unaffected by phenytoin.
These results confirm the phenytoin effect on K+ currents and suggest that the drug may be considered a selective blocker of delayed rectifier K+ channels.

British Journal of Pharmacology (1998) 124, 1698–1702; doi:10.1038/sj.bjp.0702035
Tumour necrosis factor‐α as a target of melanocortins in haemorrhagic shock, in the anaesthetized rat
Authors: Altavilla Domenica , Cainazzo Maria‐Michela , Squadrito Francesco , Guarini Salvatore , Bertolini Alfio , Bazzani Carla 
Published: January 2005

The cytokine tumour necrosis factor‐α (TNF‐α) is involved (mostly through the activation of inducible nitric oxide synthase) in the pathogenesis of circulatory shock. On the other hand, melanocortin peptides are potent and effective in reversing haemorrhagic shock, both in animals (rat, dog) and in humans. This prompted us to study the influence of the melanocortin peptide ACTH‐(1–24) on the blood levels of TNF‐α in haemorrhage‐shocked rats and on the in vitro production of TNF‐α by lipopolysaccharide (LPS)‐activated macrophages. Plasma levels of TNF‐α were undetectable before starting bleeding and greatly increased 20 min after bleeding termination in saline‐treated rats. In rats treated with ACTH‐(1–24) the almost complete restoration of cardiovascular function was associated with markedly reduced levels of TNF‐α 20 min after bleeding termination. On the other hand, ACTH‐(1–24) did not influence TNF‐α plasma levels in sham‐operated, unbled rats. In vitro, ACTH‐(1–24) (25–100 nM) dose‐dependently reduced the LPS‐stimulated production of TNF‐α by peritoneal macrophages harvested from untreated, unbled rats. These results indicate that inhibition of TNF‐α overproduction may be an important component of the mechanism of action of melanocortins in reversing haemorrhagic shock.British Journal of Pharmacology (1998) 124, 1587–1590; doi:10.1038/sj.bjp.0702038
Cytokine induction of NO synthase II in human DLD‐1 cells: roles of the JAK‐STAT, AP‐1 and NF‐κB‐signaling pathways
Authors: Kleinert Hartmut , Wallerath Thomas , Fritz Gerhard , Ihrig‐Biedert Irmgard , Rodriguez‐Pascual Fernando , Geller David A , Forstermann Ulrich 
Published: January 2005

In human epithelial‐like DLD‐1 cells, nitric oxide synthase (NOS) II expression was induced by interferon‐γ (100 u ml−1) alone and, to a larger extent, by a cytokine mixture (CM) consisting of interferon‐γ, interleukin‐1β (50 u ml−1) and tumor necrosis factor‐α (10 ng ml−1).
CM‐induced NOS II expression was inhibited by tyrphostin B42 (mRNA down to 1%; nitrite production down to 0.5% at 300 μM) and tyrphostin A25 (mRNA down to 24%, nitrite production down to 1% at 200 μM), suggesting the involvement of janus kinase 2 (JAK‐2). Tyrphostin B42 also blocked the CM‐induced JAK‐2 phosphorylation (kinase assay) and reduced the CM‐stimulated STAT1α binding activity (gel shift analysis).
CM reduced the nuclear binding activity of transcription factor AP‐1. A heterogenous group of compounds, that stimulated the expression of c‐fos/c‐jun, enhanced the nuclear binding activity of AP‐1. This group includes the protein phosphatase inhibitors calyculin A, okadaic acid, and phenylarsine oxide, as well as the inhibitor of translation anisomycin. All of these compounds reduced CM‐induced NOS II mRNA expression (to 9% at 50 nM calyculin A; to 28% at 500 nM okadaic acid; to 18% at 10 μM phenylarsine oxide; and to 19% at 100 ng ml−1 anisomycin) without changing NOS II mRNA stability. In cotransfection experiments, overexpression of c‐Jun and c‐Fos reduced promoter activity of a 7 kb DNA fragment of the 5′‐flanking sequence of the human NOS II gene to 63%.
Nuclear extracts from resting DLD‐1 cells showed significant binding activity for transcription factor NF‐κB, which was only slightly enhanced by CM. The NF‐κB inhibitors dexamethasone (1 μM), 3,4‐dichloroisocoumarin (50 μM), panepoxydone (5 μg ml−1) and pyrrolidine dithiocarbamate (100 μM) produced no inhibition of CM‐induced NOS II induction.
We conclude that in human DLD‐1 cells, the interferon‐γ–JAK‐2‐STAT1α pathway is important for NOS II induction. AP‐1 (that is downregulated by CM) seems to be a negative regulator of NOS II expression. NF‐κB, which is probably important for basal activity of the human NOS II promoter, is unlikely to function as a major effector of CM in DLD‐1 cells.

British Journal of Pharmacology (1998) 125, 193–201; doi:10.1038/sj.bjp.0702039
The transport of the anti‐HIV drug, 2′,3′‐didehydro‐3′‐deoxythymidine (D4T), across the blood‐brain and blood‐cerebrospinal fluid barriers
Authors: Thomas Sarah A , Segal Malcolm B 
Published: January 2005

The brain is a site of infection, viral replication and sanctuary for HIV‐1. The treatment of HIV‐1 infection therefore requires that an effective agent be delivered to the brain. 2′,3′‐Didehydro‐3′‐deoxythymidine (D4T) is a nucleoside analogue which has been shown to have beneficial clinical effects in the treatment of HIV infection. However, although D4T has been detected in human CSF, the ability of this drug to cross both the blood‐brain and blood‐cerebrospinal fluid (CSF) barriers and gain entrance into the brain tissue is not known.
This study examined the CNS entry of D4T by means of the bilateral vascular brain perfusion technique in the anaesthetized guinea‐pig.
The results indicated that [3H]‐D4T had a limited ability to cross the blood‐brain barrier (BBB), which was not significantly greater than D‐[14C]‐mannitol (a slowly penetrating marker molecule). Although D4T was found to cross the blood‐CSF barrier, the presence of D4T in the CSF did not reflect levels of the drug in the brain tissue.
These results can be related to the measured low lipophilicity of D4T, the higher paracellular permeability characteristics of the choroid plexus (blood‐CSF barrier) compared to the BBB, and the sink action nature of the CSF to the brain tissue.
In conclusion, these animal studies suggest that D4T may only penetrate the brain tissue to a limited extent and consideration should be given to these findings in the clinical situation.

British Journal of Pharmacology (1998) 125, 49–54; doi:10.1038/sj.bjp.0702044
Endothelin‐1 stimulates sodium‐dependent calcium efflux from bovine adrenal chromaffin cells in culture
Authors: Houchi Hitoshi , Yoshizumi Masanori , Tsuchiya Koichiro , Hirose Masao , Kitagawa Tetsuya , Kujime Toshihide , Shimizu Eiji , Niwa Yasuharu , Minakuchi Kazuo , Tamaki Toshiaki 
Published: January 2005

The effect of endothelin (ET)‐1 on Ca2+ efflux from cultured bovine adrenal chromaffin cells was examined. ET‐1 (10−7 M) significantly increased intracellular free Ca2+ level ([Ca2+]i), 45Ca2+ uptake and catecholamine secretion in the cells. 2. ET‐1 stimulated the efflux of 45Ca2+ from the cells preloaded with 45Ca2+ in a concentration‐dependent manner (10−9–10−7 M). This stimulatory effect was inhibited by ETB receptor antagonist BQ788, but not by ETA receptor antagonist BQ123. Selective ETB receptor agonists Suc‐[Glu9, Ala11,15]‐ET‐1 and sarafotoxin S6c (SRTX) also stimulated 45Ca2+ efflux from the cells.
ET‐1, Suc‐[Glu9, Ala11,15]‐ET‐1 and SRTX increased the level of cyclic GMP in the adrenal chromaffin cells. ET‐1 induced an increase in the nitric oxide (NO) level in the cells. The stimulatory effects by which ET‐1 increases NO level and 45Ca2+ efflux were inhibited by NG‐monomethyl‐L‐arginine acetate (L‐NMMA), a competitive inhibitor of NO synthase.
The 45Ca2+ efflux stimulated by ET‐1 was inhibited by deprivation of extracellular Na+, but not by deprivation of Ca2+.
These results suggest that ET‐1 stimulates an extracellular Na+‐dependent Ca2+ efflux through the activation of NO synthase in cultured bovine adrenal chromaffin cells.

British Journal of Pharmacology (1998) 125, 55–60; doi:10.1038/sj.bjp.0702047
Involvement of barium‐sensitive K+ channels in endothelium‐dependent vasodilation produced by hypercapnia in rat mesenteric vascular beds
Authors: Okazaki Kaoru , Endou Masayuki , Okumura Fukuichiro 
Published: January 2005

We examined the vasodilatory effect of hypercapnia in the rat isolated mesenteric vascular bed. The preparation was perfused constantly (5 ml min−1 with oxygenated Krebs‐Ringer solution, and the perfusion pressure was measured. In order to keep the extracellular pH (pHe) constant (around 7.35) against a change in CO2, adequate amounts of NaHCO3 were added to Krebs‐Ringer solution.
In the endothelium intact preparations, an increase in CO2 from 2.5% to 10% in increments of 2.5% decreased the 10 μM phenylephrine (PE)‐produced increase in the perfusion pressure in a concentration‐dependent manner. Denudation of the endothelium by CHAPS (3‐[(3‐cholamidopropyl)‐dimethylammonio]‐l‐propanesulphonate) (5 mg l−1, 90 s perfusion) abolished the vasodilatory effect of hypercapnia.
An increase in CO2 from 5% to 10% reduced the increases in the perfusion pressure produced by 10 μM PE and 400 nM U‐46619 by 48% and 44%, respectively. NG‐monomethyl‐L‐arginine (100 μM) and indomethacin (10 μM) did not affect the vasodilatory effect of hypercapnia, whereas the vasodilatory response of the preparation to hypercapnia disappeared when the preparation was contracted by 60 mM K+ instead of PE or U‐46619.
The vasodilatory effect of hypercapnia observed in the PE‐ or U‐46619‐precontracted preparation was affected by neither tetraethylammonium (1 mM), apamin (500 μM), glibenclamide (10 μM), nor 4‐aminopyridine (1.5 mM). On the other hand, pretreatment with Ba2+ at a concentration of 0.3 mM abolished the hypercapnia‐produced vasodilation.
An increase in the concentration of K+ in Krebs‐Ringer solution from 4.5 mM to 12.5 mM in increments of 2 mM reduced the PE‐produced increase in the perfusion pressure in a concentration‐dependent manner. Pretreatment of the preparations with not only Ba2+ (0.3 mM) but also CHAPS abolished the vasodilatory effect of K+.
The results suggest that an increase in CO2 produces vasodilation by an endothelium‐dependent mechanism in the rat mesenteric vascular bed. The membrane hyperpolarization of the endothelial cell by an activation of the inward rectifier K+ channel seems to be the mechanism underlying the hypercapnia‐produced vasodilation. Neither nitric oxide nor prostaglandins are involved in this response.

British Journal of Pharmacology (1998) 125, 168–174; doi:10.1038/sj.bjp.0702048