bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of the endothelin receptor subtype mediating epithelium‐derived relaxant nitric oxide release from guinea‐pig trachea
Authors: Emanueli Costanza , Ricciardolo Fabio , Vergnani Luciana , Bertrand Claude , Ricci Franco , Manzoli Nadia , Folkerts Gert , Nijkamp Frans P. , Geppetti Pierangelo 
Published: January 2005

The endothelin (ET) receptor subtype that mediates niric oxide (NO)‐dependent airway relaxation in tracheal tube preparations precontracted with carbachol and pretreated with indomethacin was investigated. The release of NO induced by ET from guinea‐pig trachea using a recently developed porphyrinic microsensor was also measured.
ET‐1 (1 pM–100 nM) contracted tracheal tube preparations pretreated with the NO‐synthase inhibitor, L‐NMMA, and relaxed, in an epithelium‐dependent manner, preparations pretreated with the inactive enantiomer D‐NMMA. The effect of L‐NMMA was reversed by L‐Arg, but not by D‐Arg.
The selective ETB receptor agonists, IRL 1620 or sarafotoxin S6c, both (1 pM–100 nM) contracted tracheal tube preparations in a similar manner either after treatment with D‐NMMA or with L‐NMMA. In the presence of the ETA receptor antagonist, FR139317 (10 μM), ET‐1 administration resulted in a contraction that was similar after either L‐NMMA or D‐NMMA. In the presence of the ETB receptor antagonist, BQ788 (1 μM), ET‐1 relaxed and contracted tracheas pretreated with D‐NMMA and L‐NMMA, respectively.
Exposure of tracheal segments to ET‐1 (1–1000 nM) caused a concentration‐dependent increase in NO release that was reduced by L‐NMMA. IRL1620 (1 μM) did not cause any significant NO release. FR139317 (10 μM), but not, BQ788 (1 μM), inhibited the NO release induced by ET‐1.
These results demonstrate that in the isolated guinea‐pig trachea activation of ETB receptors results in a contractile response, whereas activation of ETA receptors cause both a contraction, and an epithelium‐dependent relaxation that is mediated by NO release.

British Journal of Pharmacology (1998) 125, 963–968; doi:10.1038/sj.bjp.0702174
Venous versus arterial actions of diethylamine/nitric oxide (DEA/NO) complex and S‐nitroso‐N‐acetylpenicillamine (SNAP) in vivo
Authors: Ng Sylvia S W , Pang Catherine C Y 
Published: January 2005

We studied the effects of diethylamine/NO complex (DEA/NO) and S‐nitroso‐N‐acetylpenicillamine (SNAP), relative to those of sodium nitroprusside (SNP) and nitroglycerin (NTG), on mean arterial pressure (MAP), mean circulatory filling pressure (MCFP), arterial resistance (Ra), venous resistance (Rv), heart rate (HR), cardiac output (CO) and stroke volume (SV) in groups of Inactin‐anaesthetized rats pre‐treated with i.v. mecamylamine (3.7 μmol kg−1) and noradrenaline (6.8 nmol kg−1 min−1). Doses of each that reduced MAP by 30%, 80% and the lowest dose that maximally reduced MAP were examined to allow a comparison of the compounds' dilator actions at equivalent effective depressor doses.
DEA/NO (4, 32 and 256 μg kg−1 min−1), SNAP (4, 32 and 256 μg kg−1 min−1) and SNP (8, 32 and 128 μg kg−1 min−1) caused similar dose‐dependent reductions in MAP and Ra, and increases in CO and SV. NTG (0.2, 0.8 and 6.4 μg kg−1 min−1) dose‐dependently reduced Ra, and increased CO and SV, but lowered MAP only at the highest dose.
DEA/NO, SNAP and SNP but not NTG lowered MCFP with efficacy: DEA/NO>SNAP>SNP. All four drugs reduced Rv with efficacy: DEA/NO ≈amp; SNAP>SNP ≈amp; NTG.
Therefore, all compounds lowered Ra and Rv. DEA/NO, SNAP and SNP but not NTG reduced MCFP. The pharmacological profiles of DEA/NO and SNAP resemble SNP more than NTG.

British Journal of Pharmacology (1998) 125, 1247–1251; doi:10.1038/sj.bjp.0702175
Learning impairments induced by glutamate blockade using dizocilpine (MK‐801) in monkeys
Authors: Harder J. A. , Aboobaker A. A. , Hodgetts T. C. , Ridley R. M. 
Published: January 2005

This study investigated the effects of dizocilpine (MK‐801) on learning ability in a non‐human primate. Acquisition and reversal learning of visual discrimination tasks and acquisition of visuo‐spatial discrimination tasks were assessed in marmosets using the Wisconsin General Test Apparatus. Dizocilpine impaired acquisition of visuo‐spatial (conditional) tasks requiring spatial responses to coloured objects, and perceptually difficult visual discrimination tasks in which stimulus objects are painted black. Dizocilpine did not, however, impair either acquisition or reversal of a simple visual discrimination task using easily discriminated, coloured objects.
Motor effects of dizocilpine treatment, which have been seen in other primates, were examined by observation of the marmosets in their home cages, using both an automated locomotor activity monitor and ‘blind’, subjective counting of the number of abnormal movements in a given time period. Locomotor activity, assessed using the automated monitor, was not significantly affected at any of the doses tested. Incoordination, assessed by human observation of abnormal movements, was significantly increased only at a dose of 30 μg kg−1 i.m., which was twice the highest dose used to assess the effects of dizocilpine on cognition.
We have, therefore, found an effect of dizocilpine on acquisition and reversal of some types of cognitive task, at a dose which does not cause significant motor effects. This demonstration of a cognitive deficit associated with glutamatergic blockade in a primate may be useful in understanding the contribution of glutamatergic dysfunction to cognitive decline in neurodegenerative disease, especially Alzheimer's disease.

British Journal of Pharmacology (1998) 125, 1013–1018; doi:10.1038/sj.bjp.0702178
Characterization of the relaxant action of urocortin, a new peptide related to corticotropin‐releasing factor in the rat isolated basilar artery
Authors: Schilling L , Kanzler Ch , Schmiedek P , Ehrenreich H 
Published: January 2005

In addition to its well established neuroendocrine and neurotransmitter effects, corticotropin releasing factor (CRF) exerts a potent vasorelaxant action. Recently, a CRF‐related peptide, urocortin, has been identified in the mammalian brain. In the present study, the cerebral vasomotor action of this peptide and the mechanism underlying its relaxant effect are characterized.
Ring segments obtained from the rat basilar artery were used for measurement of isometric force. The relaxant action of urocortin, CRF and sauvagine was studied in segments with a functionally intact endothelium.
In segments precontracted with prostaglandin F2α, urocortin, CRF and sauvagine induced concentration‐related relaxation. The order of potency was as follows (pD2±s.e.m. given in brackets): urocortin (9.32±0.07) > sauvagine (9.08±0.08) > CRF (7.50±0.07). Complete relaxation was achieved with each agonist. Relaxation was not affected by removal of the endothelium but was markedly attenuated in segments precontracted with 50 mm K+ Krebs solution. The relaxant effect of urocortin was inhibited by astressin in an apparently competitive manner. A pA2 value of 7.52 was estimated for astressin. Inhibition of urocortin‐induced relaxation was also observed in the presence of the adenylate cyclase inhibitor SQ22536 (pD2 in the presence of 300 μm SQ22536, 9.36±0.05) and the K+ channel blockers tetraethylammonium (10 mm; pD2, 8.65±0.07), iberiotoxin (100 nm; pD2, 8.88±0.08) and apamin (10 nm; pD2, 8.94±0.07). However, the inhibitory actions of SQ22536 and apamin or iberiotoxin were not additive.
The results suggest that urocortin induces relaxation of cerebral arteries by activating CRF‐R2 receptors present in the vascular wall. Relaxation appears to be mediated by adenylate cyclase stimulation and activation of Ca2+‐dependent K+ channels.

British Journal of Pharmacology (1998) 125, 1164–1171; doi:10.1038/sj.bjp.0702182
Analysis of an H1 receptor‐mediated, zinc‐potentiated vasoconstrictor action of the histidyl dipeptide carnosine in rabbit saphenous vein
Authors: O'Dowd Anne , Miller David J 
Published: January 2005

The contractile action of the dipeptide carnosine (β‐alanyl‐l‐histidine), active as a Zn·carnosine complex (Zn·Carn), was investigated in isolated rings of rabbit saphenous vein (RSV) and was found to be antagonized by the H1 antagonist mepyramine.
Mepyramine‐sensitive, histamine‐induced contractures in RSV, were smaller (73±0.1%) and less well sustained than carnosine‐induced contractures.
Schild plot values for mepyramine antagonism were, for carnosine‐induced contractures; pA2=7.97±0.12, slope=1.33±0.06 (r = 0.793) and for histamine‐induced contractures; pA2=8.48±0.07, slope=0.63±0.05, r = 0.957).
Serotonergic antagonists methiothepin and ketanserin, antagonize both carnosine‐ and histamine‐induced contractures in RSV, probably reflecting coincidental inhibition at the H1‐receptor.
Carnosine, with Zn present, can inhibit the H1‐specific binding of [3H]‐mepyramine to isolated guinea‐pig cerebellar membranes (log IC50s−2.78±0.02, −3.93±0.03 and −4.64±0.03 at 10, 30 and 80 μm Zn respectively; values corrected for the Zn‐specific inhibition which has a logIC50 of −4.20).
In the radioligand binding assay, the effect of carnosine can be described as a function of Zn·Carn concentration with an apparent logIC50 of −5.61. This value is consistent with that obtained from the functional studies on RSV.
Histamine‐induced contractures have an indomethacine‐sensitive component (27.2±8.3% of control response), not apparent with carnosine‐induced contractures.
Like histamine, carnosine evoked an H2‐mediated (cimetidine‐sensitive) relaxation in the presence of mepyramine, but was less potent (10.8±3.1% residual tension at 10 mm carnosine compared with 13.4±7.5% at 0.1 mm histamine).
Carnosine, like mepyramine, can ‘reveal’ the H2‐mediated relaxation of histamine providing further evidence that carnosine binds at the H1 receptor.
We conclude that carnosine can act at the smooth muscle H1‐receptor to provoke vasoconstriction and that it also has the potential to act at H1‐receptors in CNS.

British Journal of Pharmacology (1998) 125, 1272–1280; doi:10.1038/sj.bjp.0702184
Evidence that platelets promote tube formation by endothelial cells on matrigel
Authors: Pipili‐Synetos E , Papadimitriou E , Maragoudakis M E 
Published: January 2005

The involvement of platelets in neovascularization was investigated in the matrigel tube formation assay, an in vitro model of angiogenesis.
Platelets promoted the formation of capillary‐like structures (expressed as relative tube area) number‐ and time‐dependently. Relative tube area increased from 0.98±0.02 (n = 8) in the presence of 6.25×104, to 3.21±0.12 (n = 8) in the presence of 106 platelets/well compared to 0.54±0.04 (n = 8) in their absence. This increase was unaffected by acetyl salicylic acid (ASA), apyrase, and hirudin. Photographs from representative experiments, showed that platelets adhered along the differentiating endothelium.
Addition of α‐thrombin (0.1–1 i.u. ml−1), the nitric oxide (NO) donor sodium nitroprusside (SNP; 1–100 μm) or the NO synthase inhibitor, l‐NG‐arginine‐methylester (l‐NAME, 30–300 μm) to the assay, had no effect on tube formation compared to that seen with platelets alone.
Neuraminidase (0.01 i.u./107 platelets), which strips sialic acid residues from membrane glycoproteins, abolished the promoting effect of platelets on tube formation. The relative tube area in the presence of neuraminidase‐treated platelets was 0.81±0.03 (n = 8), in the presence of untreated platelets 1.69±0.09, P < 0.001 (n = 8) and in the absence of platelets, 0.80±0.04 (n = 8). The tetrapeptide Arg‐Gly‐Asp‐Ser (RGDS; 20–200 μm) which inhibits von Willebrand factor, fibrinogen and fibronectin‐mediated adhesion, had no effect on the promoting effect of platelets on tube formation.
These results indicate that platelets promote angiogenesis in vitro. This effect is largely independent from activation by α‐thrombin, is not modified by manipulating NO and prostaglandin metabolism and proceeds possibly through adhesion of the platelets to the differentiating endothelium.

British Journal of Pharmacology (1998) 125, 1252–1257; doi:10.1038/sj.bjp.0702191
Distribution of the perivascular nerve Ca2+ receptor in rat arteries
Authors: Wang Yanlin , Bukoski Richard D. 
Published: January 2005

We recently showed that perivascular sensory nerves of mesenteric branch arteries express a receptor for extracellular Ca2+ (CaR), and reported data indicating that this CaR mediates relaxation induced by physiologic levels of Ca2+. We have now tested whether the perivascular sensory nerve CaR‐linked dilator system is a local phenomenon restricted to the mesentery, or is present in other circulations.
Vessels from the mesenteric, renal, coronary, and cerebral circulations were studied. Immunocytochemical analysis was performed using anti‐CaR and anti‐neural cell adhesion molecule (NCAM) antibodies. Wire myography was used to assess contracation and relaxation.
Although perivascular nerves of all arteries stained for CaR protein, there were regional differences. A morphometric method used to estimate CaR positive nerve density revealed the following rank order: mesenteric branch artery>basilar artery=renal interlobar artery>main renal trunk artery>left anterior descending coronary artery.
Vessels from the mesentery, renal, coronary, and cerebral circulations showed nerve‐dependent relaxation in response to electrical field stimulation (EFS) when precontracted with serotonin in the presence of guanethidine. The degree of Ca2+‐induced relaxation of mesenteric, renal, and cerebral arteries positively correlated with the magnitude of EFS‐induced relaxation. In contrast, coronary arteries contracted at Ca2+ levels between 1.5 and 3 mmol L−1, and relaxed to a small degree to 5 mmol L−1 Ca2+.
Thus, a functional perivascular sensory nerve CaR‐linked dilator system is present to varying degrees in the mesenteric, renal, and cerebral circulations, but only to a very limited extent in the coronary circulation.

British Journal of Pharmacology (1998) 125, 1397–1404; doi:10.1038/sj.bjp.0702195
Contractile responses elicited by hydrogen peroxide in aorta from normotensive and hypertensive rats. Endothelial modulation and mechanism involved
Authors: Rodríguez‐Martínez M Angeles , García‐Cohen Edith C , Baena Ana B , González Rita , Salaíces Mercedes , Marín Jesús 
Published: January 2005

The present study analyses the influence of hypertension and endothelium on the effect induced by hydrogen peroxide (H2O2) on basal tone in aortic segments from normotensive Wistar‐Kyoto (WKY) and spontaneously hypertensive rats (SHR) of 6‐month‐old, as well as the possible mechanisms involved.
Single (1 mm) or cumulative (100 nm–10 mm) concentrations of H2O2 produced a transient contraction or a concentration‐dependent increase of basal tone, respectively, in segments from WKY and SHR. In both cases, the contractions were higher in intact segments from hypertensive than from normotensive rats, and increased by endothelium removal in both strains. Catalase (1000 u ml−1, a H2O2 scavenger) abolished the contraction elicited by 1 mm H2O2 in both strains.
Superoxide dismutase (SOD, 150 u ml−1) and dimethylsulphoxide (DMSO, 7 mm), scavengers of superoxide anions and hydroxyl radicals, respectively, did not alter H2O2‐induced contractions in intact segments from both strains. However, l‐NG‐nitroarginine methyl ester (l‐NAME, 100 μm, a nitric oxide synthase inhibitor) increased the response to H2O2 in normotensive rats, although the increase was less than that produced by endothelium removal.
Incubation of segments with 1 mm H2O2 for 15 min and subsequent washout reduced the contractile responses induced by 75 mm KCl in intact segments from SHR and in endothelium‐denuded segments from both strains; this effect being prevented by catalase (1000 u ml−1).
Indomethacin (10 μm, a cyclo‐oxygenase inhibitor) and SQ 29,548 (10 μm, a prostaglandin H2/thromboxane A2 receptor antagonist) practically abolished the contractions elicited by H2O2 in normotensive and hypertensive rats.
We conclude that: (1) the oxidant stress induced by H2O2 produces contractions mediated by generation of a product of the cyclo‐oxygenase pathway, prostaglandin H2 or more probably thromboxane A2, in normotensive and hypertensive rats; (2) oxygen‐derived free radicals are not involved in the effect of H2O2; (3) in normotensive rats, endothelium protects against H2O2‐mediated injury to contractile machinery, determined by the impairment of KCl‐induced contractions; and (4) endothelial nitric oxide has a protective role on the contractile effect induced by H2O2, that is lost in hypertension.

British Journal of Pharmacology (1998) 125, 1329–1335; doi:10.1038/sj.bjp.0702200
Functional effects of the muscarinic receptor agonist, xanomeline, at 5‐HT1 and 5‐HT2 receptors
Authors: Watson J. , Brough S. , Coldwell M. C. , Gager T. , Ho M. , Hunter A. J. , Jerman J. , Middlemiss D. N. , Riley G. J. , Brown A. M. 
Published: January 2005

Xanomeline [3(3‐hexyloxy‐1,2,5‐thiadiazol‐4‐yl)‐1,2,5,6‐tetrahydro‐1‐methylpyridine] has been reported to act as a functionally selective muscarinic partial agonist with potential use in the treatment of Alzheimer's disease. This study examined the functional activity of xanomeline at 5‐HT1 and 5‐HT2 receptors in native tissue and/or human cloned receptors.
Xanomeline had affinity for muscarinic receptors in rat cortical membranes where the ratio of the displacement affinity of [3H]‐Quinuclidinyl benzilate vs that of [3H]‐Oxotremorine‐M was 16, indicative of partial agonist activity. Radioligand binding studies on human cloned receptors confirmed that xanomeline had substantial affinity for M1, M2, M3, M4, M5 receptors and also for 5‐HT1 and 5‐HT2 receptor subtypes.
Carbachol and xanomeline stimulated basal [35S]‐GTPγS binding in rat cortical membranes with micromolar affinity. The response to carbachol was attenuated by himbacine and pirenzepine with pA2 of 8.2, 6.9 respectively consistent with the response being mediated, predominantly, via M2 and M4 receptors. Xanomeline‐induced stimulation of [35S]‐GTPγS binding was inhibited by himbacine with an apparent pKb of 6.3, was not attenuated by pirenzepine up to 3 μm and was inhibited by the selective 5‐HT1A antagonist WAY100635 with an apparent pKb of 9.4. These data suggest the agonist effect of xanomeline in this tissue is, in part, via 5‐HT1A receptors. Similar studies on human cloned receptors confirmed that xanomeline is an agonist at human cloned 5‐HT1A and 5‐HT1B receptors.
In studies using the fluorescent cytoplasmic Ca2+ indicator FLUO‐3AM, xanomeline induced an increase in cytoplasmic Ca2+ concentration in SH‐SY5Y cells expressing recombinant human 5‐HT2C receptors. Atropine antagonized this response, consistent with mediation via endogenously‐expressed muscarinic receptors. In the presence of atropine, xanomeline antagonized 5‐HT‐induced cytoplasmic changes in Ca2+ concentration in cells expressing h5‐HT2A, h5‐HT2B and h5‐HT2C receptors with potencies similar to its affinity at these receptors.
These studies indicate that xanomeline is a potent agonist at 5‐HT1A and 5‐HT1B receptors and an antagonist at 5‐HT2 receptor subtypes.

British Journal of Pharmacology (1998) 125, 1413–1420; doi:10.1038/sj.bjp.0702201
Characterization of adenosine receptors evoking excitation of mesenteric afferents in the rat
Authors: Kirkup A J , Eastwood C , Grundy D , Chessell I P , Humphrey P P A 
Published: January 2005

We examined the effects of adenosine receptor agonists and antagonists on the discharge of mesenteric afferent nerves supplying the jejunum in pentobarbitone sodium‐anaesthetized rats.
Adenosine (0.03–10 mg kg−1, i.v.), NECA (0.3–300 μg kg−1, i.v.) and the A1 receptor agonist, GR79236 (0.3–1000 μg kg−1, i.v.), each induced dose‐dependent increases in afferent nerve activity and intrajejunal pressure, hypotension and bradycardia. The A1 receptor antagonist, DPCPX (3 mg kg−1, i.v.), antagonized all the effects of GR79236 but only the haemodynamic effects of adenosine and NECA. The A2A receptor antagonist, ZM241385 (3 mg kg−1, i.v.), antagonized the hypotensive effect of NECA but none of the effects of GR79236.
The A2A receptor agonist, CGS21680 (0.3–300 μg kg−1, i.v.), and the A3 receptor agonist, IB‐MECA (0.3–300 μg kg−1, i.v.), each induced only a dose‐dependent hypotension. Subsequent administration of adenosine (3 mg kg−1, i.v.) induced increases in afferent nerve activity and intrajejunal pressure and bradycardia. ZM241385 (3 mg kg−1, i.v.) antagonized the hypotensive effect of CGS21680 but not the effects of adenosine.
Bethanechol (300 μg kg−1, i.v.) evoked increases in afferent nerve activity and intrajejunal pressure, hypotension and bradycardia. However, adenosine (3 mg kg−1, i.v.) evoked greater increases in afferent nerve activity than bethanechol despite inducing smaller increases in intrajejunal pressure.
In summary, A1 and A2B and/or A2B‐like receptors evoke adenosine‐induced increases in mesenteric afferent nerve activity and intrajejunal pressure in the anaesthetized rat. Furthermore, elevations in intrajejunal pressure do not wholly account for adenosine‐evoked excitation of mesenteric afferent nerves.

British Journal of Pharmacology (1998) 125, 1352–1360; doi:10.1038/sj.bjp.0702202
Inhibition by inorganic ions of a sustained calcium signal evoked by activation of mGlu5 receptors in rat cortical neurons and glia
Authors: Prothero Larissa S , Richards Christopher D , Mathie Alistair 
Published: January 2005

The effect of mGlu receptor agonists on intracellular calcium (Ca2+) in rat cortical neurons and glial cells was studied. The responses evoked consisted of two phases; an initial transient response followed by a sustained plateau. In both cell types the order of potency of group I mGlu receptor agonists was DHPG>1S,3R ACPD>3‐HPG.
The selective mGlu5 agonist CHPG elicited responses in both cell types as did S4C3‐HPG which is thought to be an mGlu5 agonist at high concentrations. S4‐CPG had no effect on intracellular Ca2+ levels nor did it inhibit the action of 1S,3R ACPD. These results suggest that the responses in both cell types are mediated by mGlu5 receptors.
In the absence of extracellular Ca2+ ions, 1S,3R ACPD (100 μm) induced only a transient Ca2+ response which decayed to baseline with a time constant of approximately 20 s in both cell types. Subsequent readdition of Ca2+ (2 mm) to the external solution in the continued presence of 1S,3R ACPD induced a sustained Ca2+ plateau.
The sustained Ca2+ plateau could be blocked by a number of inorganic cations, with an order of potency of Zn2+La3+>Cd2+Co2+>Ni2+>Mg2+. Similar concentrations of Zn2+ had little effect on Ca2+‐influx evoked by 25 mm K+.
It is concluded that the Ca2+‐entry pathway activated by mGlu5 receptors resembles store‐operated Ca2+‐entry pathways that have been described in other cell types.

British Journal of Pharmacology (1998) 125, 1551–1561; doi:10.1038/sj.bjp.0702203