bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nitric oxide‐mediated modulation of the endothelin‐1 signalling pathway in the human cardiovascular system
Authors: Wiley Katherine E , Davenport Anthony P 
Published: January 2005

We studied the ability of nitric oxide (NO) to physiologically antagonize endothelin‐1 (ET‐1) induced constrictions in human internal mammary artery (IMA). We also investigated the hypothesis that NO interacts directly with ET‐receptor binding in human heart and aorta.
ET‐1 potently contracted IMA (EC50 6.86 nM, 95% CI: 3.5 – 13.4 nM; n=12). The constrictor response to 10 nM ET‐1 was fully reversed by the NO‐donor diethylamine NONOate (DEA/NO; EC50 2.0 μM, 95% CI: 0.8 – 4.8 μM; n=5). The guanylate cyclase inhibitor ODQ (100 μM) reduced the response to DEA/NO but did not abolish it (EMAX 50.9±8.5% in the presence of ODQ; 113.0±8.4%, control).
The increase in cyclic GMP by 30 μM DEA/NO was abolished in the presence of 100 μM ODQ (n=6).
In saturation binding experiments the NO‐donor Diethyltriamine NONOate (DETA/NO; 1 mM) caused a 90% reduction in maximum binding of [125I]‐ET‐1 in human heart, without affecting the affinity. This reduction in binding was abolished by haemoglobin. Pre‐incubating either the radiolabel or the tissue with NO‐donors did not reduce binding. A similar effect was observed in aortic smooth muscle.
We have shown that DEA/NO is able to reverse ET‐1‐induced contractions in the human vasculature. The binding studies suggest a direct interaction between NO and the ET receptor or receptor‐ligand complex in human ventricular and aortic tissue. NO is released continuously in vivo, thus this apparent modification of ET‐receptor binding may provide an additional mechanism by which NO counter‐balances the effects of ET.

British Journal of Pharmacology (2001) 132, 213–220; doi:10.1038/sj.bjp.0703834
A comparison of the effect of nitroparacetamol and paracetamol on liver injury
Authors: Futter L E , Al‐Swayeh O A , Moore P K 
Published: January 2005

Paracetamol (5 mmol kg−1, i.p.) caused liver damage in rats as indicated by increased plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and glutamate dehydrogenase (GDH) activities. No change in plasma bilirubin or creatinine was noted. An equimolar dose of nitroparacetamol (a nitric oxide (NO)‐releasing derivative of paracetamol) did not alter plasma levels of any of the markers of liver/kidney damage. No difference in plasma or liver paracetamol was apparent in animals injected with paracetamol or nitroparacetamol. These results indicate that NO released from nitroparacetamol exhibits hepatoprotective activity in these animals and suggest that nitroparacetamol may therefore be considered as a safer alternative to paracetamol in the clinic.British Journal of Pharmacology (2001) 132, 10–12; doi:10.1038/sj.bjp.0703837
Chlorpromazine inhibits store‐operated calcium entry and subsequent noradrenaline secretion in PC12 cells
Authors: Choi Se‐Young , Kim Yong‐Hyun , Lee Yong‐Kyu , Kim Kyong‐Tai 
Published: January 2005

The effect of chlorpromazine on the store‐operated Ca2+ entry activated via the phospholipase C signalling pathway was investigated in PC12 cells.
Chlorpromazine inhibited the sustained increase after the initial peak in the intracellular Ca2+ concentration produced by bradykinin while having no effect on the initial transient response. The inhibition was lowered by the removal of extracellular free Ca2+. However, chlorpromazine did not inhibit bradykinin‐induced inositol 1,4,5‐trisphosphate production.
Chlorpromazine inhibited the bradykinin‐induced noradrenaline secretion in a concentration‐dependent manner (IC50: 24±5 μM, n=3).
To test for a direct effect of chlorpromazine on store‐operated Ca2+ entry, thapsigargin, an inhibitor of microsomal Ca2+‐ATPase, was used to induce store‐operated Ca2+ entry in PC12 cells. Chlorpromazine reduced the thapsigargin‐induced sustained Ca2+ level (IC50: 24±2 μM, n=3), and the inhibition also occluded the inhibitory action of 1‐[‐[3‐(4‐methoxyphenyl) propoxy]‐4‐methoxyphenyl]‐1H‐imidazole hydrochloride (SK&F96365).
The results suggest that chlorpromazine negatively modulates the store‐operated Ca2+ entry activated subsequent to PLC activation.

British Journal of Pharmacology (2001) 132, 411–418; doi:10.1038/sj.bjp.0703840
Two subtypes of G protein‐coupled nucleotide receptors, P2Y1 and P2Y2 are involved in calcium signalling in glioma C6 cells
Authors: Sabała Paweł , Czajkowski Rafał , Przybyłek Krzysztof , Kalita Katarzyna , Kaczmarek Leszek , Barańska Jolanta 
Published: January 2005

In glioma C6 cells, the stimulation of P2Y receptors by ADP, ATP and UTP initiated an increase in the intracellular Ca2+ concentration, in a process that involved the release of Ca2+ from InsP3‐sensitive store and the capacitative, extracellular Ca2+ entry. The presence of external Ca2+ was not necessary to elevate Ca2+.
The rank order of potencies of nucleotide analogues in stimulating [Ca2+]i was: 2MeSADP > ADP > 2MeSATP = 2ClATP > ATP > UTP. α,β‐Methylene ATP, adenosine and AMP were ineffective.
ADP and UTP effects were additive, while actions of ATP and UTP were not additive on [Ca2+]i increase. Similarly, cross‐desensitization between ATP and UTP but not between ADP and UTP occurred.
Suramin, a non‐specific nucleotide receptors inhibitor, antagonized ATP‐, UTP‐ and ADP‐evoked Ca2+ responses. PPADS, a selective antagonist of the P2Y1 receptor‐generated InsP3 accumulation, decreased ADP‐initiated Ca2+ response with no effect on ATP and UTP.
Pertussis toxin (PTX) reduced ADP‐ and ATP‐induced Ca2+ increases. Short‐term treatment with TPA, inhibited both ATP and ADP stimulatory effects on [Ca2+]i.
ADP inhibited isoproterenol‐induced cyclic AMP accumulation. PTX blocked this effect, but PPADS did not.
RT – PCR analysis revealed the molecular identity of P2Y receptors expressed by glioma C6 cells to be both P2Y1 and P2Y2.
It is concluded that both P2Y1 and P2Y2 receptors co‐exist in glioma C6 cells. ADP acts as agonist of the first, and ATP and UTP of the second one. Both receptors are linked to phospholipase C (PLC).

British Journal of Pharmacology (2001) 132, 393–402; doi:10.1038/sj.bjp.0703843
Influence of reduced glutathione on the proliferative response of sulfamethoxazole‐specific and sulfamethoxazole‐metabolite‐specific human CD4+ T‐cells
Authors: Burkhart Christoph , Von Greyerz Salome , Depta Jan P H , Naisbitt Dean J , Britschgi Markus , Park Kevin B , Pichler Werner J 
Published: January 2005

Hypersensitivity to the drug sulfamethoxazole (SMX) is thought to be a consequence of bioactivation to the hydroxylamine metabolite (SMX‐NHOH) and further oxidation to the ultimate reactive metabolite, nitroso‐sulfamethoxazole (SMX‐NO). SMX‐NO covalently modifies self proteins which in turn might be recognized as neo‐antigens by T‐cells. The antioxidant glutathione (GSH) is known to protect cells from reactive metabolites by conjugation and subsequent dissociation to SMX‐NHOH and/or SMX.
To study the reactivity of T‐cells to SMX metabolites and their respective role in the generation of drug‐specific T‐cells, we analysed the effect of GSH on the response of PBMC to SMX and its metabolites SMX‐NHOH and SMX‐NO. Furthermore, we monitored the proliferative response of drug‐specific T‐cell clones in the presence or absence of GSH.
We found that addition of GSH to peripheral blood mononuclear cells had no effect on the SMX‐specific response but enhanced the proliferation to SMX‐metabolites. The response of SMX‐NO‐specific T‐cell clones was abrogated when GSH was present during the covalent haptenation of antigen presenting cells (APC). Conversely, SMX‐specific T‐cell clones gained reactivity through the conversion of SMX‐NO to the parent drug by GSH. While GSH had no effect on the initial activation of T‐cell clones, it prevented covalent binding to APCs, reduced toxicity and thereby led to proliferation of drug‐specific T‐cells to non‐reactive drug metabolites.
Our data support the concept that in allergic individuals T‐cells recognize the non‐covalently bound parent drug rather than APC covalently modified by SMX‐NO.

British Journal of Pharmacology (2001) 132, 623–630; doi:10.1038/sj.bjp.0703845
The effects of P2Y receptor agonists and adenosine on prostaglandin production by the guinea‐pig uterus
Authors: Aitken Heather , Poyser N L , Hollingsworth M 
Published: January 2005

This study has investigated the effects adenosine 5′‐triphosphate (ATP), analogues of ATP, uridine 5′‐triphosphate (UTP) and adenosine on prostaglandin output from the guinea‐pig uterus superfused in vitro, and from guinea‐pig endometrium and myometrium cultured for 24 h.
ATP, 2‐methylthio ATP and adenosine increased the outputs of prostaglandin F2α (PGF2α) and 6‐keto‐PGF1α (reflecting PGI2 production), and UTP increased the output of PGF2α from the superfused guinea‐pig uterus. These findings support the hypothesis that the contractile effects of ATP, 2‐methylthio ATP, UTP and adenosine are mediated by prostaglandins.
Suramin (a P2 receptor antagonist) and 8‐sulphophenyltheophylline (an A receptor antagonist) blocked the stimulatory actions of ATP and adenosine, respectively, on PGF2α output, suggesting that ATP acts on P2 receptors (probably of the P2Y type) and adenosine acts on A receptors in the guinea‐pig uterus to increase PGF2α production.
ATP, 2‐methylthio ATP, α,β‐methylene ATP, β,γ‐methylene ATP, UTP and adenosine increased the output of PGF2α from guinea‐pig endometrium and myometrium after 24 h of culture, with a greater stimulatory effect being exerted on the endometrium than on the myometrium. Little or no stimulatory effect was seen after 2 and 8 h of culture. In addition the effects of ATP, ATP analogues, UTP and adenosine on the outputs of PGE2 and 6‐keto‐PGF1α from cultured endometrium and myometrium were more variable, with both stimulation and inhibition being observed.
The stimulatory effects of ATP and adenosine on PGF2α output from the endometrium and myometrium were associated with an increase in the prostaglandin synthesizing capacity of both tissues, due probably to an increase in the amount of prostaglandin H synthase present.

British Journal of Pharmacology (2001) 132, 709–721; doi:10.1038/sj.bjp.0703848
The differential effect of propofol on contractility of isolated myocardial trabeculae of rat and guinea‐pig
Authors: Klarenbosch J van , Stienen G J M , Ruijter W de , Scheffer G J , Lange J J de 
Published: January 2005

The effects of propofol on myocardial contractility were studied in rat, in which the contractile activation mainly depends on calcium derived from the sarcoplasmic reticulum (SR), and guinea‐pig, in which transsarcolemmal influx of calcium plays a major role.
Intact and chemically skinned trabeculae from the right ventricle were studied. Intact trabeculae were electrically stimulated and force development during steady state and post rest contractions was measured. In saponin skinned trabeculae Ca2+ uptake and release by the SR was studied. In Triton skinned trabeculae the influence of propofol on calcium sensitivity of the myofilaments was studied.
In intact rat trabeculae propofol in concentrations of 28, 112 and 280 μM did not change peak force development nor the pattern of post rest contraction. In guinea‐pig trabeculae propofol significantly reduced peak force to respectively 64, 40 and 23% of control values and the post rest contractions were potentiated. In skinned trabeculae propofol did not affect Ca2+ handling by the SR, nor did it change force production and Ca2+ sensitivity of the myofilaments.
This study shows that, in contrast to rat, in guinea‐pig propofol directly depresses myocardial contractility, probably by decreasing transsarcolemmal Ca2+ influx. There is no significant influence of propofol on Ca2+ handling by the SR, nor on the contractile proteins.

British Journal of Pharmacology (2001) 132, 742–748; doi:10.1038/sj.bjp.0703849
Structure‐activity relationship for the endogenous cannabinoid, anandamide, and certain of its analogues at vanilloid receptors in transfected cells and vas deferens
Authors: Ross Ruth A , Gibson T Michael , Brockie Heather C , Leslie Mark , Pashmi Ghazaleh , Craib Susan J , Di Marzo Vincenzo , Pertwee Roger G 
Published: January 2005

This study was directed at exploring the structure‐activity relationship for anandamide and certain of its analogues at the rat VR1 receptor in transfected cells and at investigating the relative extent to which anandamide interacts with CB1 and vanilloid receptors in the mouse vas deferens.
pKi values for displacement of [3H]‐resiniferatoxin from membranes of rVR1 transfected CHO cells were significantly less for anandamide (5.78) than for its structural analogues N‐(4‐hydroxyphenyl)‐arachidonylamide (AM404; 6.18) and N‐(3‐methoxy‐4‐hydroxy)benzyl‐arachidonylamide (arvanil; 6.77).
pEC50 values for stimulating 45Ca2+ uptake into rVR1 transfected CHO cells were significantly less for anandamide (5.80) than for AM404 (6.32) or arvanil (9.29). Arvanil was also significantly more potent than capsaicin (pEC50=7.37), a compound with the same substituted benzyl polar head group as arvanil.
In the mouse vas deferens, resiniferatoxin was 218 times more potent than capsaicin as an inhibitor of electrically‐evoked contractions. Both drugs were antagonized to a similar extent by capsazepine (pKB=6.93 and 7.18 respectively) but were not antagonized by SR141716A (1 μM). Anandamide was less susceptible than capsaicin to antagonism by capsazepine (pKB=6.02) and less susceptible to antagonism by SR141716A (pKB=8.66) than methanandamide (pKB=9.56). WIN55212 was antagonized by SR141716A (pKB=9.02) but not by capsazepine (10 μM).
In conclusion, anandamide and certain of its analogues have affinity and efficacy at the rat VR1 receptor. In the mouse vas deferens, which seems to express vanilloid and CB1 receptors, both receptor types appear to contribute to anandamide‐induced inhibition of evoked contractions.

British Journal of Pharmacology (2001) 132, 631–640; doi:10.1038/sj.bjp.0703850
Bradykinin attenuates the [Ca2+]i response to angiotensin II of renal juxtamedullary efferent arterioles via an EDHF
Authors: Marchetti Jeannine , Praddaude Françoise , Rajerison Rabary , Ader Jean‐Louis , Alhenc‐Gelas François 
Published: January 2005

Bradykinin (BK) effect on the [Ca2+]i response to 1 nM angiotensin II was examined in muscular juxtamedullary efferent arterioles (EA) of rat kidney.
BK (10 nM) applied during the angiotensin II‐stimulated [Ca2+]i increase, induced a [Ca2+]i drop (73±2%). This drop was prevented by de‐endothelialization and suppressed by HOE 140, a B2 receptor antagonist. It was neither affected by L‐NAME or indomethacin, nor mimicked by sodium nitroprusside, 8‐bromo‐cyclic GMP or PGI2. The BK effect did not occur when the [Ca2+]i increase was caused by 100 mM KCl‐induced membrane depolarization and was abolished by 0.1 μM charybdotoxin, a K+ channel blocker.
Although proadifen prevented the BK‐caused [Ca2+]i fall, more selective cytochrome P450 inhibitors, 17‐octadecynoic acid (50 μM) and 7‐ethoxyresorufin (10 μM) were without effect.
Increasing extracellular potassium from 5 to 15 mM during angiotensin II stimulation caused a [Ca2+]i decrease (26±4%) smaller than BK which was charybdotoxin‐insensitive. Inhibition of inward rectifying K+ channels by 30 μM BaCl2 and/or of Na+/K+ ATPase by 1 mM ouabain abolished the [Ca2+]i decrease elicited by potassium but not by BK.
A voltage‐operated calcium channel blocker, nifedipine (1 μM) did not prevent the BK effect but reduced the [Ca2+]i drop.
These results indicate that the BK‐induced [Ca2+]i decrease in angiotensin II‐stimulated muscular EA is mediated by an EDHF which activates charybdotoxin‐sensitive K+ channels. In these vessels, EDHF seems to be neither a cytochrome P450‐derived arachidonic acid metabolite nor K+ itself. The closure of voltage‐operated calcium channels is not the only cellular mechanism involved in this EDHF‐mediated [Ca2+]i decrease.

British Journal of Pharmacology (2001) 132, 749–759; doi:10.1038/sj.bjp.0703851
Direct cardiac effects of intracoronary bupivacaine, levobupivacaine and ropivacaine in the sheep
Authors: Chang Dennis H‐T , Ladd Leigh A , Copeland Susan , Iglesias Miguel A , Plummer John L , Mather Laurence E 
Published: January 2005

The racemic local anaesthetic agent bupivacaine is widely used clinically for its long duration of action. Levobupivacaine and ropivacaine are bupivacaine enantiopure congeners, developed to improve upon the clinical safety of bupivacaine, especially the risk of fatal arrhythmogenesis.In previous preclinical studies of the safety of these drugs with intravenous administration in conscious ewes over a wide dose range, we found that central nervous system (CNS) excito‐toxicity reversed the cardiac depressant effects when doses approached the convulsant threshold and thus precluded accurate comparison of their cardiovascular system (CVS) effects.To study CVS effects over a wide range of doses with minimal CNS and other influences, brief (3 min) infusions of bupivacaine, levobupivacaine or ropivacaine were administered into the left main coronary arteries of previously instrumented conscious ewes (∼50 Kg body weight). After dose‐ranging studies, the drugs were compared in a randomized, blinded, parallel group design. Equimolar doses were increased from 8 μmol (∼amp;2.5 mg) in 8 μmol increments, to either a fatal outcome or a 40 μmol (∼amp;12.5 mg) maximum.All three drugs produced tachycardia, decreased myocardial contractility and stroke volume and widening of electrocardiographic QRS complexes. Thirteen of 19 animals died of ventricular fibrillation: four of six with bupivacaine (mean±s.e.mean actual fatal dose: 21.8±6.4 μmol), five of seven with levobupivacaine (22.9±3.5 μmol), four of six with ropivacaine (22.9±5.9 μmol). No significant differences in survival or in fatal doses between these drugs were found.The findings suggest that ropivacaine, levobupivacaine and bupivacaine have similar intrinsic ability to cause direct fatal cardiac toxicity when administered by left intracoronary arterial infusion in conscious sheep and do not explain the differences between the drugs found with intravenous dosage.British Journal of Pharmacology(2001)132, 649–658; doi:10.1038/sj.bjp.0703858
Angiotensin II is involved in nitric oxide synthase and cyclo‐oxygenase inhibition‐induced leukocyte‐endothelialcell interactions in vivo
Authors: Alvarez Angeles , Piqueras Laura , Bello Regina , Canet Amparo , Moreno Lucrecia , Kubes Paul , Sanz Maria‐Jesus 
Published: January 2005

Chronic inhibition of nitric oxide synthase (NOS) provokes a hypertensive state which has been shown to be angiotensin II (Ang‐II) dependent. In addition to raising blood pressure, NOS inhibition also causes leukocyte adhesion. The present study was designed to define the role of Ang‐II in hypertension and in the leukocyte‐endothelial cell interactions induced by acute NOS or cyclo‐oxygenase (COX) inhibition using intravital microscopy within the rat mesenteric microcirculation.
While pretreatment with an Ang‐II AT1 receptor antagonist (losartan) reversed the prompt increase in mean arterial blood pressure (MABP) caused by indomethacin, it had no effect on the increase evoked by systemic L‐NAME administration.
Pretreatment with losartan inhibited the leukocyte rolling flux, adhesion and emigration which occurs after 60 min NOS inhibition by 83, 80 and 70% respectively, and returned leukocyte rolling velocity to basal levels.
Losartan significantly reduced the leukocyte‐endothelial cell interaction elicited by COX inhibition. In contrast, leukocyte recruitment induced by acute mast cell activation was not inhibited by losartan.
AT1 receptor blockade also prevented the drop in haemodynamic parameters such as mean red blood cell velocity (Vmean) and shear rate caused by NOS and COX inhibition.
In this study, we have demonstrated a clear role for Ang‐II in the leukocyte‐endothelial cell interactions and haemodynamic changes which arise in the absence of NO or prostacyclin (PGI2). This is of interest since leukocyte recruitment, which culminates in the vascular lesions that occur in hypertension, atherosclerosis and myocardial ischemia‐reperfusion injury, might be prevented using AT1 Ang‐II receptor antagonists.

British Journal of Pharmacology (2001) 132, 677–684; doi:10.1038/sj.bjp.0703867
Upregulation of vasopressin V1A receptor mRNA and protein in vascular smooth muscle cells following cyclosporin A treatment
Authors: Cottet‐Maire Florence , Avdonin Pavel V , Roulet Emmanuelle , Buetler Timo M , Mermod Nicolas , Ruegg Urs T 
Published: January 2005

The major side effects of the immunosuppressive drug cyclosporin A (CsA) are hypertension and nephrotoxicity. It is likely that both are caused by local vasoconstriction.

We have shown previously that 20 h treatment of rat vascular smooth muscle cells (VSMC) with therapeutically relevant CsA concentrations increased the cellular response to [Arg8]vasopressin (AVP) by increasing about 2 fold the number of vasopressin receptors.

Displacement experiments using a specific antagonist of the vasopressin V1A receptor (V1AR) showed that the vasopressin binding sites present in VSMC were exclusively receptors of the V1A subtype.

Receptor internalization studies revealed that CsA (10−6 M) did not significantly alter AVP receptor trafficking.

V1AR mRNA was increased by CsA, as measured by quantitative polymerase chain reaction. Time‐course studies indicated that the increase in mRNA preceded cell surface expression of the receptor, as measured by hormone binding.

A direct effect of CsA on the V1AR promoter was investigated using VSMC transfected with a V1AR promoter‐luciferase reporter construct. Surprisingly, CsA did not increase, but rather slightly reduced V1AR promoter activity. This effect was independent of the cyclophilin‐calcineurin pathway.

Measurement of V1AR mRNA decay in the presence of the transcription inhibitor actinomycin D revealed that CsA increased the half‐life of V1AR mRNA about 2 fold.

In conclusion, CsA increased the response of VSMC to AVP by upregulating V1AR expression through stabilization of its mRNA. This could be a key mechanism in enhanced vascular responsiveness induced by CsA, causing both hypertension and, via renal vasoconstriction, reduced glomerular filtration.

British Journal of Pharmacology (2001) 132, 909–917; doi:10.1038/sj.bjp.0703878
Role of ETBand B2receptors in theex vivoplatelet inhibitory properties of endothelin and bradykinin in the mouse
Authors: Labonté Julie , Brochu Isabelle , Honoré Jean‐Claude , D'Orléans‐Juste Pedro 
Published: January 2005

We have developed a model to study the inhibitory properties of endogenous autacoids triggered by systemically‐administered vasoactive peptides, on platelet aggregationex vivoin the mouse.Adenosine diphosphate (ADP) (0.5 – 10 μM) induces a concentration‐dependent aggregation of platelet‐rich plasma derived from C57BL/6 mice. Intravenously‐administered endothelin‐1 (0.01 – 1 nmol kg−1), the selective ETBagonist, IRL‐1620 (0.01 – 1 nmol kg−1) or bradykinin (1 – 100 nmol kg−1) significantly reduced in a dose‐dependent fashion the ADP‐induced platelet aggregation.The non‐selective cyclo‐oxygenase (COX) inhibitor, indomethacin, a selective COX‐2 inhibitor NS‐398 or the prostacyclin synthase inhibitor, tranylcypromine (10 mg kg−1), markedly reduced the inhibitory properties of endothelin‐1, whereas only a combination of both indomethacin, NS‐398 or tranylcypromine andL‐NAME (10 mg kg−1) were required to abolish the response to bradykinin.An ETB‐selective antagonist (BQ‐788) or knockout of the B2receptor gene (in B2knockout mice) abolishes the platelet inhibitory properties of endothelin‐1 and bradykinin, respectively.Our results suggest that intravenously‐administered endothelin‐1 and bradykinin, through ETBand B2receptor activation, respectively, inhibit platelet aggregationex vivoin the mouse. The inhibitory properties of endothelin‐1 require the activation of COX‐2 and the subsequent generation of prostacyclin. In addition to the two previously mentioned factors, nitric oxide is required for the anti‐aggregatory effects of bradykinin.British Journal of Pharmacology(2001)132, 934–940; doi:10.1038/sj.bjp.0703880