bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of central aromatic amino acid DOPA decarboxylase inhibition on the motor actions of L‐DOPA and dopamine agonists in MPTP‐treated primates
Authors: Treseder Sarah A , Jackson Michael , Jenner Peter 
Published: January 2005

Endogenous L‐DOPA may act as a neuromodulator contributing to the production of motor activity. We now investigate the effects of the centrally acting aromatic amino acid dopa decarboxylase (AADC) inhibitor NSD‐1015 (3‐hydroxybenzyl hydrazine) on the motor actions of L‐DOPA and dopamine agonist drugs in MPTP treated common marmosets.
Pretreatment with NSD‐1015 (10–50 mg kg−1; i.p.) worsened baseline motor deficits in MPTP‐treated common marmosets. Similarly, it abolished L‐DOPA (5–18 mg kg−1 s.c.) induced locomotor activity and reversal of disability. NSD‐1015 pretreatment inhibited dopamine formation and elevated L‐DOPA levels in plasma.
The increase in locomotor activity and improvement in disability produced by the administration of the D‐1 agonist A‐86929 (0.03–0.04 mg kg−1 s.c.) or the D‐2 agonist quinpirole (0.05–0.3 mg kg−1 i.p.) was abolished by NSD‐1015 (25 mg kg−1 i.p.) pretreatment. While the effects of a low dose combination of A‐86929 (0.04 mg kg−1 s.c.) and quinpirole (0.05 mg kg−1 i.p.) were inhibited by NSD‐1015 (25 mg kg−1 i.p.), there was little effect on the action of a high dose combination of these drugs (0.08 mg kg−1 A‐86929 and 0.1 mg kg−1 quinpirole).
Following central AADC inhibition with NSD‐1015 (25 mg kg−1 i.p.), locomotor behaviour induced by administration of high dose combinations of A‐86929 (0.08 mg kg−1 s.c.) and quinpirole (0.1 mg kg−1 i.p.) was unaffected by L‐DOPA (5 mg kg−1 s.c.) pretreatment.
These results do not support a role for endogenous L‐DOPA in spontaneous or drug induced locomotor activity. Rather, they strengthen the argument for the importance of endogenous dopaminergic tone in the motor actions of dopamine agonists.

British Journal of Pharmacology (2000) 129, 1355–1364; doi:10.1038/sj.bjp.0703189
Distinct Ca2+ signalling mechanisms induced by ATP and sphingosylphosphorylcholine in porcine aortic smooth muscle cells
Authors: Chin Ting‐Yu , Chueh Sheau‐Huei 
Published: January 2005

The increase in the cytosolic Ca2+ concentration ([Ca2+]i) following repetitive stimulation with ATP or sphingosylphosphorylcholine (SPC) in single porcine aortic smooth muscle cells was investigated using the Ca2+ indicator, fura‐2.
The ATP‐induced [Ca2+]i increase resulted from both Ca2+ release and Ca2+ influx. The former was stimulated by phospholipase C activation, while the latter occurred predominantly via the receptor‐operated Ca2+ channels (ROC), rather than the store‐operated Ca2+ channels (SOC) or the voltage‐operated Ca2+ channel (VOC). Furthermore, the P2X5 receptor was shown to be responsible for the ATP‐induced Ca2+ influx.
A reproducible [Ca2+]i increase was induced by repetitive ATP stimulation, but was abolished by removal of extracellular Ca2+ or inhibition of intracellular Ca2+ release using U‐73122 or thapsigargin, and was restored by Ca2+ readdition in the former case.
SPC only caused Ca2+ release, and the amplitude of the repetitive SPC‐induced [Ca2+]i increases declined gradually. However, a reproducible [Ca2+]i increase was seen in cells in which protein kinase C being inhibited, which increased the SPC‐induced Ca2+ influx, rather than IP3 generation.
In conclusion, although the amplitude of the ATP‐induced Ca2+ release, measured when Ca2+ influx was blocked, or of the Ca2+ influx when Ca2+ release was blocked, progressively decreased following repetitive stimulation, the overall [Ca2+]i increase for each stimulation under physiological conditions remained the same, suggesting that the Ca2+ stores were replenished by an influx of Ca2+ during stimulation. The SPC‐induced [Ca2+]i increase resulted solely from Ca2+ release and decreased gradually following repetitive stimulation, but the decrease could be prevented by stimulating Ca2+ influx, further supporting involvement of the intracellular Ca2+ stores in Ca2+ signalling.

British Journal of Pharmacology (2000) 129, 1365–1374; doi:10.1038/sj.bjp.0703190
Mechanisms of suppression of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells by andrographolide
Authors: Chiou Wen‐Fei , Chen Chieh‐Fu , Lin Jin‐Jung 
Published: January 2005

Andrographolide, an active component found in leaves of Andrographis paniculata, has been reported to exhibit nitric oxide (NO) inhibitory property in endotoxin‐stimulated macrophages, however, the detailed mechanisms remain unclear. In the present study we investigated the effect of andrographolide on the expression of inducible NO synthase (iNOS) mRNA, protein, and enzyme activity in RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS) plus interferon‐γ (IFN‐γ).
RAW 264.7 cells stimulated with LPS/IFN‐γ activated NO production; in this condition andrographolide (1–100 μM) inhibited NO production in a dose‐dependent manner with an IC50 value of 17.4±1.1 μM. Andrographolide also reduces the expression of iNOS protein level but without a significant effect on iNOS mRNA. The reduction of iNOS activity is thought to be caused by decreased expression of iNOS protein.
In a protein stability assay, andrographolide moderately but significantly reduced the amount of iNOS protein as suggested by accelerating degradation. Furthermore, andrographolide also inhibited total protein de novo synthesis as demonstrated by [35S]‐methionine incorporation.
As a whole, these data suggest that andrographolide inhibits NO synthesis in RAW 264.7 cells by reducing the expression of iNOS protein and the reduction could occur through two additional mechanisms: prevention of the de novo protein synthesis and decreasing the protein stability via a post‐transcriptional mechanism. It is also possible that inhibition of iNOS protein expression and NO production under immune stimulation and/or bacteria infection may explain, in part, the beneficial effects of andrographolide as an anti‐inflammatory agent.

British Journal of Pharmacology (2000) 129, 1553–1560; doi:10.1038/sj.bjp.0703191
Modulation by dihydropyridine‐type calcium channel antagonists of cytokine‐inducible gene expression in vascular smooth muscle cells
Authors: Cattaruzza Marco , Wachter Rolf , Wagner Andreas H , Hecker Markus 
Published: January 2005

The 1,4‐dihydropyridine nifedipine is frequently used in the therapy of hypertension and heart failure. In addition, nifedipine has been shown to exert distinct anti‐arteriosclerotic effects both in experimental animal models and in patients. In the present study we have investigated the hypothesis that the latter effect of this class of drugs is mediated by an interference with the expression of pro‐arteriosclerotic gene products in the vessel wall. Moreover, to elucidate as to whether nifedipine acts via L‐type calcium channel blockade, its effects were compared to those of another dihydropyridine, Bay w 9798, which has no calcium‐antagonistic properties in concentrations up to 10 μM, as verified by superfusion bioassay.
Both, nifedipine and Bay w 9798, in concentrations ranging from 0.01 to 1 μM, augmented the interleukin‐1β/tumour necrosis factor‐α (IL‐1β/TNF‐α)‐induced expression of the inducible isoform of nitric oxide synthase (iNOS) in rat aortic cultured smooth muscle cells (raSMC) 2–3 fold, as judged by RT–PCR and Western blot analyses.
In contrast, cytokine‐induced mRNA expression of monocyte chemoattractant protein 1 (MCP‐1) in these cells was down‐regulated by more than 60% in the presence of both dihydropyridines, as judged by RT–PCR and Northern blot analyses.
Nuclear run‐on assays and incubation with the transcription‐terminating drug actinomycin D revealed that both drugs acted at the level of mRNA synthesis rather than stability.
These findings suggest that 1,4‐dihydropyridines such as nifedipine affect the expression of both potentially pro‐arteriosclerotic (MCP‐1) and anti‐arteriosclerotic (iNOS) gene products in the vessel wall at the level of transcription, and that these effects are unrelated to their calcium channel‐blocking properties.

British Journal of Pharmacology (2000) 129, 1155–1162; doi:10.1038/sj.bjp.0703192
Histamine H3 receptors mediate inhibition of noradrenaline release from intestinal sympathetic nerves
Authors: Blandizzi Corrado , Tognetti Martina , Colucci Rocchina , Tacca Mario Del 
Published: January 2005

The present study investigates whether presynaptic histamine receptors regulate noradrenaline release from intestinal sympathetic nerves. The experiments were performed on longitudinal muscle‐myenteric plexus preparations of guinea‐pig ileum, preincubated with [3H]‐noradrenaline.
In the presence of rauwolscine, electrically‐induced [3H]‐noradrenaline release was inhibited by histamine or R‐α‐methylhistamine, whereas it was unaffected by pyridylethylamine, impromidine, pyrilamine, cimetidine, thioperamide or clobenpropit. The inhibitory effects of histamine or R‐α‐methylhistamine were antagonized by thioperamide or clobenpropit, but not by pyrilamine or cimetidine. In the absence of rauwolscine, none of these drugs modified the release of [3H]‐noradrenaline.
The modulatory action of histamine was attenuated by pertussis toxin and abolished by N‐ethylmaleimide. Tetraethylammonium or 4‐aminopyridine enhanced the evoked tritium outflow and counteracted the inhibitory effect of histamine. However, the blocking effects of tetraethylammonium and 4‐aminopyridine were no longer evident when their enhancing actions were compensated by reduction of Ca2+ concentration in the superfusion medium.
Histamine‐induced inhibition of tritium output was enhanced by ω‐conotoxin or low Ca2+ concentration, whereas it was not modified by nifedipine, forskolin, rolipram, phorbol myristate acetate, H7 or lavendustin A.
The present results indicate that presynaptic H3 receptors, located on sympathetic nerve endings, mediate an inhibitory control on intestinal noradrenergic neurotransmission. It is suggested that these receptors are coupled to Gi/Go proteins which modulate the activity of N‐type Ca2+ channels through a direct link, thus reducing the availability of extracellular Ca2+ at the level of noradrenergic nerve terminals.

British Journal of Pharmacology (2000) 129, 1387–1396; doi:10.1038/sj.bjp.0703194
Involvement of nitric oxide in the modulation of dural arterial blood flow in the rat
Authors: Messlinger K , Suzuki A , Pawlak M , Zehnter A , Schmidt R F 
Published: January 2005

Nitric oxide (NO) has been proposed to be a key molecule in the pathogenesis of migraine pain and other headaches that are linked to vascular disorders. Several lines of evidence indicate that the meningeal vascularization is crucially involved in the generation of these headaches. In an experimental model in the rat a dominating role of calcitonin gene‐related peptide (CGRP) in causing neurogenic vasodilatation and increased blood flow has been shown. The aim of the present study was to clarify the role of NO in this model with regard to the meningeal blood flow.
The blood flow in and around the medial meningeal artery (dural arterial flow) was recorded in the exposed parietal dura mater encephali of barbiturate anaesthetized rats using laser Doppler flowmetry. Local electrical stimulation of the dura mater (pulses of 0.5 ms delivered at 7.5–17.5 V and 5 or 10 Hz for 30 s) caused temporary increases in dural arterial flow for about 1 min that reached peaks of 1.6–2.6 times the basal flow. The effects of NO synthase (NOS) inhibitors on the basal flow and the electrically evoked increases in flow were examined.
Systemic (i.v.) administration of Nω‐nitro‐L‐arginine methyl ester (L‐NAME) at cumulative doses of 10 and 50 mg kg−1 lowered the basal flow to 87 and 72%, respectively, of the control and reduced the evoked increases in blood flow to 82 and 44% on an average. Both these effects could partly be reversed by 300 mg kg−1 L‐arginine. The systemic arterial pressure was increased by L‐NAME at both doses. Injection of the stereoisomer D‐NAME at same doses did not change basal flow and evoked increases in flow.
Topical application of L‐NAME (10−4–10−2 M) was effective only at the highest concentration, which caused lowering of the basal blood flow to 78% of the control; the evoked increases in flow were not changed. Topical application of 2‐amino‐5,6‐dihydro‐6‐methyl‐4H‐1,3‐thiazine (AMT), a specific inhibitor of the inducible NOS, at concentrations of 10−4–10−2 M lowered the basal flow to 89, 87.5 and 85%, respectively, but did not significantly change the evoked flow increases. Same concentrations of 7‐nitroindazole monosodium salt (7‐NINA), a specific inhibitor of the neuronal NOS, had no significant effects on basal flow and evoked increases in flow.
It is concluded that NO is involved in the maintenance of the basal level of dural arterial blood flow as well as in the electrically evoked flow increases, which have been shown to be mainly mediated by CGRP released from dural afferent fibres. The most important source of NO is probably the endothelium of dural arterial vessels. The synergistic effect of NO and CGRP on the stimulated blood flow may be in part due to a NO mediated facilitation of the CGRP release.

British Journal of Pharmacology (2000) 129, 1397–1404; doi:10.1038/sj.bjp.0703220
Contribution of B2 receptors for bradykinin in Arthus reaction‐induced plasma extravasation in wild‐type or B2 transgenic knockout mice
Authors: Samadfam R , Teixeira C , Bkaily G , Sirois P , De Brum‐Fernandes A , D'Orleans‐Juste P 
Published: January 2005

The aim of the present study was to investigate the contribution of bradykinin (BK) B1 and B2 receptors in a model of type III hypersensitivity, the reverse passive Arthus reaction (RPA), in wild‐type mice and transgenic B2 knockout littermates.
BK (10 μg mouse−1) or bovine serum albumin (0.5 mg mouse−1) induced a sustained Evans blue extravasation for more than 80 min in naive or rabbit anti‐bovine serum albumin‐treated mice (RPA model), respectively. The response to the two stimuli was prevented by the B2 receptor antagonist, HOE‐140, but not by [Leu8]desArg9‐BK (B1 receptor antagonist).
In contrast to the wild‐type littermates, RPA and bradykinin were unable to trigger an increase in plasma extravasation in B2 knockout mice.
Furthermore, endothelin‐1 (5 μg mouse−1) and a selective NK‐1 receptor agonist [Sar9,Met (O2)11]‐SP (20 μg mouse−1), triggered a significant increase in peritoneal plasma extravasation in both wild‐type and B2 knockout animals.
A pretreatment with indomethacin (200 μg mouse−1) significantly reduced the RPA‐induced but not the BK‐induced increase in Evans blue extravasation. Furthermore, RPA, but not BK, triggered a significant indomethacin‐sensitive increase in peritoneal prostaglandin E2 content.
Our results suggest a pivotal role for B2 receptors in the mechanism of plasma extravasation which occurs during the reverse passive Arthus reaction in the mouse. Moreover, our results suggest an important contribution of prostanoids in the plasma leakage mechanisms triggered by RPA but not by bradykinin.

British Journal of Pharmacology (2000) 129, 1732–1738; doi:10.1038/sj.bjp.0703225
Diadenosine polyphosphates as antagonists of the endogenous P2Y1 receptor in rat brain capillary endothelial cells of the B7 and B10 clones
Authors: Vigne Paul , Breittmayer Jean Philippe , Frelin Christian 
Published: January 2005

Diadenosine polyphosphates (ApnAs, n=2–7) are considered as stress mediators in the cardiovascular system. They act both via identified P2 purinoceptors and via yet to be characterized receptors. This study analyses the actions of ApnAs in clones of rat brain capillary endothelial cells that express P2Y1 receptors (B10 cells) or both P2Y1 and P2Y2 receptors (B7 cells).
B10 cells responded to Ap3A with rises in intracellular Ca2+ concentration ([Ca2+]i). This response was prevented by adenosine‐3′‐phosphate‐5′‐phosphate, an antagonist of P2Y1 receptors. It was largely suppressed by a treatment with apyrase VII or with creatine phosphokinase/creatine phosphate to degrade contaminating ADP.
ApnAs inhibited ADP induced increases in [Ca2+]i mediated by P2Y1 receptors by shifting ADP concentration‐response curves to larger concentrations. Apparent Ki values were estimated to be 6 μM for Ap4A, 10 μM for Ap5A and 47 μM for Ap6A. Ap2A and Ap3A were much less active.
ApnAs were neither agonists nor antagonists of the endogenous P2Y2 receptor in B7 cells.
ApnAs are neither agonists nor antagonists of the Gi‐coupled, ADP receptor in B10 cells.
The results suggest that most actions of ApnAs in B7 and B10 cells can be accounted for by endogenous P2Y1 receptors. Ap4A, Ap5A and Ap6A are specific antagonists of endogenous Ca2+‐coupled P2Y1 receptors.

British Journal of Pharmacology (2000) 129, 1506–1512; doi:10.1038/sj.bjp.0703228
Effects of cannabinoid receptor agonists on neuronally‐evoked contractions of urinary bladder tissues isolated from rat, mouse, pig, dog, monkey and human
Authors: Martin R S , Luong L A , Welsh N J , Eglen R M , Martin G R , MacLennan S J 
Published: January 2005

This study investigated the cannabinoid receptor, known to inhibit neuronally‐evoked contractions of the mouse isolated urinary bladder, in bladder sections isolated from mouse, rat, dog, pig non‐human primate or human.
The CB1‐like pharmacology of the cannabinoid receptor in mouse isolated bladder observed previously was confirmed in this study by the rank order of agonist potencies: CP 55940WIN 55212‐2>HU 210>JWH 015>anandamide, the high affinity of the CB1 selective antagonist, SR 141716A (apparent pKB 8.7), and the low affinity of the CB2 antagonist, SR 144528 (apparent pKB<6.5). In these studies, SR 141716A (10–100 nM) significantly potentiated electrically‐evoked contractions in this tissue by an undetermined mechanism.
A similar rank order of agonist potencies was determined in rat isolated bladder sections (CP 55, 940WIN 55212‐2>JWH 015). In this tissue, the maximal inhibitory effect of all agonists was lower than in the mouse bladder. Indeed, the effects of both HU 210 and anandamide were too modest to quantify potency accurately.
In the rat isolated bladder, SR 141716A (30 nM) or SR 144528 (100 nM), reversed the inhibitory effect of WIN 55212‐2 (apparent pKB=8.4 and 8.0, respectively) or JWH 015 (apparent pKB=8.2 and 7.4, respectively). These findings may demonstrate pharmacological differences between the rat and mouse orthologues of the CB1 receptor. Alternatively, they may be attributed to a mixed population of CB1 and CB2 receptors that jointly influence neurogenic contraction of the rat bladder, but cannot be differentiated without more selective ligands.
WIN 55212‐2 had no effect on electrically‐evoked contractions of bladder sections isolated from dog, pig, cynomolgus monkey and human. These findings suggest that the effect of cannabinoid agonists to inhibit neurogenic contraction of the mouse and rat bladder is not conserved across all mammalian species.

British Journal of Pharmacology (2000) 129, 1707–1715; doi:10.1038/sj.bjp.0703229
Selective cyclo‐oxygenase‐2 inhibition with celecoxib elevates blood pressure and promotes leukocyte adherence
Authors: Muscará Marcelo N , Vergnolle Nathalie , Lovren Fina , Triggle Christopher R , Elliott Susan N , Asfaha Samuel , Wallace John L 
Published: January 2005

Selective inhibitors of cyclo‐oxygenase‐2 have been shown to be effective anti‐inflammatory drugs with reduced gastrointestinal toxicity relative to conventional nonsteroidal anti‐inflammatory drugs (NSAIDs). In the present study, we examined the possibility that selective COX‐2 inhibition, by blocking prostacyclin synthesis, would increase blood pressure and cause leukocyte adherence and platelet aggregation.
Normal rats and rats with hypertension induced by chronic administration of Nω‐nitro‐L‐arginine methylester were given celecoxib (10 mg kg−1) daily for 3 weeks. Celecoxib significantly elevated of blood pressure in both the normal and hypertensive rats (mean increase of >33 mm Hg after 3 weeks).
In normal rats, celecoxib had no effect on serum 6‐keto prostaglandin (PG)F1α levels. Hypertensive rats exhibited a significant increase (82%) in serum 6‐keto PGF1α levels, and this was reduced to the levels of normal rats by treatment with celecoxib.
Rats treated with celecoxib exhibited significant increases in weight gain (20%), plasma arginine‐vasopressin levels (148%) and plasma urea (69%) relative to vehicle‐treated controls. Plasma creatinine levels were unaffected by treatment with celecoxib, while plasma renin levels were significantly decreased (30%) relative to controls.
Superfusion of mesenteric venules with celecoxib (3 μM) in vivo resulted in significant increases in leukocyte adherence to the endothelium in both normal and hypertensive rats.
These studies suggest that suppression of COX‐2 significantly influences vascular and/or renal function, leading to elevated blood pressure and leukocyte adherence.

British Journal of Pharmacology (2000) 129, 1423–1430; doi:10.1038/sj.bjp.0703232
Negative inotropic effects of isoprenaline on isolated left atrial assays from aged transgenic mice with cardiac over‐expression of human β2‐adrenoceptors
Authors: Prendergast C E , Shankley N P , Black J W 
Published: January 2005

The action of isoprenaline has been evaluated in an isolated, left atrial assay, from aged transgenic mice with cardiac‐specific over‐expression of the β2‐adrenoceptor. In the assay, isoprenaline produced a negative inotropic concentration‐response curve that was not altered by incubation with CGP‐20712A (1 μM), a β1‐adrenoceptor antagonist. However, after incubation with ICI‐118,551 (300 nM), a selective β2‐adrenoceptor antagonist, isoprenaline produced a positive inotropic concentration‐effect curve that was located to the left of the negative inotropic curve. This suggests that the negative inotropic effect was mediated by a homogenous population of negatively‐coupled β2‐adrenoceptors. In the presence of CGP‐20712A (300 nM), the positive curve was shifted to the right, suggesting that the positive inotropic effect was mediated, at least in part, by β1‐adrenoceptors. These results differ substantially from those previously obtained in young transgenic mice. An outline of an explanatory model, based on a concept of over‐expressed receptors ‘stealing’ G‐proteins, is suggested.British Journal of Pharmacology (2000) 129, 1285–1288; doi:10.1038/sj.bjp.0703238
Anti‐NO action of carvedilol in cell‐free system and in vascular endothelial cells
Authors: Yoshioka Toshimasa , Iwamoto Noriko , Tsukahara Fujiko , Irie Kaoru , Urakawa Ikuko , Muraki Takamura 
Published: January 2005

Carvedilol, an adrenoceptor blocker with antioxidant activity, was studied for its ability to interact with NO in a cell‐free condition and in an endothelial cell line (ECV304).
In a cell‐free system, carvedilol attenuated NO‐dependent reduction of carboxy‐2‐phenyl‐4,4,5,5‐tetramethyl‐imidazoline‐1‐oxyl‐3‐oxide induced by a NO donor, 1‐hydroxy‐2‐oxo‐3‐(aminopropyl)‐3‐isopropyl‐1‐triazene (NOC5), which was determined by electron paramagnetic resonance (EPR) spectrometry. The EPR study also showed that nitrosylhaemoglobin formation in rat red blood cells by the addition of NO‐saturated solution was attenuated by prior incubation with 0.1–10 μM carvedilol.
NO‐induced fluorescence in 4,5‐diaminofluorescein‐2 diacethyl (DAF‐2DA)‐loaded ECV304 cells was attenuated by carvedilol but not by labetalol. The IC50 of carvedilol for NOC5 or sodium nitroprusside‐induced fluorescence of DAF‐2DA in ECV304 cells was 1.0×10−7 M, which was similar to the reported IC50 of carvedilol for the antioxidant effect.
Cell toxicity induced by a NO donor determined by the number of viable cells after 24 h treatment with 2‐2′(hydroxynitrosohydrazino)bis‐ethanamine was significantly attenuated by pretreatment with 1 μM carvedilol.
Both free and cell‐associated carvedilol quenched NO. Because NO mediates both physiological and pathophysiological processes, NO quenching by the drug may have diverse clinical implications depending upon specific functions of local NO in tissues where carvedilol is distributed.

British Journal of Pharmacology (2000) 129, 1530–1535; doi:10.1038/sj.bjp.0703241