bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of calcium channels by opioid‐ and adenosine‐receptor agonists in neurons of the nucleus accumbens
Authors: Chieng Billy , Bekkers John M 
Published: January 2005

The pharmacological effects of opioid‐ and adenosine‐receptor agonists on neural signalling were investigated by measuring drug actions on barium current flowing through calcium channels in acutely‐dissociated neurons of the rat nucleus accumbens (NAc).
Under whole‐cell voltage clamp, opioids acted via μ, but not δ or κ, receptors to partially inhibit barium current. Mean inhibition was 35±2% (±s.e.mean, n=33) for methionine‐enkephalin and 37±1% (n=65) for the selective μ receptor agonist DAMGO, both measured at saturating agonist concentrations in neurons with diameter 20 μm. EC50 for DAMGO was 100 nM. Perfusion of naloxone reversed the current inhibition by DAMGO.
Adenosine also partially inhibited barium current in these neurons. Mean inhibition was 28±2% (n=29) for adenosine and 33±3% (n=27) for the selective A1 receptor agonist N6CPA, both at saturating concentrations in neurons with diameter 20 μm. EC50 for N6CPA was 34 nM. Adenosine inhibition was reversed by perfusion of an A1 receptor antagonist, 8‐cyclopentyl‐1,3‐dipropylxanthine, while the selective A2A receptor agonist, CGS 21680, had no effect.
Inhibition by opioids and adenosine was mutually occlusive, suggesting a converging pathway onto calcium channels.
These actions involved a G‐protein‐coupled mechanism, as demonstrated by the partial relief of inhibition by strong depolarization and by the application of N‐ethylmaleimide or GTP‐γ‐S.
Inhibition of barium current by opioids had their greatest effect in large neurons, that is, in presumed interneurons. In contrast, opioid inhibition in neurons with diameter 15 μm was 11±2% (n=26) for methionine‐enkephalin and 11±4% (n=17) for DAMGO, both measured at saturating agonist concentrations. Adenosine inhibition in neurons with diameter 15 μm was 22±5% (n=9).
These results implicate the interneurons as a locus for the modulation of the excitability of projection neurons in the NAc during the processes of addiction and withdrawal.

British Journal of Pharmacology (2001) 133, 337–344; doi:10.1038/sj.bjp.0704072
Respective contributions of α‐adrenergic and non‐adrenergic mechanisms in the hypotensive effect of imidazoline‐like drugs
Authors: Bruban Véronique , Feldman Josiane , Greney Hugues , Dontenwill Monique , Schann Stephan , Jarry Christian , Payard Marc , Boutin Jean , Scalbert Elizabeth , Pfeiffer Bruno , Renard Pierre , Vanhoutte Paul , Bousquet Pascal 
Published: January 2005

The hypotensive effect of imidazoline‐like drugs, such as clonidine, was first attributed to the exclusive stimulation of central α2‐adrenoceptors (α2ARs).
However, a body of evidence suggests that non‐adrenergic mechanisms may also account for this hypotension.
This work aims (i) to check whether imidazoline‐like drugs with no α2‐adrenergic agonist activity may alter blood pressure (BP) and (ii) to seek a possible interaction between such a drug and an α2ARs agonist α‐methylnoradrenaline (α‐MNA).
We selected S23515 and S23757, two imidazoline‐like drugs with negligible affinities and activities at α2ARs but with high affinities for non‐adrenergic imidazoline binding sites (IBS).
S23515 decreased BP dose‐dependently (−27±5% maximal effect) when administered intracisternally (i.c.) to anaesthetized rabbits. The hypotension induced by S23515 (100 μg kg−1 i.c.) was prevented by S23757 (1 mg kg−1 i.c.) and efaroxan (10 μg kg−1 i.c.), while these compounds, devoid of haemodynamic action by themselves, did not alter the hypotensive effect of α‐MNA (3 and 30 μg kg−1 i.c.). Moreover, the α2ARs antagonist rauwolscine (3 μg kg−1 i.c.) did not prevent the effect of S23515.
Finally, whilst 3 μg kg−1 of S23515 or 0.5 μg kg−1 of α‐MNA had weak hypotensive effects, the sequential i.c. administration of these two drugs induced a marked hypotension (−23±2%).
These results indicate that an imidazoline‐like drug with no α2‐adrenergic properties lowers BP and interacts synergistically with an α2ARs agonist.

British Journal of Pharmacology (2001) 133, 261–266; doi:10.1038/sj.bjp.0704080
Characteristics of the pulse waveform during altered nitric oxide synthesis in the rabbit
Authors: Weinberg P D , Habens F , Kengatharan M , Barnes S E , Matz J , Änggård E E , Carrier M J 
Published: January 2005

Nitrovasodilators produce characteristic changes in the shape of the peripheral pulse wave. Similar changes might also be caused by alteration of endogenous NO activity, which would allow such activity to be assessed in vivo.
We investigated whether manipulation of the NO pathway influences the pulse waveform, and the mechanisms involved. The pulse wave in the ear of normal rabbits was examined by reflectance photoplethysmography before and during infusion of vasoactive agents. Pulse wave velocity was assessed by using an additional sensor on the rear foot.
A diastolic peak was observed in the ear pulse; its timing was consistent with it being a reflection of the systolic peak from the lower body. The height of the dicrotic notch marking the start of this diastolic wave was decreased by acetylcholine or an NO donor, and further decreased by a phosphodiesterase type V inhibitor. The acetylcholine‐induced decreases were blocked by inhibiting NO synthesis with NG‐nitro‐L‐arginine methyl ester (L‐NAME) but were unaffected by the inactive enantiomer D‐NAME.
These data demonstrate that NO influences the height of the notch in the pulse wave. Heart rate and blood pressure were altered during acetylcholine or L‐NAME infusion, but there were no changes in pulse wave amplitude or velocity, or in the timing of the diastolic peak or dicrotic notch. The slope of the pulse wave between the systolic peak and notch changed substantially. These effects are most convincingly explained by changes in wave reflection, not only from the lower body but also from more proximal sites.

British Journal of Pharmacology (2001) 133, 361–370; doi:10.1038/sj.bjp.0704084
[125I]‐S36057: a new and highly potent radioligand for the melanin‐concentrating hormone receptor
Authors: Audinot Valérie , Lahaye Chantal , Suply Thomas , Beauverger Philippe , Rodriguez Marianne , Galizzi Jean‐Pierre , Fauchère Jean‐Luc , Boutin Jean A 
Published: January 2005

Shortened, more stable and weakly hydrophobic analogues of melanin‐concentrating hormone (MCH) were searched as candidates for radioiodination. Starting from the dodecapeptide MCH6 – 17, we found that: (1) substitution of Tyr13 by a Phe residue; (2) addition of a 3‐iodo‐Tyr residue at the N‐terminus; and (3) addition of a hydrophilic spacer 8‐amino‐3,6‐dioxyoctanoyl between the 3‐iodo‐Tyr and MCH6 – 17 (compound S36057), led to an agonist more potent than MCH itself in stimulating [35S]‐GTPγS binding at membranes from HEK293 cells stably expressing the human MCH receptor.
Specific binding of [125I]‐S36057 was found in HEK293 and CHO cell lines stably expressing the human MCH receptor. This radioligand recognized a similar number of binding sites (ca. 800 fmol mg−1) than [125I]‐[3‐iodo Tyr13]‐MCH.
However, the KD for [125I]‐S36057 obtained from saturation studies (0.037 nM) or from binding kinetics (0.046 nM) was at least 10 fold higher to that of [125I]‐[3‐iodo Tyr13]‐MCH (0.46 nM).
Affinities determined for a series of MCH analogues were similar with both radioligands, S36057 being the most potent compound tested (Ki=0.053 nM).
Finally, [125I]‐S36057 also potently labelled the MCH receptor in membranes from whole rat brain (KD 0.044 nM, Bmax=11 fmol mg−1).
In conclusion, [125I]‐S36057 is a more potent and more stable radioligand than [125I]‐[3‐iodo Tyr13]‐MCH that will represent a reliable tool for binding assays in the search of novel MCH ligands. It should also provide great help for autoradiographic studies of the MCH receptor distribution in the central nervous system.

British Journal of Pharmacology (2001) 133, 371–378; doi:10.1038/sj.bjp.0704085
Endothelium‐dependent relaxation induced by cathepsin G in porcine pulmonary arteries
Authors: Glusa Erika , Adam Christine 
Published: January 2005

Serine proteinases elicit profound cellular effects in various tissues mediated by activation of proteinase‐activated receptors (PAR). In the present study, we investigated the vascular effects of cathepsin G, a serine proteinase that is present in the azurophil granules of leukocytes and is known to activate several cells that express PARs.
In prostaglandin F2α (3 μM)‐precontracted rings from porcine pulmonary arteries with intact endothelium, cathepsin G caused concentration‐dependent relaxant responses (pEC50=9.64±0.12). The endothelium‐dependent relaxant effect of cathepsin G could also be demonstrated in porcine coronary arteries (pEC50=9.23±0.07). In pulmonary arteries the cathepsin G‐induced relaxation was inhibited after blockade of nitric oxide synthesis by L‐NAME (200 μM) and was absent in endothelium‐denuded vessels. Bradykinin‐ and cathepsin G‐induced relaxant effects were associated with a 5.7 fold and 2.4 fold increase in the concentration of cyclic GMP, respectively.
Compared with thrombin and trypsin, which also produced an endothelium‐dependent relaxation in pulmonary arteries, cathepsin G was 2.5 and four times more potent, respectively. Cathepsin G caused only small homologous desensitization. In cathepsin G‐challenged vessels, thrombin was still able to elicit a relaxant effect.
The effects of cathepsin G were blocked by soybean trypsin inhibitor (IC50=0.043 μg ml−1), suggesting that proteolytic activity is essential for induction of relaxation. Recombinant acetyl‐eglin C proved to be a potent inhibitor (IC50=0.14 μg ml−1) of the cathepsin G effect, whereas neither indomethacin (3 μM) nor the thrombin inhibitor hirudin (5 ATU ml−1) elicited any inhibitory activity. Due to their polyanionic structure defibrotide (IC50=0.11 μg ml−1), heparin (IC50=0.48 μg ml−1) and suramin (IC50=1.85 μg ml−1) diminished significantly the relaxation in response to the basic protein cathepsin G.
In conclusion, like thrombin and trypsin, cathepsin G is able to induce endothelium‐dependent vascular relaxation. It can be released from activated leukocytes at sites of vascular injury and inflammation and, therefore, sufficiently high concentrations might be reached locally in the vascular space to induce vasodilatation.

British Journal of Pharmacology (2001) 133, 422–428; doi:10.1038/sj.bjp.0704089
Vascular actions of MDMA involve α1 and α2‐adrenoceptors in the anaesthetized rat
Authors: McDaid John , Docherty James R 
Published: January 2005

We have investigated the effects of methylenedioxymethamphetamine (MDMA, ‘ecstasy’), i.v., on diastolic blood pressure (DBP) in pithed and pentobarbitone anaesthetized rats.
In pithed rats, the non‐selective 5‐HT receptor antagonist methiothepin (0.1 mg kg−1) and the α2‐adrenoceptor antagonists methoxyidazoxan and yohimbine (1 mg kg−1) showed significant α1‐adrenoceptor antagonist potency, but methiothepin did not show α2‐adrenoceptor antagonist potency. MDMA (1 and 5 mg kg−1) produced pressor responses which were significantly reduced by the α1‐adrenoceptor antagonist prazosin (0.1 mg kg−1), yohimbine (1 mg kg−1) or methiothepin (0.1 mg kg−1), but not by the 5‐HT2 receptor antagonist ritanserin (1 mg kg−1).
In anaesthetized rats, antagonists revealed two phases with three components to the effects of MDMA (5 mg kg−1) on DBP: an initial pressor response, a later pressor component at 1 min, the sustained depressor response. Methoxyidazoxan, methiothepin or the combination ritanserin/prazosin significantly reduced the initial pressor response, although neither of the latter compounds alone had any effect.
The pressor response to MDMA (5 mg kg−1) at 1 min was converted to a depressor response by prazosin and to a lesser extent methiothepin and methoxyidazoxan.
The depressor response to MDMA (5 mg kg−1) was significantly reduced by methoxyidazoxan (0.1 mg kg−1), and by the noradrenaline re‐uptake blocker cocaine 10 mg kg−1 but not 1 mg kg−1. However, the most marked reduction in the depressor response was produced by the combination of methoxyidazoxan and cocaine.
It is concluded that the initial pressor response to MDMA (5 mg kg−1) in anaesthetized rats involves α2‐ and possibly α1‐adrenoceptors and 5‐HT2 receptors, the pressor component at 1 min is largely α1‐adrenoceptor mediated, and the sustained depressor response involves α2‐adrenoceptors.

British Journal of Pharmacology (2001) 133, 429–437; doi:10.1038/sj.bjp.0704094
Protection of vascular wall function in insulin‐resistant rats from copper oxidative stress
Authors: O'Brien Sheila F , Davidge Sandra T , Zhang Yunlong , Russell James C 
Published: January 2005

The effects of oxidative stress on vascular function in the insulin‐resistant state were assessed in mesenteric resistance arteries of obese, insulin‐resistant (cp/cp) and lean, normal (+/?) JCR : LA‐cp rats.
Nitric oxide‐mediated relaxation of noradrenaline‐contracted arteries in response to acetylcholine was impaired after 2 h of incubation with Cu2+ in both genotypes, with or without the continuing presence of Cu2+. Relaxation was enhanced on initial exposure to Cu2+, and post‐incubation removal of the Cu2+ resulted in a greater impairment of relaxation. Arteries from cp/cp rats were less impaired in function by Cu2+ incubation than were those of +/? controls.
Sodium nitroprusside‐mediated relaxation was impaired by exposure to Cu2+, with an accompanying increase in EC50.
The impairment in acetylcholine‐mediated relaxation in the arteries from both cp/cp and +/? rats was completely inhibited by co‐incubation with copper‐zinc superoxide dismutase and catalase, confirming that the impairment associated with Cu2+ incubation was due to oxidative stress.
The impairment appears to involve both smooth muscle and the endothelium.
The cp/cp rats showed greater resistance to the effects of oxidative stress on arterial function, possibly due to an adaptation to oxidative stress on arterial function associated with the insulin‐resistant state.

British Journal of Pharmacology (2001) 133, 477–484; doi:10.1038/sj.bjp.0704095
The C6‐2B glioma cell P2YAC receptor is pharmacologically and molecularly identical to the platelet P2Y12 receptor
Authors: Jin Jianguo , Tomlinson Wendy , Kirk Ian P , Kim Young B , Humphries Robert G , Kunapuli Satya P 
Published: January 2005

P2Y receptor activation in many cell types leads to phospholipase C activation and accumulation of inositol phosphates, while in blood platelets, C6‐2B glioma cells, and in B10 microvascular endothelial cells a P2Y receptor subtype, which couples to inhibition of adenylyl cyclase, historically termed P2YAC, (P2TAC or P2T in platelets) has been identified. Recently, this receptor has been cloned and designated P2Y12 in keeping with current P2 receptor nomenclature.
Three selective P2T receptor antagonists, with a range of affinities, inhibited ADP‐induced aggregation of washed human or rat platelets, in a concentration‐dependent manner, with a rank order of antagonist potency (pIC50, human: rat) of AR‐C78511 (8.5 : 9.1)>AR‐C69581 (6.2 : 6.0)>AR‐C70300 (5.4 : 5.1). However, these compounds had no effect on ADP‐induced platelet shape change.
All three antagonists had no significant effect on the ADP‐induced inositol phosphate formation in 1321N1 astrocytoma cells stably expressing the P2Y1 receptor, when used at concentrations that inhibit platelet aggregation.
These antagonists also blocked ADP‐induced inhibition of adenylyl cyclase in rat platelets and C6‐2B cells with identical rank orders of potency and overlapping concentration – response curves.
RT – PCR and nucleotide sequence analyses revealed that the C6‐2B cells express the P2Y12 mRNA.
These data demonstrate that the P2YAC receptor in C6‐2B cells is pharmacologically identical to the P2TAC receptor in rat platelets.

British Journal of Pharmacology (2001) 133, 521–528; doi:10.1038/sj.bjp.0704114
Disturbance of the prejunctional modulation of cholinergic neurotransmission during chronic granulomatous inflammation of the mouse ileum
Authors: De Man Joris G , Moreels Tom G , De Winter Benedicte Y , Bogers Johannes J , Van Marck Eric A , Herman Arnold G , Pelckmans Paul A 
Published: January 2005

The effect of chronic granulomatous inflammation of the intestine was studied on the prejunctional modulation of cholinergic nerve activity in the mouse ileum.
Contractions to carbachol (0.01–0.3 μM) and to electrical field stimulation (EFS, 0.25–8 Hz) of enteric neurons were higher in inflamed ileum as compared to control ileum. However, when the neurally‐mediated contractions to EFS were expressed as percentage of the direct smooth muscle contraction to carbachol, the responses to EFS were similar in control and inflamed ileum.
Atropine (1 μM) abolished all contractions to EFS and carbachol in control and inflamed ileum. DMPP (3–30 μM), a nicotinic receptor agonist, induced concentration‐dependent contractions that were more pronounced in inflamed ileum as compared to control ileum. Hexamethonium (100 μM), a nicotinic receptor blocker, significantly inhibited the contractions to EFS in inflamed ileum but not in control ileum.
In control ileum, histamine (10–100 μM) and the histamine H1 receptor agonist HTMT (3–10 μM) inhibited the contractions to EFS concentration‐dependently without affecting the contractions to carbachol. The inhibitory effect of histamine and HTMT was prevented by the histamine H1 antagonist mepyramine (5–10 μM) but not by the H2‐ and H3‐receptor antagonists cimetidine and thioperamide (both 10 μM). In chronically inflamed ileum however, histamine (10–100 μM) and HTMT (3–10 μM) failed to inhibit the contractions to EFS. The histamine H2 and H3 receptor agonists dimaprit and R(−)‐α‐methylhistamine did not affect the contractions to EFS in control and inflamed ileum.
The α2‐receptor agonist UK 14.304 (0.01–0.1 μM) inhibited the contractions to EFS in control and inflamed ileum without affecting the contractions to carbachol. The effect of UK 14.304 was reversed by the α2‐receptor antagonist yohimbine (1 μM). The inhibitory effect of UK 14.304 on contractions to EFS was of similar potency in control and inflamed ileum.
Our results suggest that the prejunctional modulation of cholinergic nerve activity by nicotinic and histaminic H1 receptors is disturbed during chronic intestinal inflammation whereas the modulation by α2‐receptors is preserved. Such a disturbance of cholinergic nerve activity may contribute to the motility disturbances that are often observed during chronic intestinal diseases in humans.

British Journal of Pharmacology (2001) 133, 695–707; doi:10.1038/sj.bjp.0704115
Physiological antagonism of endothelin‐1 in human conductance and resistance coronary artery
Authors: Wiley Katherine E , Davenport Anthony P 
Published: January 2005

The ability of four endogenous vasodilators, nitric oxide (NO; 0.01 – 30 μM), atrial (ANP), brain (BNP) and C‐type (CNP) natriuretic peptide (0.1 – 300 nM), to reverse endothelin‐1 (ET‐1; 10 nM) constrictions in human resistance and conductance coronary arteries (CA) in vitro was investigated.
ET‐1 (0.1 – 300 nM) constricted resistance CA more potently than conductance CA (P<0.05; EC50 values 2.98 nM (95% CI: 1.49 – 5.95 nM and 8.58 (4.72 – 15.6 nM) respectively)).
The NO‐donor diethylamine NONOate fully reversed the ET‐1 constriction in conductance CA (EMAX 127±9.16%), however only partial reversal was observed in resistance CA (EMAX 78.8±8.13; P<0.05). The soluble guanylate cyclase inhibitor 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (100 μM) reduced the maximum response to diethylamine NONOate to 76.9±14.4% in conductance CA (P<0.05), but had no effect on resistance CA (EMAX 77.2±18.4%).
There was no difference between responses to ANP in conductance and resistance CA (EC50 values 4.25 nM (0.84 – 21.4 nM) and 18.4 nM (2.92 – 116 nM), EMAX 53.1±14.7% and 48.6±11.8% respectively).
BNP was a more potent vasodilator of conductance than resistance CA. In conductance CA the mean EC50 value was 2.4 nM (0.74 – 7.75 nM), EMAX 54.5±14.9%. Concentration‐response curves to BNP were incomplete in resistance CA.
Concentration‐response curves to CNP were incomplete in both conductance and resistance CA.
The greater potency of ET‐1 in resistance vessels may exacerbate the effects of increased circulating levels of the peptide in disease. Only NO could fully reverse ET‐1 mediated constrictions in conductance CA, and none of the dilators tested could completely counteract constrictions in resistance CA.

British Journal of Pharmacology (2001) 133, 568–574; doi:10.1038/sj.bjp.0704119
In vivo pharmacology of BIIR 561 CL, a novel combined antagonist of AMPA receptors and voltage‐dependent Na+ channels
Authors: Wienrich M , Brenner M , Löscher W , Palluk R , Pieper M , Potschka H , Weiser T 
Published: January 2005

Glutamate receptors of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) subtype and voltage‐gated Na+ channels are associated with diseases of the central nervous system characterized by neuronal over‐excitation as in epilepsy or cerebral ischaemia. In animal models, AMPA receptor antagonists and Na+ channel blockers provide protection in these conditions.
Dimethyl‐{2‐[2‐(3‐phenyl‐[1,2,4]oxadiazol‐5‐yl)‐phenoxyl]‐ethyl}‐amine hydrochloride (BIIR 561 CL) combines both, AMPA receptor – and Na+ channel blocking properties in one molecule. Here, BIIR 561 CL was investigated in vivo.
BIIR 561 CL protected mice against AMPA‐induced toxicity with an ED50 value of 4.5 mg kg−1 following subcutaneous (s.c.) administration. A 0.1% solution of BIIR 561 CL provided local anaesthesia in the corneal reflex test in rabbits. In mice, the compound prevented tonic seizures in the maximal electroshock (MES) model with an ED50 value of 3.0 mg kg−1 s.c. In amygdala‐kindled rats, BIIR 561 CL inhibited seizures at doses of 3 and 11 mg kg−1 following intraperitoneal (i.p.) injection.
The data show that the combination of blocking AMPA receptor‐ and voltage‐gated Na+ channels in one molecule induces effective protection in animal models of neuronal over‐excitation.

British Journal of Pharmacology (2001) 133, 789–796; doi:10.1038/sj.bjp.0704132