bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacology of nociceptin and its receptor: a novel therapeutic target
Authors: Calo' Girolamo , Guerrini Remo , Rizzi Anna , Salvadori Severo , Regoli Domenico 
Published: January 2005

Nociceptin (NC), alias Orphanin FQ, has been recently identified as the endogenous ligand of the opioid receptor‐like 1 receptor (OP4). This new NC/OP4 receptor system belongs to the opioid family and has been characterized pharmacologically with functional and binding assays on native (mouse, rat, guinea‐pig) and recombinant (human) receptors, by using specific and selective agonists (NC, NC(1–13)NH2) and a pure and competitive antagonist, [Nphe1]NC(1–13)NH2. The similar order of potency of agonists and affinity values of the antagonist indicate that the same receptor is present in the four species. OP4 is expressed in neurons, where it reduces activation of adenylyl cyclase and Ca2+ channels while activating K+ channels in a manner similar to opioids. In this way, OP4 mediates inhibitory effects in the autonomic nervous system, but its activities in the central nervous system can be either similar or opposite to those of opioids. In vivo experiments have demonstrated that NC modulates a variety of biological functions ranging from nociception to food intake, from memory processes to cardiovascular and renal functions, from spontaneous locomotor activity to gastrointestinal motility, from anxiety to the control of neurotransmitter release at peripheral and central sites. These actions have been demonstrated using NC and various pharmacological tools, as antisense oligonucleotides targeting OP4 or the peptide precursor genes, antibodies against NC, an OP4 receptor selective antagonist and with data obtained from animals in which the receptor or the peptide precursor genes were knocked out. These new advances have contributed to better understanding of the pathophysiological role of the NC/OP4 system, and ultimately will help to identify the therapeutic potential of new OP4 receptor ligands.British Journal of Pharmacology (2000) 129, 1261–1283; doi:10.1038/sj.bjp.0703219
Effects of inhibitors of small‐ and intermediate‐conductance calcium‐activated potassium channels, inwardly‐rectifying potassium channels and Na+/K+ ATPase on EDHF relaxations in the rat hepatic artery
Authors: Andersson David A , Zygmunt Peter M , Movahed Pouya , Andersson Tomas L G , Högestätt Edward D 
Published: January 2005

In the rat hepatic artery, the SKCa inhibitors UCL 1684 (300 nM) completely blocked, and scyllatoxin (1 μM) and d‐tubocurarine (100 μM) partially inhibited EDHF relaxations when each of them was combined with charybdotoxin (300 nM).
The IKCa inhibitors clotrimazole (3 μM) and 2‐chlorophenyl‐bisphenyl‐methanol (3 μM) strongly depressed EDHF relaxations when each of them was combined with apamin (300 nM). The cytochrome P450 mono‐oxygenase inhibitor ketoconazole (10 μM) had no effect in the presence of apamin.
Ciclazindol (10 μM), which abolishes EDHF relaxations in the presence of apamin, almost completely prevented the calcium ionophore (A23187) stimulated 86Rb+ influx via the Gardos channel (IKCa) in human erythrocytes.
The Na+/K+ ATPase inhibitor ouabain (500 μM) and the KIR blocker Ba2+ (30 μM) neither alone nor in combination inhibited EDHF relaxations. Ba2+ was also without effect in the presence of either apamin or charybdotoxin.
In contrast to EDHF, an increase in extracellular [K+] from 4.6 mM to 9.6, 14.6 and 19.6 mM inconsistently relaxed arteries. In K+‐free physiological salt solution, re‐admission of K+ always caused complete and sustained relaxations which were abolished by ouabain but unaffected by Ba2+.
The present study provides pharmacological evidence for the involvement of SKCa and IKCa in the action of EDHF in the rat hepatic artery. Our results are not consistent with the idea that EDHF is K+ activating Na+/K+ ATPase and KIR in this blood vessel.

British Journal of Pharmacology (2000) 129, 1490–1496; doi:10.1038/sj.bjp.0703226
Biphasic effect of bimoclomol on calcium handling in mammalian ventricular myocardium
Authors: Nánási Péter P , Sárközi Sándor , Szigeti Gyula , Jóna István , Szegedi Csaba , Szabó Ágnes , Bányász Tamás , Magyar János , Szigligeti Péter , Körtvély Ágnes , Csernoch László , Kovács László , Jednákovits Andrea 
Published: January 2005

Concentration‐dependent effects of bimoclomol, the novel heat shock protein coinducer, on intracellular calcium transients and contractility were studied in Langendorff‐perfused guinea‐pig hearts loaded with the fluorescent calcium indicator dye Fura‐2. Bimoclomol had a biphasic effect on contractility: both peak left ventricular pressure and the rate of force development significantly increased at a concentration of 10 nM or higher. The maximal effect was observed between 0.1 and 1 μM, and the positive inotropic action disappeared by further increasing the concentration of bimoclomol. The drug increased systolic calcium concentration with a similar concentration‐dependence. In contrast, diastolic calcium concentration increased monotonically in the presence of bimoclomol. Thus low concentrations of the drug (10–100 nM) increased, whereas high concentrations (10 μM) decreased the amplitude of intracellular calcium transients.
Effects of bimoclomol on action potential configuration was studied in isolated canine ventricular myocytes. Action potential duration was increased at low (10 nM), unaffected at intermediate (0.1–1 μM) and decreased at high (10–100 μM) concentrations of the drug.
In single canine sarcoplasmic calcium release channels (ryanodine receptor), incorporated into artificial lipid bilayer, bimoclomol significantly increased the open probability of the channel in the concentration range of 1–10 μM. The increased open probability was associated with increased mean open time. The effect of bimoclomol was again biphasic: the open probability decreased below the control level in the presence of 1 mM bimoclomol.
Bimoclomol (10 μM–1 mM) had no significant effect on the rate of calcium uptake into sarcoplasmic reticulum vesicles of the dog, indicating that in vivo calcium reuptake might not substantially be affected by the drug.
In conclusion, the positive inotropic action of bimoclomol is likely due to the activation of the sarcoplasmic reticulum calcium release channel in mammalian ventricular myocardium.

British Journal of Pharmacology (2000) 129, 1405–1412; doi:10.1038/sj.bjp.0703230
Cardiovascular profile of the calcium sensitizer EMD 57033 in open‐chest anaesthetized pigs with regionally stunned myocardium
Authors: De Zeeuw Sandra , Trines Serge A I P , Krams Rob , Verdouw Pieter D , Duncker Dirk J 
Published: January 2005

Ca2+ sensitizers enhance systolic function, but may impair relaxation in vitro; these effects may differ in stunned and normal myocardium. We therefore studied the effect of EMD 57033 on systolic and diastolic function of normal and stunned porcine myocardium in vivo.
Myocardial stunning by 15 min coronary occlusion and 30 min reperfusion abolished systolic shortening (SS) (baseline 13±1%) and decreased end‐systolic elastance (Ees) from 67±7 to 47±5 mmHg mm−1 (both P<0.05). Maximum rate of fall of myocardial elastance (dE/dtmin) decreased from −850±100 to −320±30 mmHg mm−1 s−1, while the time constant τe of the decay of elastance increased from 58±3 to 68±6 ms (both P<0.05). End‐diastolic elastance (Eed) was unchanged although the zero pressure intercept (L0,ed) had increased.
In the stunned region, EMD 57033 (0.2 mg kg−1 min−1 for 60 min, i.v., n=7) increased SS to 19±2%, Ees to 287±40 mmHg mm−1, dE/dtmin to −3630±640 mmHg mm−1 s−1 and decreased τe to 50±3 ms, while Eed remained unchanged. In the normal region, EMD 57033 increased SS from 14±2 to 18±3%, Ees from 59±4 to 263±23 mmHg mm−1, dE/dtmin from −480±70 to −2280±700 mmHg mm−1 s−1 and decreased τe from 91±12 to 61±3 ms (all P<0.05), while Eed remained unchanged. These responses were minimally affected by adrenoceptor blockade (n=7). Vehicle (n=7) had no effect on either region.
EMD 57033 increased cardiac output (up to 27±8%) and LVdP/dtmax (86±19%). Mean aortic pressure decreased (19±7%) due to systemic vasodilation that was not amenable to blockade of adrenoceptors or NO synthesis.
In conclusion, EMD 57033 restored systolic and diastolic function of stunned myocardium, and produced similar improvements in systolic and diastolic function in normal myocardium.

British Journal of Pharmacology (2000) 129, 1413–1422; doi:10.1038/sj.bjp.0703231
Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663
Authors: Van Heek Margaret , Farley Constance , Compton Douglas S , Hoos Lizbeth , Alton Kevin B , Sybertz Edmund J , Davis Harry R 
Published: January 2005

Previous studies described the metabolism‐based discovery of a potent, selective inhibitor of intestinal absorption of cholesterol, SCH58235 (Ezetimibe). Here we demonstrate that the phenolic glucuronide (SCH60663) of SCH58235, was more potent at inhibiting cholesterol absorption in rats than SCH58235, when administered by the intraduodenal route.
To understand the increased potency of the glucuronide, the metabolism and distribution of SCH58235 and SCH60663 were studied in bile duct‐cannulated rats.
One minute after intraduodenal delivery of SCH58235, significant levels of compound were detected in portal plasma; >95% was glucuronidated, indicating that the intestine was metabolizing SCH58235 to its glucuronide. When intraduodenally delivered as SCH58235, the compound was glucuronidated, moved through the intestinal wall, into portal plasma, through the liver, and into bile. However, when delivered as SCH60663, >95% of the compound remained in the intestinal lumen and wall, which may explain its increased potency. Significant inhibition of cholesterol absorption and glucuronidation of SCH58235 occurred when SCH58235 was intravenously injected into bile duct‐cannulated rats. Autoradiographic analysis demonstrated that drug related material was located throughout the intestinal villi, but concentrated in the villus tip.
These data indicate that (a) SCH58235 is rapidly metabolized in the intestine to its glucuronide; (b) once glucuronidated, the dose is excreted in the bile, thereby delivering drug related material back to the site of action and (c) the glucuronide is more potent than the parent possibly because it localizes to the intestine. Taken together, these data may explain the potency of SCH58235 in the rat (ID50=0.0015 mg kg−1) and rhesus monkey (ID50=0.0005 mg kg−1).

British Journal of Pharmacology (2000) 129, 1748–1754; doi:10.1038/sj.bjp.0703235
The in vivo pharmacological profile of CS‐747, a novel antiplatelet agent with platelet ADP receptor antagonist properties
Authors: Sugidachi Atsuhiro , Asai Fumitoshi , Ogawa Taketoshi , Inoue Teruhiko , Koike Hiroyuki 
Published: January 2005

CS‐747 is a novel antiplatelet agent that generates an active metabolite, R‐99224, in vivo. CS‐747 itself was totally inactive in vitro. This study examined in vivo pharmacological profiles of CS‐747 after single oral administration to rats.
Orally administered CS‐747 (0.3–10 mg kg−1) partially but significantly decreased [3H]‐2‐methylthio‐ADP binding to rat platelets. CS‐747 (3 mg kg−1, p.o.) treatment neutralized ADP‐induced decreases of cyclic AMP concentrations induced by prostaglandin E1, suggesting that metabolites of CS‐747 interfere with Gi‐linked P2T receptor.
CS‐747 (0.3 and 3 mg kg−1, p.o.) markedly inhibited ex vivo washed platelet aggregation in response to ADP but not to thrombin. CS‐747 also exhibited a marked inhibition of ADP‐induced ex vivo platelet aggregation in PRP with a rapid onset (<0.5 h) and long duration (>3 days) of action (ED50 at 4 h=1.2 mg kg−1).
R‐99224 (IC50=45 μM) inhibited in vitro PRP aggregation in a concentration‐related manner.
CS‐747 prevented thrombus formation in a dose‐related manner with an ED50 value of 0.68 mg kg−1. CS‐747 was more potent than clopidogrel (6.2 mg kg−1) and ticlopidine (>300 mg kg−1).
CS‐747, clopidogrel, and ticlopidine prolonged the bleeding time. The order of potency of these agents in this activity was the same as that in antiaggregatory and antithrombotic activities.
These findings indicate that CS‐747 is an orally active and a potent antiplatelet and antithrombotic agent with a rapid onset and long duration of action, and warrants clinical evaluations of the agent.

British Journal of Pharmacology (2000) 129, 1439–1446; doi:10.1038/sj.bjp.0703237
Identification of the cytochrome P450 enzymes involved in the metabolism of cisapride: in vitro studies of potential co‐medication interactions
Authors: Bohets H , Lavrijsen K , Hendrickx J , Van Houdt J , Van Genechten V , Verboven P , Meuldermans W , Heykants J 
Published: January 2005

Cisapride is a prokinetic drug that is widely used to facilitate gastrointestinal tract motility.
Structurally, cisapride is a substituted piperidinyl benzamide that interacts with 5‐hydroxytryptamine‐4 receptors and which is largely without central depressant or antidopaminergic side‐effects.
The aims of this study were to investigate the metabolism of cisapride in human liver microsomes and to determine which cytochrome P‐450 (CYP) isoenzyme(s) are involved in cisapride biotransformation. Additionally, the effects of various drugs on the metabolism of cisapride were investigated.
The major in vitro metabolite of cisapride was formed by oxidative N‐dealkylation at the piperidine nitrogen, leading to the production of norcisapride.
By using competitive inhibition data, correlation studies and heterologous expression systems, it was demonstrated that CYP3A4 was the major CYP involved. CYP2A6 also contributed to the metabolism of cisapride, albeit to a much lesser extent.
The mean apparent Km against cisapride was 8.6±3.5 μM (n=3). The peak plasma levels of cisapride under normal clinical practice are approximately 0.17 μM; therefore it is unlikely that cisapride would inhibit the metabolism of co‐administered drugs.
In this in vitro study the inhibitory effects of 44 drugs were tested for any effect on cisapride biotransformation. In conclusion, 34 of the drugs are unlikely to have a clinically relevant interaction; however, the antidepressant nefazodone, the macrolide antibiotic troleandomycin, the HIV‐1 protease inhibitors ritonavir and indinavir and the calcium channel blocker mibefradil inhibited the metabolism of cisapride and these interactions are likely to be of clinical relevance. Furthermore, the antimycotics ketoconazole, miconazole, hydroxy‐itraconazole, itraconazole and fluconazole, when administered orally or intravenously, would inhibit cisapride metabolism.

British Journal of Pharmacology (2000) 129, 1655–1667; doi:10.1038/sj.bjp.0703246
Effect of heparin on antigen‐induced airway responses and pulmonary leukocyte accumulation in neonatally immunized rabbits
Authors: Preuss Janet M H , Page Clive P 
Published: January 2005

The effect of single administrations of aerosolized heparin, low molecular weight heparin (LMWH) and the linear polyanionic molecule, polyglutamic acid (PGA) were examined on antigen‐induced airway hyperresponsiveness and leukocyte accumulation in neonatally immunized rabbits.
Adult litter‐matched NZW rabbits immunized within 24 h of birth with Alternaria tenuis antigen were treated with heparin, LMWH or PGA prior to or following antigen challenge (Alternaria tenuis). For each drug‐treated group, a parallel group of rabbits were treated with the appropriate vehicle. In all groups, airway responsiveness to inhaled histamine and bronchoalveolar lavage (BAL) was performed 24 h prior to and following antigen challenge.
Basal lung function in terms of resistance (RL) and dynamic compliance (Cdyn) and acute bronchoconstriction was unaltered by pre‐treatment with heparin, LMWH or PGA compared to their respective vehicles 24 h prior to or following antigen challenge.
In vehicle‐treated animals, airway hyperresponsiveness to inhaled histamine was indicated by an increase in the maximal responses of the cumulative concentration‐effect curves to histamine and reductions in RLPC50 and CdynPC35 values 24 h following antigen challenge.
Heparin and LMWH given prior to antigen challenge significantly inhibited the development of airway hyperresponsiveness, whereas PGA did not. When given following antigen challenge, all three drugs failed to inhibit the development of airway hyperresponsiveness.
Eosinophil and neutrophil cell numbers in BAL fluid increased significantly 24 h following antigen challenge. Heparin, LMWH and PGA failed to inhibit the increase in cell numbers following antigen challenge whether given prior to or following antigen challenge.

British Journal of Pharmacology (2000) 129, 1585–1596; doi:10.1038/sj.bjp.0703247
Neuropeptide Y regulates intracellular calcium through different signalling pathways linked to a Y1‐receptor in rat mesenteric small arteries
Authors: Prieto Dolores , Buus Carsten L , Mulvany Michael J , Nilsson Holger 
Published: January 2005

Simultaneous measurements of intracellular calcium concentration ([Ca2+]i) and tension were performed to clarify whether the mechanisms which cause the neuropeptide Y (NPY)‐elicited contraction and potentiation of noradrenaline contractions, and the NPY inhibition of forskolin responses are linked to a single or different NPY receptor(s) in rat mesenteric small arteries.
In resting arteries, NPY moderately elevated [Ca2+]i and tension. These effects were antagonized by the selective Y1 receptor antagonist, (R)‐N2‐(diphenacetyl)‐N‐[(4‐hydroxyphenyl)methyl]‐D‐arginineamide (BIBP 3226) (apparent pKB values of 8.54±0.25 and 8.27±0.17, respectively).
NPY (0.1 μM) caused a near 3 fold increase in sensitivity to noradrenaline but did not significantly modify the tension‐[Ca2+]i relationship for this agonist. BIBP 3226 competitively antagonized the contractile response to NPY in arteries submaximally preconstricted with noradrenaline (pA2 7.87±0.20).
In arteries activated by vasopressin, the adenylyl cyclase activator forskolin (3 μM) induced a maximum relaxation and a return of [Ca2+]i to resting levels. NPY completely inhibited these effects. The contractile responses to NPY in arteries maximally relaxed with either sodium nitroprusside (SNP) or nifedipine were not significantly higher than those evoked by the peptide at resting tension, in contrast to the contractions to NPY in forskolin‐relaxed arteries. BIBP 3226 competitively antagonized the contraction to NPY in forskolin‐relaxed arteries with a pA2 of 7.92±0.29.
Electrical field stimulation (EFS) at 8–32 Hz caused large contractions in arteries relaxed with either forskolin or noradrenaline in the presence of phentolamine. These responses to EFS were inhibited by BIBP 3226. Similar EFS in resting, non‐activated arteries did not produce any response.
The present results suggest that different intracellular pathways are linked to a single NPY Y1 receptor in intact rat mesenteric small arteries, and provide little support for involvement of other postjunctional NPY receptors in the contractile responses to NPY. Neurally released NPY also seems to act through Y1 receptors, and may serve primarily as an inhibitor of vasodilatation.

British Journal of Pharmacology (2000) 129, 1689–1699; doi:10.1038/sj.bjp.0703256
Allosteric modulators affect the efficacy of partial agonists for recombinant GABAA receptors
Authors: Maksay Gábor , Thompson Sally A , Wafford Keith A 
Published: January 2005

Different α subunits of human γ‐aminobutyric acid type A (GABAA) receptors were transiently expressed together with β3 and γ2 subunits in Xenopus oocytes to examine the interactions of various GABAA agonists and representative allosteric modulators. Chloride currents elicited by agonists were measured using two electrode voltage clamp electrophysiology.
Where compounds behaved as full agonists, i.e. GABA on all subtypes and 4,5,6,7‐tetrahydroisoxazolo [5,4‐c]pyridin‐3‐ol (THIP) on α2β3γ2 GABAA receptors, agonist concentration‐response curves were shifted to the left by the benzodiazepine full agonist chlordiazepoxide and the anticonvulsant loreclezole, or to the right by the inverse agonist 6,7‐dimethoxy‐4‐ethyl‐β‐carboline‐3‐carboxylic acid methyl ester (DMCM), with no effect on the maximal currents (Imax).
In contrast, maximal responses for different partial GABAA agonists on all benzodiazepine‐sensitive αxβ3γ2 GABAA receptors were enhanced by chlordiazepoxide. Imax values for piperidine‐4‐sulphonic acid (P4S) on α1β3γ2, THIP on α3β3γ2, and 5‐(4‐piperidyl)isothiazol‐3‐ol (thio‐4‐PIOL) on α2β3γ2 and α5β3γ2 GABAA receptors were increased by chlordiazepoxide, while that for P4S on α1β3γ2 receptors was decreased by DMCM.
The Imax values for partial agonists were also enhanced by pentobarbitone, the neurosteroid allopregnanolone and loreclezole irrespective of receptor subtype or the nature of the partial agonist.
In the light of models of ligand‐gated ion channel receptor activation we suggest two possible mechanisms of action for the effects of allosteric modulators on partial agonist receptor activation: either selective modulation of agonist affinity for the open/closed state, or direct modulation of the gating process itself.

British Journal of Pharmacology (2000) 129, 1794–1800; doi:10.1038/sj.bjp.0703259
Mepyramine but not cimetidine or clobenpropit blocks pertussis toxin‐induced histamine sensitization in rats
Authors: Vleeming W , Hendriksen C F M , Van De Kuil A , Van Den Hout J W E , De Wildt D J 
Published: January 2005

The effects of pertussis toxin (PT) and the role of histaminergic H1, H2 and H3 receptor blockade on the actions of histamine on blood pressure, heart rate, blood gas values, and mortality were studied in anaesthetized rats.
Four days after treatment with PT, histamine dose‐dependently decreased mean arterial blood pressure (MAP) and PT enhanced the histamine‐induced decrease in MAP. In the PT but not in the inactivated PT (IPT) or saline treated group three out of six animals died after the highest dose of histamine (300 mg kg−1, i.v.)
In order to determine the type of histamine receptor that mediates HS, 4 days after PT the selective antagonists mepyramine (H1), cimetidine (H2) and clobenpropit (H3) were administered 20 min before the challenge with histamine. Mepyramine completely inhibited both the enhanced histamine‐induced decrease in MAP and mortality brought about by PT. Cimetidine and clobenpropit had no protective effects, but rather enhanced the histamine‐induced mortality elicited by PT.
The present study shows that PT caused HS in rats which is primarily mediated via H1 and secondarily via H2 and H3 receptors. These results are considered to be a first step in the elucidation of the mechanism(s) of the HS test used in the quality control of acellular pertussis vaccine.

British Journal of Pharmacology (2000) 129, 1801–1807; doi:10.1038/sj.bjp.0703263