bluuebunny/crossref_metadata_2025_split huggingface dataset:
The nonpeptide B2 receptor antagonist FR173657: inhibition of effects of bradykinin related to its role in nociception
Authors: Griesbacher Thomas , Amann Rainer , Sametz Wolfgang , Diethart Sabine , Juan Heinz 
Published: January 2005

The nonpeptide bradykinin B2 receptor antagonist, FR173657 ((E)‐3‐(6‐acetamido‐3‐pyridyl)‐N‐[N‐(2, 4‐dichloro‐3‐[(2‐methyl‐8‐quinolinyl) oxymethyl] phenyl]‐N‐methylaminocarbonylmethyl] acrylamide), was tested in models involving bradykinin‐induced activation of primary afferent neurones in vitro and in vivo.
Bradykinin‐induced contractions of the rabbit isolated iris sphincter muscle mediated by tachykinin release from trigeminal afferent neurones were inhibited in a non‐competitive manner by FR173657. A pKB value of 7.9 was calculated. Effects of substance P were unaffected by FR173657.
Nociceptive behavioural responses following intraplantar injection of bradykinin in unanaesthetized rats were reduced by 0.3 μmol kg−1 FR173657 s.c. (P<0.05), and completely abolished by 3 μmol kg−1 (P<0.05). Peroral administration of 5 μmol kg−1 FR173657 abolished the bradykinin effects (P<0.05); lower doses had no significant effect.
Shortening by intraplantar injection of bradykinin of the paw withdrawal latency in response to radiant heat was abolished by 3 μmol kg−1 FR173657 s.c. (P<0.05), while 300 nmol kg−1 had an intermediate effect. Hyperalgesia induced by prostaglandin E2 remained unaffected by FR173657.
Blood pressure reflexes following i.p. instillation of bradykinin in anaesthetized rats were inhibited by FR173657 s.c. with an ID50 of 1.1 μmol kg−1, while the peptidic B2 antagonist icatibant (Hoe‐140; d‐Arg0‐[Hyp3, Thi5, d‐Tic7, Oic8]‐bradykinin) caused inhibition at significantly lower doses (ID50 8.5 nmol kg−1 P<0.001). Responses to hydrochloric acid i.p. remained unaffected by FR173657.
FR173657 or similar nonpeptide compounds may be useful for the development of drugs for diseases involving pain induced by the release of endogenous kinins, i.e. especially in acute inflammatory conditions.

British Journal of Pharmacology (1998) 124, 1328–1334; doi:10.1038/sj.bjp.0701938
Development of endothelin receptors in perinatal rabbit pulmonary resistance arteries
Authors: Docherty Cheryl , MacLean Margaret R. 
Published: January 2005

Contractile responses to endothelin‐1 (ET‐1) and sarafotoxin S6c (S6c) were studied in pulmonary resistance arteries (∼320 μm i.d.) from fetal, 0–24 h, 4 day and 7 day rabbits. The effects of the ETA‐selective antagonist FR139317, the selective ETB receptor antagonist BQ‐788 and the non‐selective ETA/ETB receptor antagonist SB 209670, on these responses, were determined. Acetylcholine‐induced vasodilation and noradrenaline‐evoked contractions were also examined.
ET‐1 potency was in the following order (pEC50 values): fetal (8.7) = 0–24 h (8.8) = 4 day (8.6) > 7 day (8.0). The order of potency for S6c was 7 days (11.1) = 4 days (10.8) >0–24 h (9.7) > fetal (8.6). Hence, S6c and ET‐1 were equipotent in the fetus but S6c was increasingly more potent than ET‐1 with increasing age, being some 1000 times more potent by 7 days. By 7 days, responses to ET‐1 were also resistant to both FR139317 and BQ‐788. FR139317 inhibited responses to ET‐1 in vessels from 0–24 h and 4 day, but not fetal, rabbits (pKb: 6.4 in 4 day rabbits). BQ‐788 inhibited responses to ET‐1 at all age points except for 7 days (pKb: 6.7 at 0–24 h; 6.2 at 4 days). BQ‐788 inhibited responses to S6c at all age points (pKb: 8.5 at 4 days). SB 209670 inhibited responses to ET‐1 and S6c at 0–24 h and 4 days (pKb for ET‐1: 8.3 and 8.0 respectively; pKb for S6c: 9.2 and 10.2 respectively).
Acetylcholine (1 μm) induced vasodilation at all age points (inhibited by 100 μm l‐Nω‐nitroarginine methylester) although the degree of vasodilation was significantly reduced (∼75%) at 0–24 h. Noradrenaline induced contraction at all age points except 7 days and its response was significantly enhanced at 0–24 h.
Over the first week of life, the potency of S6c increases whilst that to ET‐1 decreases suggesting differential development of responses to ET‐1 and S6c and heterogeneity of ETA‐ or ‘ETB‐like’ receptor‐mediated responses. There is no synergism between ETA and ETB receptors at birth but this is established by 7 days. Immediately after birth rabbit Pulmonary Resistance Arteries are hyperresponsive to ET‐1 and noradrenaline but exhibit impaired nitric‐oxide dependent vasodilation.

British Journal of Pharmacology (1998) 124, 1165–1174; doi:10.1038/sj.bjp.0701950
Effects of the neuroprotectant lubeluzole on the cytotoxic actions of veratridine, barium, ouabain and 6‐hydroxydopamine in chromaffin cells
Authors: Cano‐Abad María F. , López Manuela G. , Hernández‐Guijo Jesús M. , Zapater Pedro , Gandía Luis , Sánchez‐García Pedro , García Antonio G. 
Published: January 2005

Incubation of bovine adrenal chromaffin cells with veratridine (10–100 μm) during 24 h, caused a concentration‐dependent release of the cytosolic lactate dehydrogenase (LDH) into the bathing medium, an indicator of cell death. Lubeluzole or its R(−) enantiomer, R91154, did not enhance LDH release. Both lubeluzole and R91154 (0.3–10 μm) decreased the veratridine‐induced LDH release.
Penfluridol did not increase LDH release at concentrations 0.003–1 μm; 3–10 μm increased LDH release to 50–60%, after 24 h exposure. Penfluridol (0.03–0.3 μm) did not protect against the cytotoxic effects of veratridine; at 1 μm, 15% protection was produced. Higher concentrations (3–10 μm) enhanced the cytotoxic effects of veratridine.
Ba2+ ions caused a concentration‐dependent increase of LDH release. This cytotoxic effect was partially prevented by 3 μm lubeluzole and fully counteracted by 1 μm penfluridol. R91154 was less potent than lubeluzole and only protected against the lesion induced by 0.5 mm Ba2+.
Ouabain (10 μm during 24 h) increased LDH release to about 30%. Both lubeluzole (0.3–10 μm) and the lower concentrations of penfluridol (0.003–0.3 μm) prevented the ouabain cytotoxic effects. At higher concentrations (3 μm), penfluridol increased drastically the ouabain cytotoxic effects.
6‐Hydroxydopamine (6‐OHDA) caused significant cytotoxic effects at 30 and 100 μm. Lubeluzole (3–10 μm) or penfluridol (0.03–0.3 μm) had no cytoprotective effects against 6‐OHDA.
Lubeluzole (3 μm), R91154 (3 μm) and penfluridol (1 μm) blocked the current through Na+ channels in voltage‐clamped chromaffin cells (INa) by around 20–30%. Ca2+ current through Ca2+ channels (ICa) was inhibited 57% by lubeluzole and R91154 and 50% by penfluridol. The effects of penfluridol were not washed out, but those of lubeluzole and R91154 were readily reversible.
Lubeluzole (3 μm) induced reversible blockade of the oscillations of the cytosolic Ca2+, [Ca2+]i, in fura‐2‐loaded cells exposed to 30 or 100 μm veratridine. Penfluridol (1 μm) inhibited those oscillations in an irreversible manner.
The results suggest that lubeluzole and its R‐isomer caused cytoprotection against veratridine cell damage, by blocking the veratridine stimulated Na+ and Ca2+ entry, as well as the [Ca2+]i oscillations. The Ba2+ and ouabain cytotoxic effects were prevented more efficiently by penfluridol, likely by blocking the plasmalemmal Na+/Ca2+ exchanger. It remains dubious whether these findings are relevant to the reported neuroprotective action of lubeluzole in stroke; the doubt rests in the stereoselective protecting effects of lubeluzole in in vivo stroke models, as opposed to its lack of stereoselectivity in the in vitro model reported here.

British Journal of Pharmacology (1998) 124, 1187–1196; doi:10.1038/sj.bjp.0701955
The effects of brucine and alcuronium on the inhibition of [3H]acetylcholine release from rat striatum by muscarinic receptor agonists
Authors: Doležal Vladimír , Tuček Stanislav 
Published: January 2005

Radioligand binding experiments indicate that the affinity of muscarinic receptors for their agonists may be enhanced by allosteric modulators. We have now investigated if brucine can enhance the inhibitory effects of muscarinic receptor agonists on the electrically evoked release of [3H]acetylcholine ([3H]ACh) from superfused slices of rat striatum.
The evoked release of [3H]ACh was inhibited by all agonists tested (i.e., furmethide, oxotremorine‐M, bethanechol and oxotremorine).
Brucine enhanced the inhibitory effects of furmethide, oxotremorine‐M and bethanechol on the evoked [3H]ACh release without altering the inhibitory effect of oxotremorine.
Alcuronium was applied for comparison and found to diminish the inhibitory effect of furmethide on the evoked [3H]ACh release.
The results demonstrate that it is possible both to enhance and diminish the functional effects of muscarinic receptor agonists by allosteric modulators.
The direction of the observed effects of brucine and alcuronium on [3H]ACh release fully agrees with the effects of these modulators on the affinities of human M4 receptors for furmethide, oxotremorine‐M, bethanechol and oxotremorine, as described by Jakubík et al. (1997). This supports the view that the presynaptic muscarinic receptors responsible for the autoinhibition of ACh release in rat striatum belong to the M4 muscarinic receptor subtype.

British Journal of Pharmacology (1998) 124, 1213–1218; doi:10.1038/sj.bjp.0701966
Modulation of relaxation to levcromakalim by s‐nitroso‐n‐acetylpenicillamine (SNAP) and 8‐bromo cyclic GMP in the rat isolated mesenteric artery
Authors: White Richard , Hiley C. Robin 
Published: January 2005

Levcromakalim caused concentration‐dependent relaxations of methoxamine‐induced tone in both endothelium‐denuded and intact vessels. Its potency was reduced by the nitric oxide donor, S‐nitroso‐N‐acetylpenicillamine (SNAP; 0.1 μm or 1 μm) in both denuded and intact vessels. The maximal relaxation (Rmax) was reduced only in denuded vessels.
SNAP was more potent in endothelium‐denuded than intact vessels but there were no differences in Rmax. Glibenclamide (10 μm) did not affect relaxation to SNAP in endothelium‐denuded or intact vessels.
The soluble guanylyl cyclase inhibitor, 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ, 10 μm) increased the potency and Rmax of levcromakalim in endothelium‐intact vessels. ODQ had no effect in denuded vessels.
ODQ (10 μm) reduced the vasorelaxant potency of SNAP in both intact and endothelium‐denuded vessels by 190‐fold and 620‐fold, respectively.
8‐bromo cyclic GMP (10 or 30 μm) reduced both the potency and Rmax of levcromakalim in de‐endothelialized vessels, but had no effect in intact vessels although it reduced both the potency and Rmax of levcromakalim in intact vessels incubated with ODQ (10 μm).
In the presence of ODQ (10 μm), SNAP (0.1 μm or 1 μm) reduced the potency of levcromakalim in intact vessels, without altering Rmax, but had no effect in denuded vessels. SNAP (50 μm) reduced both the potency and Rmax of levcromakalim in intact and endothelium‐denuded vessels.
Therefore, although SNAP causes relaxation principally through generation of cyclic GMP, it can modulate the actions of levcromakalim through mechanisms both dependent on, and independent of, cyclic GMP; the former predominate in endothelium‐denuded vessels and the latter in intact vessels.

British Journal of Pharmacology (1998) 124, 1219–1226; doi:10.1038/sj.bjp.0701973
Potent antihyperglycaemic property of a new imidazoline derivative S‐22068 (PMS 847) in a rat model of NIDDM
Authors: Pelé‐Tounian Agnès , Wang Xuan , Rondu Frédéric , Lamouri Azzdine , Touboul Estera , Marc Sylvie , Dokhan Raymond , Pfeiffer Bruno , Manechez Dominique , Renard Pierre , Guardiola‐Lemaître Béatrice , Godfroid Jean‐Jacques , Pénicaud Luc , Ktorza Alain 
Published: January 2005

Recent data suggest that some imidazoline derivatives can lower plasma glucose in experimental animal models of diabetes. We studied the activity of an imidazoline S‐22068, in rat model of non‐insulin‐dependent diabetes mellitus (NIDDM) produced with a low dose of streptozotocin (35 mg kg−1, i.v.) in the adult.
The respective increase over basal value in glucose (ΔG) and insulin (ΔI), and the rate of glucose disappearance (K), were measured during a 30 min intravenous glucose tolerance test. After an intraperitoneal injection of S‐22068 (24 mg kg−1), ΔG (mM min −1) was decreased (91.67±5.83 vs 120.5±3.65; P<0.001), whereas K was increased (1.74±0.09 vs 1.18±0.05; P<0.001). Although insulinaemia was increased at time‐point 0 of the test, ΔI was unchanged.
During oral glucose tolerance tests (OGTT), S‐22068 (24 mg kg−1, p.o.) improved glucose tolerance, and its efficiency was potentiated after chronic treatment (15 days). Basal glycaemia was unaffected by the treatment. Under the same conditions, a higher dose of S‐22068 (40 mg kg−1) further improved glucose tolerance without causing hypoglycaemia.
Binding experiments revealed that S‐22068 displays no affinity for either adrenoceptors or the two imidazoline receptors I1 or I2.
These results demonstrate that S‐22068 improves glucose tolerance without causing hypoglycaemia. Thus S‐22068 represents a new potential option in the treatment of NIDDM.

British Journal of Pharmacology (1998) 124, 1591–1596; doi:10.1038/sj.bjp.0701989
Purinoceptor activation of chloride transport in cystic fibrosis and CFTR‐transfected pancreatic cell lines
Authors: O'Reilly Catherine M , O'Farrell Anne M , Ryan Michael P 
Published: January 2005

The regulation of chloride efflux from cystic fibrosis pancreatic adenocarcinoma cells (CFPAC‐1) and wild‐type CFTR‐transfected CFPAC‐1 cells (TPAC) was compared.
Forskolin (10 μM) stimulated chloride efflux from the corrected TPAC cells but not from CFPAC‐1 cells. Chloride efflux from both cell types was activated by thapsigargin (0.5 μM).
The nucleotides ATP and UTP and the non‐hydrolyzable ATP analogue, adenosine 5′‐O‐(3‐thio) triphosphate (ATPγS), stimulated chloride efflux from both cell types. None of the other P2 purinoceptor agonists investigated elicited a response. The order of potency was ATPUTPATPγS.
Adenosine (10–100 μM) activated choride efflux from the TPAC but not the CFPAC cell line with no increase in intracellular cyclic AMP. Small but statistically significant inhibitions of the adenosine‐(50 μM)‐stimulated increase in chloride efflux were elicited by the A1 receptor antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (CPX, 100 nM) and the A2 receptor antagonist 3,7‐dimethyl‐1‐propylargylxanthine (DMPX, 10 μM). The A2A receptor antagonist 8‐(3‐chlorostyryl)caffeine (CSC, 100 nM) had no significant effect.
These results provide evidence for the regulation of chloride efflux by P2Y2 purinoceptors in genetically‐corrected and CF pancreatic cell lines. Studies with adenosine receptor antagonists indicate some possible involvement of A1 and A2 (but not A2A) receptors in the adenosine stimulation of chloride efflux, but the relatively small effects of the inhibitors coupled with lack of increase in cyclic AMP and a response only in the CFTR‐transfected cells also suggests a possible direct effect of adenosine on CFTR.

British Journal of Pharmacology (1998) 124, 1597–1606; doi:10.1038/sj.bjp.0701990
Involvement of ETA and ETB receptors in the activation of phospholipase D by endothelins in cultured rat cortical astrocytes
Authors: Servitja Joan‐Marc , Masgrau Roser , Sarri Elisabet , Picatoste Fernando 
Published: January 2005

This study was performed to characterize the receptor subtypes involved in the endothelin stimulation of phospholipase D (PLD) in rat cortical astrocytes in primary culture. PLD activity was determined by measuring the formation of [32P]phosphatidylbutanol in [32P]orthophosphate prelabelled cells stimulated in the presence of 25 mM butanol.
The agonists endothelin‐1 (ET‐1), endothelin‐3 (ET‐3), sarafotoxin 6c (S6c) and IRL 1620 elicited PLD activation in a concentration‐dependent manner. The potencies of ET‐1, ET‐3 and S6c were similar. The maximal effects evoked by the ETB‐preferring agonists, ET‐3, S6c and IRL 1620, were significantly lower than the maximal response to the non‐selective agonist ET‐1.
The response to 1 nM ET‐1 was inhibited by increasing concentrations of the ETA receptor antagonist BQ‐123 in a biphasic manner. A high potency component of the inhibition curve (24.2±3.5% of the ET‐1 response) was defined at low (up to 1 μM) concentrations of BQ‐123, yielding an estimated Ki value for BQ‐123 of 21.3±2.5 nM. In addition, the presence of 1 μM BQ‐123 significantly reduced the maximal response to ET‐1 but did not change the pD2 value.
Increasing concentrations of the ETB selective antagonist BQ‐788 inhibited the S6c response with a Ki of 17.8±0.8 nM. BQ‐788 also inhibited the effect of ET‐1, although, in this case, two components were defined, accounting for approximately 50% of the response, and showing Ki values of 20.9±5.1 nM and 439±110 nM, respectively. The ET‐1 concentration‐response curve was shifted to the right by 1 μM BQ‐788, also revealing two components. Only one of them, corresponding to 69.8±4.4% of the response, was sensitive to BQ‐788 which showed a Ki value of 28.8±8.9 nM.
Rapid desensitization was achieved by preincubation with ET‐1 or S6c. In cells pretreated with S6c neither ET‐3 nor S6c activated PLD, but ET‐1 still induced approximately 40% of the response shown by non‐desensitised cells. This remaining response was insensitive to BQ‐788, but fully inhibited by BQ‐123.
In conclusion, endothelins activate PLD in rat cortical astrocytes acting through both ETA and ETB receptors, and this response desensitizes rapidly in an apparently homologous fashion. The percentage contribution of ETA and ETB receptors to the ET‐1 response was found to be approximately 20% and 80%, respectively, when ETB receptors were not blocked, and 30–50% and 50–70%, respectively, when ETB receptors were inhibited or desensitized. These results may be relevant to the study of a possible role of PLD in the proliferative effects shown by endothelins on cultured and reactive astrocytes.

British Journal of Pharmacology (1998) 124, 1728–1734; doi:10.1038/sj.bjp.0701997
Effect of increased cardiac output on liver blood flow, oxygen exchange and metabolic rate during longterm endotoxin‐induced shock in pigs
Authors: Šantak Borislav , Radermacher Peter , Adler Jens , Iber Thomas , Rieger Karen M , Wachter Ulrich , Vogt Josef , Georgieff Michael , Träger Karl 
Published: January 2005

We investigated hepatic blood flow, O2 exchange and metabolism in porcine endotoxic shock (Control, n=8; Endotoxin, n=10) with administration of hydroxyethylstarch to maintain arterial pressure (MAP)>60 mmHg.
Before and 12, 18 and 24 h after starting continuous i.v. endotoxin we measured portal venous and hepatic arterial blood flow, intracapillary haemoglobin O2 saturation (Hb‐O2%) of the liver surface and arterial, portal and hepatic venous lactate, pyruvate, glyercol and alanine concentrations. Glucose production rate was derived from the plasma isotope enrichment during infusion of [6,6‐2H2]‐glucose.
Despite a sustained 50% increase in cardiac output endotoxin caused a progressive, significant fall in MAP. Liver blood flow significantly increased, but endotoxin affected neither hepatic O2 delivery and uptake nor mean intracapillary Hb‐O2% and Hb‐O2% frequency distributions.
Endotoxin nearly doubled endogenous glucose production rate while hepatic lactate, alanine and glycerol uptake rates progressively decreased significantly. The lactate uptake rate even became negative (P<0.05 vs Control). Endotoxin caused portal and hepatic venous pH to fall significantly concomitant with significantly increased arterial, portal and hepatic venous lactate/pyruvate ratios.
During endotoxic shock increased cardiac output achieved by colloid infusion maintained elevated liver blood flow and thereby macro‐ and microcirculatory O2 supply. Glucose production rate nearly doubled with complete dissociation of hepatic uptake of glucogenic precursors and glucose release. Despite well‐preserved capillary oxygenation increased lactate/pyruvate ratios reflecting impaired cytosolic redox state suggested deranged liver energy balance, possibly due to the O2 requirements of gluconeogenesis.

British Journal of Pharmacology (1998) 124, 1689–1697; doi:10.1038/sj.bjp.0701998
Influence of chronic hypoxia on the contributions of non‐inactivating and delayed rectifier K currents to the resting potential and tone of rat pulmonary artery smooth muscle
Authors: Osipenko O. N. , Alexander D. , MacLean M. R. , Gurney A. M. 
Published: January 2005

Exposing rats to chronic hypoxia increased the 4‐aminopyridine (4‐AP) sensitivity of pulmonary arteries. 1 mm 4‐AP caused smooth muscle cell depolarization and contraction in arteries from hypoxic rats, but had little effect in age‐matched controls. Chronic hypoxia downregulated delayed rectifier K+ current (IK(V)), which was nearly 50% blocked by 1 mm 4‐AP, and non‐inactivating K+ current (IK(N)), which was little affected by 1 mm 4‐AP. The results suggest that IK(N) determines resting potential in control rats and that its downregulation following hypoxia leads to depolarization, which activates IK(V) and increases its contribution to resting potential. The hypoxia‐induced increase in 4‐AP sensitivity thus reflects a switch in the major K+ current determining resting potential, from IK(N) to IK(V). This has important implications for the actions and specificity of pulmonary vasodilator drugs.British Journal of Pharmacology (1998) 124, 1335–1337; doi:10.1038/sj.bjp.0702006
Histamine H1‐receptor‐mediated increase in the Ca2+ transient without a change in the Ca2+ current in electrically stimulated guinea‐pig atrial myocytes
Authors: Yoshimoto Kimihiro , Hattori Yuichi , Houzen Hideki , Kanno Morio , Yasuda Keishu 
Published: January 2005

The effects of histamine on the intracellular Ca2+ concentration ([Ca2+]i), action potential and membrane currents were assessed in single atrial myocytes prepared from guinea‐pigs.
Histamine caused a concentration‐dependent increase in the [Ca2+]i transient in indo1/AM loaded myocytes when stimulated electrically at 0.5 Hz. However, the maximum increase in [Ca2+]i transient produced by histamine was less than 50% of that elicited by isoprenaline. The histamine‐induced increase in [Ca2+]i transient was significantly inhibited by chlorpheniramine, but not by cimetidine.
Pretreatment with nifedipine nearly completely suppressed the histamine‐induced increase in [Ca2+]i transient. Cyclopiazonic acid did not affect the histamine response.
In the whole‐cell current‐clamp mode of the patch‐clamp method, both histamine and isoprenaline prolonged action potential duration (APD) in atrial myocytes. In the presence of Co2+ or nifedipine, the isoprenaline‐induced APD prolongation was abolished and an APD shortening effect was manifested, while histamine still increased APD. The APD prolongation elicited by histamine was reversed by chlorpheniramine.
In the voltage‐clamp mode, the histamine‐sensitive membrane current was inwardly rectifying and reversed close to the calculated value of the K+ equilibrium potential. Histamine had no apparent effect on L‐type Ca2+ current, in contrast to the pronounced effect of isoprenaline.
These results indicate that in guinea‐pig atrial myocytes stimulation of H1‐receptors with histamine does not directly activate Ca2+ channels but causes an elevation of [Ca2+]i transient by increasing Ca2+ influx through the channels during the prolonged repolarization of action potentials resulting from inhibition of the outward K+ current.

British Journal of Pharmacology (1998) 124, 1744–1750; doi:10.1038/sj.bjp.0702008