bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of prostacyclin and prostaglandin E2 receptor mediated responses in adult rat dorsal root ganglion cells, in vitro
Authors: Rowlands Dewi K , Kao Chung‐lei , Wise Helen 
Published: January 2005

Primary cultures of adult rat dorsal root ganglia (DRG) were prepared to examine the properties of prostacyclin (IP) receptors and prostaglandin E2 (EP) receptors in sensory neurones.
IP receptor agonists, cicaprost and iloprost, stimulated adenylyl cyclase activity with EC50 values of 22 and 28 nM, respectively. Prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2) were 7 fold less potent than cicaprost and iloprost, with PGE2 displaying a lower maximal response.
Adenylyl cyclase activation by iloprost, PGE1 and PGE2, but not by forskolin, was highly dependent on DRG cell density. Although the potency of iloprost and PGE2 for stimulating adenylyl cyclase was unchanged, their maximal responses were significantly increased at low cell density.
Both IP and EP2/4 receptors could be down‐regulated by agonist pretreatment, however the presence of cyclo‐oxygenase (COX) inhibitors did not prevent this apparent down‐regulation of IP and EP2/4 receptors at high DRG cell densities.
Stimulation of adenylyl cyclase by the neuropeptide calcitonin gene‐related peptide was also decreased at high DRG cell density, whereas the responses to β‐adrenoceptor agonists were increased at high DRG cell density.
Addition of nerve growth factor (NGF), or the addition of anti‐neurotrophin antibodies during the 5‐day culture of DRG cells, had no effect on IP receptor‐mediated responses.
These results indicate that Gs‐coupled receptors involved in nociception are regulated in a variable manner in adult rat sensory neurones, and that this cell density‐dependent regulation may be agonist‐independent for IP and EP2/4 receptors.

British Journal of Pharmacology (2001) 133, 13–22; doi:10.1038/sj.bjp.0704028
Cerebral vasoconstriction produced by vasopressin in conscious goats: role of vasopressin V1 and V2 receptors and nitric oxide
Authors: Fernández Nuria , Martínez María Angeles , García‐Villalón Angel Luis , Monge Luis , Diéguez Godofredo 
Published: January 2005

To examine the role of vasopressin V1 and V2 receptors, nitric oxide and prostanoids in the cerebrovascular effects of arginine vasopressin, cerebral blood flow was electromagnetically measured in awake goats.
In 16 animals, vasopressin (0.03 – 1 μg), injected into the cerebral circulation, caused increments of resting cerebrovascular resistance which ranged from 18% (0.03 μg, P<0.01) to 79% (1 μg, P<0.01). Desmopressin (0.03 – 1 μg, four goats) did not affect significantly cerebrovascular resistance.
The cerebrovascular resistance increases by vasopressin were reduced significantly by the antagonist for vasopressin V1 receptors d(CH2)5Tyr(Me)‐AVP in a rate depending way (five (six goats) and 15 (four goats) μg min−1), and by the mixed antagonist for vasopressin V1 and V2 receptors desGly‐d(CH2)5‐D‐Tyr(Et)Val‐AVP (5 μg min−1, four goats), and they were not significantly affected by the antagonist for vasopressin V2 receptors d(CH2)5, D‐Ile2, Ile4‐AVP (5 μg min−1, four goats).
The inhibitor of nitric oxide synthesis Nw‐nitro‐L‐arginine methyl ester (L‐NAME, 47 mg kg−1 i.v., five goats) augmented cerebrovascular resistance by 130% (P<0.01), and for 24 h after this treatment the cerebrovascular effects of vasopressin were potentiated.
The inhibitor of cyclo‐oxygenase meclofenamate (6 mg kg−1 i.v., five goats) did not modify significantly resting haemodynamic variables measured or the cerebrovascular effects of vasopressin.
Therefore, the vasopressin‐induced cerebral vasoconstriction may be mediated by vasopressin V1 receptors, without involvement of vasopressin V2 receptors, and may be modulated by nitric oxide but not by prostanoids.

British Journal of Pharmacology (2001) 132, 1837–1844; doi:10.1038/sj.bjp.0704034
Mobilization of rat stomach ECL‐cell histamine in response to short‐ or long‐term treatment with omeprazole and/or YF 476 studied by gastric submucosal microdialysis in conscious rats
Authors: Konagaya T , Bernsand M , Norlén P , Håkanson R 
Published: January 2005

Mobilization of histamine from the ECL cells was monitored by gastric submucosal microdialysis in conscious rats. The ECL cells are known to operate under gastrin control and the purpose of the present study was to examine their in situ response to short‐term (12 h) as well as long‐term (28 days) hypergastrinaemia, induced by treatment with the proton pump inhibitor omeprazole.
Hypergastrinaemia promptly raised the histamine concentration in the microdialysate. The effect was prevented by CCK2 receptor blockade (YF476). On day 7 of omeprazole treatment the microdialysate histamine concentration reached a peak, five times higher than before treatment. Subsequently (14 and 28 days), less histamine was mobilized.
Gastrin infusion (4 h) raised the microdialysate histamine concentration in a dose‐dependent manner in fasted rats and freely fed rats and in rats treated with omeprazole for a week. However, while fasted and fed rats responded to low doses of gastrin, the omeprazole‐treated rats required large doses of gastrin to respond.
When the amount of histamine mobilized was related to the serum gastrin concentration the following EC50 values could be calculated: fasted rats 2.3×10−10 M, freely fed rats 2.5×10−10 M, omeprazole‐treated rats 8.7×10−10 M. The maximal histamine responses in the three groups were 18.4 pmol 4 h−1±0.8, 21.9 pmol 4 h−1±1.2 and 68.0 pmol 4 h−1±3.5, respectively.
The results suggest that ECL cells, exposed to a high gastrin concentration for a week, respond with a shift in the receptor‐ligand binding affinity from high to low. Apparently, CCK2 receptors of the ECL cells are subject to dynamic changes with respect to ligand‐binding affinity.

British Journal of Pharmacology (2001) 133, 37–42; doi:10.1038/sj.bjp.0704037
Inhibition of m3 muscarinic acetylcholine receptors by local anaesthetics
Authors: Hollmann Markus W , Ritter Carsten H , Henle Philipp , De Klaver Manuela , Kamatchi Ganesan L , Durieux Marcel E 
Published: January 2005

Muscarinic m1 receptors are inhibited by local anaesthetics (LA) at nM concentrations. To elucidate in more detail the site(s) of LA interaction, we compared these findings with LA effects on m3 muscarinic receptors.
We expressed receptors in Xenopus oocytes. Using two‐electrode voltage clamp, we measured the effects of lidocaine, QX314 (permanently charged) and benzocaine (permanently uncharged) on Ca2+‐activated Cl−‐currents (ICl(Ca)), elicited by acetyl‐β‐methylcholine bromide (MCh). We also characterized the interaction of lidocaine with [3H]‐quinuclydinyl benzylate ([3H]‐QNB) binding to m3 receptors. Antisense‐injection was used to determine the role of specific G‐protein α subunits in mediating the inhibitory effects of LA. Using chimeric receptor constructs we investigated which domains of the muscarinic receptors contribute to the binding site for LA.
Lidocaine inhibited m3‐signalling in a concentration‐dependent, reversible, non‐competitive manner with an IC50 of 370 nM, approximately 21 fold higher than the IC50 (18 nM) reported for m1 receptors. Intracellular inhibition of both signalling pathways by LA was similar, and dependent on the Gq‐ protein α subunit. In contrast to results reported for the m1 receptor, the m3 receptor lacks the major extracellular binding site for charged LA. The N‐terminus and third extracellular loop of the m1 muscarinic receptor molecule were identified as requirements to obtain extracellular inhibition by charged LA.

British Journal of Pharmacology (2001) 133, 207–216; doi:10.1038/sj.bjp.0704040
Murine ventricular L‐type Ca2+ current is enhanced by zinterol viaβ1‐adrenoceptors, and is reduced in TG4 mice overexpressing the human β2‐adrenoceptor
Authors: Heubach Jürgen F , Graf Eva M , Molenaar Peter , Jäger Andreas , Schröder Frank , Herzig Stefan , Harding Sian E , Ravens Ursula 
Published: January 2005

The functional coupling of β2‐adrenoceptors (β2‐ARs) to murine L‐type Ca2+ current (ICa(L)) was investigated with two different approaches. The β2‐AR signalling cascade was activated either with the β2‐AR selective agonist zinterol (myocytes from wild‐type mice), or by spontaneously active, unoccupied β2‐ARs (myocytes from TG4 mice with 435 fold overexpression of human β2‐ARs). Ca2+ and Ba2+ currents were recorded in the whole‐cell and cell‐attached configuration of the patch‐clamp technique, respectively.
Zinterol (10 μM) significantly increased ICa(L) amplitude of wild‐type myocytes by 19±5%, and this effect was markedly enhanced after inactivation of Gi‐proteins with pertussis‐toxin (PTX; 76±13% increase). However, the effect of zinterol was entirely mediated by the β1‐AR subtype, since it was blocked by the β1‐AR selective antagonist CGP 20712A (300 nM). The β2‐AR selective antagonist ICI 118,551 (50 nM) did not affect the response of ICa(L) to zinterol.
In myocytes with β2‐AR overexpression ICa(L) was not stimulated by the activated signalling cascade. On the contrary, ICa(L) was lower in TG4 myocytes and a significant reduction of single‐channel activity was identified as a reason for the lower whole‐cell ICa(L). The β2‐AR inverse agonist ICI 118,551 did not further decrease ICa(L). PTX‐treatment increased current amplitude to values found in control myocytes.
In conclusion, there is no evidence for β2‐AR mediated increases of ICa(L) in wild‐type mouse ventricular myocytes. Inactivation of Gi‐proteins does not unmask β2‐AR responses to zinterol, but augments β1‐AR mediated increases of ICa(L). In the mouse model of β2‐AR overexpression ICa(L) is reduced due to tonic activation of Gi‐proteins.

British Journal of Pharmacology (2001) 133, 73–82; doi:10.1038/sj.bjp.0704045
The properties of ryanodine‐sensitive Ca2+ release in mouse gastric smooth muscle cells
Authors: Tokutomi Yoshiko , Tokutomi Naofumi , Nishi Katsuhide 
Published: January 2005

Under voltage‐clamped conditions, gastric smooth muscle cells of BALB/c mice developed spontaneous (STOCs) and caffeine‐ (ICAF) and carbachol‐induced (ICCh) transient outward currents.
In fura‐2 microscopic measurements of intracellular Ca2+ concentration ([Ca2+]i), caffeine and carbachol (CCh) provoked similar transient [Ca2+]i elevations.
Both ICCh and CCh‐induced [Ca2+]i elevation of single smooth muscle cells occurred in an ‘all‐or‐nothing’ fashion in contrast to the reproducible caffeine responses.
On the basis of the suppression of STOCs and ICAF by nicardipine, tetraethylammonium and iberiotoxin, but not by charybdotoxin nor apamin, it was suggested that both currents were generated by large conductance type Ca2+‐activated K+ channels.
In measurements of isometric tension, caffeine produced relaxation of gastric smooth muscle strips in a concentration‐dependent manner (0.1 – 3 mM). The concentration‐dependent relaxation with caffeine was mimicked by dibutyryl cyclic AMP which produced potentiation of contraction triggered by 50 mM KCl.
At caffeine concentrations >3 mM, a transient contraction followed by relaxation was provoked as the quasi maximal response to caffeine. In the quasi maximal response, caffeine acted as a potent relaxant in smooth muscle strips precontracted with 50 mM KCl or 3 μM CCh.
The relaxation with caffeine was significantly accelerated in those strips precontracted with KCl or CCh. All these results suggest that ryanodine‐sensitive Ca2+ release, which is triggered by caffeine, is an important modifier of Ca2+ homeostasis in the cytoplasm and the contractility of gastric smooth muscle cells of mice.

British Journal of Pharmacology (2001) 133, 125–137; doi:10.1038/sj.bjp.0704048
Depressor and regionally‐selective vasodilator effects of human and rat urotensin II in conscious rats
Authors: Gardiner S M , March J E , Kemp P A , Davenport A P , Bennett T 
Published: January 2005

The regional haemodynamic effects of rat or human urotensin II (U‐II) 3, 30, 300 and 3000 pmol kg−1, i.v.) were assessed in separate groups of conscious, unrestrained, male, Sprague‐Dawley rats (n=8 in each). Rat and human U‐II had similar effects. At a dose of 3 pmol kg−1, neither peptide had any significant action, while at a dose of 30 pmol kg−1, there was a transient mesenteric vasodilatation (significant only for rat U‐II). At doses of 300 and 3000 pmol kg−1, there were dose‐dependent tachycardias, and mesenteric and hindquarters hyperaemic vasodilatations. Thus, in conscious rats, the predominant cardiovascular action of rat and human U‐II is vasodilatation. This is in contrast to recent findings with human U‐II in non‐human primates, but is consistent with effects on human isolated resistance vessels.British Journal of Pharmacology (2001) 132, 1625–1629; doi:10.1038/sj.bjp.0704051
Effects of yohimbine on the antinociceptive and place conditioning effects of opioid agonists in rodents
Authors: Morales Lydia , Perez‐Garcia Carmen , Alguacil Luis F 
Published: January 2005

The pharmacological modulation of opioid actions by drugs acting on heterologous mechanisms could be useful to overcome some of the main problems associated with the use of opiate agonists. Based on previous findings on the interactions between yohimbine and opioid drugs, we have further studied the effects of yohimbine on the antinociceptive and positive‐negative reinforcing effects of morphine (μ opioid receptor‐preferring agonist), U‐50,488 (κ agonist) and SNC80 (δ agonist).
Pretreatment with yohimbine completely blocked the antinociception provided by the three opioid agonists in the mouse tail‐immersion test.
A similar blockade of SNC80 and U‐50,488‐induced antinociception was observed with yohimbine in the mouse hot plate test at the same doses. In this paradigm, the effect of the κ agonist was very slight and the actions of yohimbine rather variable.
In place conditioning experiments with SD (Sprague – Dawley) male rats, yohimbine alone was inactive but it limited the preference induced by morphine and SNC80 and the aversive effect of U‐50,488. Impaired novelty preference was also observed with the combination of yohimbine and U‐50,488.
It is concluded that yohimbine tends to limit opioid antinociception and the addictive potential of μ and δ opioid agonists. More selective drugs could help to understand the mechanisms involved in these actions.

British Journal of Pharmacology (2001) 133, 172–178; doi:10.1038/sj.bjp.0704057
IL‐17‐induced cytokine release in human bronchial epithelial cells in vitro: role of mitogen‐activated protein (MAP) kinases
Authors: Laan Martti , Lötvall Jan , Chung K Fan , Lindén Anders 
Published: January 2005

Recent data indicate that interleukin (IL)‐17 may contribute to neutrophilic airway inflammation by inducing the release of neutrophil‐mobilizing cytokines from airway cells. The aim of this study was to evaluate the role of mitogen activated protein kinases in IL‐17 induced release of IL‐8 and IL‐6 in bronchial epithelial cells.
Transformed human bronchial epithelial cells (16HBE) were stimulated with either IL‐17 or vehicle. Both groups were treated either with SB202190 (inhibitor of p38 MAP kinase), PD98059 (inhibitor of extracellular‐signal‐regulated kinase [ERK] pathway), Ro‐31‐7549 (protein kinase C [PKC] inhibitor), LY 294002 (a phosphatidylinositol 3‐kinase [PI 3‐kinase] inhibitor) or vehicle. IL‐6 and IL‐8 levels were measured in conditioned media by ELISA.
The IL‐17‐induced release of IL‐6 and IL‐8 was concentration‐dependently inhibited by SB202190 and by PD98059 in bronchial epithelial cells without affecting cell proliferation or survival.
Ro‐31‐7549 and LY294002 had no significant effect on IL‐17‐induced IL‐6 or IL‐8 release in bronchial epithelial cells.
Taken together, these data indicate a role for p38 and ERK kinase pathways in IL‐17‐induced release of neutrophil‐mobilizing cytokines in human bronchial epithelial cells. These mechanisms constitute potential pharmacotherapeutical targets for inhibition of the IL‐17‐mediated airway neutrophilia.

British Journal of Pharmacology (2001) 133, 200–206; doi:10.1038/sj.bjp.0704063
Drug‐disease interactions: reduced β‐adrenergic and potassium channel antagonist activities of sotalol in the presence of acute and chronic inflammatory conditions in the rat
Authors: Kulmatycki Kenneth M , Abouchehade Kassem , Sattari Saeed , Jamali Fakhreddin 
Published: January 2005

Inflammation may influence response to pharmacotherapy.
We investigated the effect of inflammation on response to sotalol, a β‐adrenergic receptor and potassium channel antagonist. Racemic sotalol (40 mg kg−1) was administered to healthy, acutely (interferonα 2a‐induced) and chronically (Mycobacterium butyricum‐induced adjuvant arthritis) inflamed male Sprague‐Dawley rats (n=4 – 6/group). Another group of interferon‐treated rats received 3 mg kg−1 of anti‐TNF antibody infliximab. Electrocardiogram (ECG) recorded and plasma sotalol concentration monitored for 6 h. The study was repeated in acutely inflamed rats following administration of stereochemically pure individual sotalol enantiomers [40 mg kg−1 S (potassium channel blocker) or 20 mg kg−1 R (β‐adrenergic/potassium channel blocker)].
Chronic arthritis was readily evident. Acute arthritis was associated with elevated segmented neutrophils and increased plasma nitrite and tumour necrosis factor (TNF) concentrations. Sotalol affected ECG in all rats. In both inflamed groups, however, response to sotalol in prolongation of QT interval (potassium channel sensitivity) was reduced. The effect of PR interval (β‐adrenergic activity) was also reduced following administration of the racemate and R‐enantiomer. No significant differences in pharmacokinetics were observed between control and inflamed rats.
Infliximab reduced nitrite and TNF concentrations and reversed the effect of acute inflammation on both PR and QT intervals.
The reduced electrocardiographic responses to sotalol is likely due to the influence of inflammation on the action of the drug on both β‐adrenergic and potassium channel receptors secondary to over‐expression of pro‐inflammatory cytokines and/or nitric oxide.
Our observation may have therapeutic consequences in all conditions where inflammatory mediators are increased.

British Journal of Pharmacology (2001) 133, 286–294; doi:10.1038/sj.bjp.0704067
A new HMG‐CoA reductase inhibitor, rosuvastatin, exerts anti‐inflammatory effects on the microvascular endothelium: the role of mevalonic acid
Authors: Stalker Timothy J , Lefer Allan M , Scalia Rosario 
Published: January 2005

Recent studies have reported that hydroxymethylglutaryl coenzyme A (HMG‐CoA) reductase inhibitors have vasculoprotective effects independent of their lipid‐lowering properties, including anti‐inflammatory actions. We used intravital microscopy of the rat mesenteric microvasculature to examine the effects of rosuvastatin, a new HMG‐CoA reductase inhibitor, on leukocyte‐endothelium interactions induced by thrombin.
Intraperitoneal administration of 0.5 and 1.25 mg kg−1 rosuvastatin 18 h prior to the study, significantly and dose‐dependently attenuated leukocyte rolling, adherence, and transmigration in the rat mesenteric microvasculature superfused with 0.5 u ml‐1 thrombin. This protective effect of rosuvastatin was reversed by intraperitoneal injection of 25 mg kg−1 mevalonic acid 18 h before the study.
Immunohistochemical detection of the endothelial cell adhesion molecule P‐selectin showed a 70% decrease in endothelial cell surface expression of P‐selectin in thrombin‐stimulated rats given 1.25 mg kg−1 rosuvastatin. In addition, rosuvastatin enhanced release of nitric oxide (NO) from the vascular endothelium as measured directly in rat aortic segments. Moreover, rosuvastatin failed to attenuate leukocyte‐endothelium interactions in peri‐intestinal venules of eNOS−/− mice.
These data indicate that rosuvastatin exerts important anti‐inflammatory effects via inhibition of endothelial cell adhesion molecule expression, and that this protective action of rosuvastatin requires release of nitric oxide by the vascular endothelium. These data also demonstrate that the mechanism of the non‐lipid lowering actions of HMG‐CoA reductase inhibitors in vivo may be due to reduced formation or availability of mevalonic acid within endothelial cells.

British Journal of Pharmacology (2001) 133, 406–412; doi:10.1038/sj.bjp.0704070
Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism‐dependent haptenation and T‐cell proliferation in vivo
Authors: Naisbitt Dean J , Gordon S Fraser , Pirmohamed Munir , Burkhart Christoph , Cribb Alistair E , Pichler Werner J , Park B Kevin 
Published: January 2005

Sulphamethoxazole has been associated with the occurrence of hypersensitivity reactions. There is controversy as to whether the immune response is metabolism‐dependent or ‐independent. We have therefore investigated the site of antigen formation and the nature of the drug signal presented to the immune system in vivo.
Male Wistar rats were dosed with sulphamethoxazole, sulphamethoxazole hydroxylamine or nitroso sulphamethoxazole. Antigen formation on cell surfaces was determined by flow cytometry using a specific anti‐sulphamethoxazole antibody. Immunogenicity was determined by assessment of ex vivo T‐cell proliferation.
Administration of nitroso sulphamethoxazole, but not sulphamethoxazole or sulphamethoxazole hydroxylamine, resulted in antigen formation on the surface of lymphocytes, splenocytes and epidermal keratinocytes, and a strong proliferative response of splenocytes on re‐stimulation with nitroso sulphamethoxazole. Rats dosed with sulphamethoxazole or sulphamethoxazole hydroxylamine did not respond to any of the test compounds.
CD4+ or CD8+ depleted cells responded equally to nitroso sulphamethoxazole. The proliferative response to nitroso sulphamethoxazole was seen even after pulsing for only 5 min, and was not inhibited by glutathione. Responding cells produced IFN‐γ, but not IL‐4.
Haptenation of cells by sulphamethoxazole hydroxylamine was seen after depletion of glutathione by pre‐treating the rats with diethyl maleate. Splenocytes from the glutathione‐depleted sulphamethoxazole hydroxylamine‐treated rats responded weakly to nitroso sulphamethoxazole, but not to sulphamethoxazole or sulphamethoxazole hydroxylamine.
Dosing of rats with sulphamethoxazole produced a cellular response to nitroso sulphamethoxazole (but not to sulphamethoxazole or its hydroxylamine) when the animals were primed with complete Freund's adjuvant.
These studies demonstrate the antigenicity of nitroso sulphamethoxazole in vivo and provide evidence for the role of drug metabolism and cell surface haptenation in the induction of a cellular immune response in the rat.

British Journal of Pharmacology (2001) 133, 295–305; doi:10.1038/sj.bjp.0704074