bluuebunny/crossref_metadata_2025_split huggingface dataset:
The possible mechanisms of the antiproliferative effect of fullerenol, polyhydroxylated C60, on vascular smooth muscle cells
Authors: Lu Liang‐Huei , Lee Yuan‐Teh , Chen Huei‐Wen , Chiang Long Y. , Huang Huei‐Chen 
Published: January 2005

The possible mechanisms of the antiproliferative effect of polyhydroxylated fullerene (fullerenol), a novel free radical trapper, were studied in rat vascular smooth muscle cells (A7r5 cells) and compared with the effect of ascorbic acid.
Fullerenol‐1 and ascorbic acid inhibited the proliferative responses in a number of cells, including rat aortic smooth muscle cells (A7r5 cells), human coronary artery smooth muscle cells, and human CEM lymphocytes (CEM cells) in a concentration dependent manner.
At the concentration range of 10−6 to 10−2 M, fullerenol‐1 and ascorbic acid concentration‐dependently inhibited the proliferative responses stimulated by serum in A7r5 cells. Fullerenol‐1 was more potent than ascorbic acid.
The production of O2− induced by alloxan, a diabetogenic compound, was reduced by fullerenol‐1 (10−4 M) in the presence of A7r5 cells.
The cytosolic protein kinase C activity of A7r5 cells stimulated by phorbol ester was reduced by 10−3 M fullerenol‐1, but not ascorbic acid (10−4–10−2 M) and fullerenol‐1 at lower concentrations (10−6–10−4 M).
In contrast, the membraneous protein tyrosine kinase activity of A7r5 cells stimulated by foetal calf serum was significantly reduced by fullerenol‐1 (10−6–10−3 M) and ascorbic acid (10−4–10−2 M). Again, the inhibitory activity of fullerenol‐1 was greater than that of ascorbic acid.
Our results demonstrate that fullerenol‐1 and ascorbic acid exhibit inhibitory effects on transduction signals in addition to their antioxidative property. It is suggested that the antiproliferative effect of fullerenol‐1 on vascular smooth muscle cells may partly be mediated through the inhibition of protein tyrosine kinase.

British Journal of Pharmacology (1998) 123, 1097–1102; doi:10.1038/sj.bjp.0701722
Effect of RX 821002 at 5‐HT1A‐receptors in rabbit spinal cord in vivo
Authors: Ogilvie Jane , Clarke Rob W. 
Published: January 2005

The activity of RX 821002 (2‐methoxy idazoxan) at 5‐HT1A‐receptors in the spinal cord has been investigated in decerebrated, spinalized rabbits. Reflexes evoked in medial gastrocnemius motoneurones by electrical stimulation of the sural nerve were unaffected by intrathecal (i.th.) administration of RX 821002 (111 and 664 nmol cumulative, n=7), although the highest dose of this drug did produce a significant increase in heart rate of 28±7 beats min−1. Subsequent administration of the 5‐HT1A‐receptor agonist (±)‐8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT) at 300 nmol, i.th., facilitated reflexes to a median of 144% of pre‐drug controls, an effect that was partially reversed (to a median value of 120% of pre‐drug values) by subsequent administration of the 5‐HT1A‐receptor antagonist WAY‐100635, at 185 nmol i.th.
In a separate set of experiments, 8‐OH‐DPAT was given at 30 nmol i.th. and potentiated reflexes to a median of 170% of pre‐drug levels (n=8). Subsequent administration of RX 821002 (at a cumulative dose of 1.11 μmol, i.th., n=5) significantly reduced gastrocnemius responses to a median of 154% of control values.
After a 3 h recovery period, 8‐OH‐DPAT was re‐administered at 30 nmol, i.th., and increased reflexes to a median value of 151% of pre‐drug levels, an effect not significantly different from when it was given alone. WAY‐100635 dose‐dependently antagonized this effect, causing significant reductions in reflexes at a cumulative dose of 0.55 nmol, i.th., and complete reversal of the effects of 8‐OH‐DPAT at a cumulative dose of 5.5 nmol.
These data show that, at intrathecal doses up to 664 nmol, RX 821002 is devoid of agonist activity at 5‐HT1A‐receptors. It appears to be a very weak antagonist at these sites in vivo, being some 2000 times less potent than WAY‐100635. The inability of WAY‐100635 to block completely the effects of high doses of 8‐OH‐DPAT has been noted previously and can be explained by non‐selective actions of the agonist. However, it would appear that a 30 nmol i.th. dose of 8‐OH‐DPAT is selective for 5‐HT1A receptors in this preparation.

British Journal of Pharmacology (1998) 123, 1138–1142; doi:10.1038/sj.bjp.0701729
Neurogenic and non‐neurogenic responses in the urinary bladder of hibernating hamster
Authors: Pinna Christian , Knight Gillian E. , Puglisi Lina , Burnstock Geoffrey 
Published: January 2005

Purinergic and cholinergic components of parasympathetic neurotransmission and contractile responses to exogenous α,β‐methylene ATP, acetylcholine, substance K, substance P, calcitonin gene‐related peptide, vasoactive intestinal polypeptide and capsaicin have been investigated in the urinary bladder of hibernating hamsters (4 weeks), cold exposed (4 weeks) and age‐matched controls.
Electrical field stimulation (EFS) evoked increased frequency‐dependent contractions in the detrusor strips from hibernating hamsters compared with those obtained from cold‐exposed and age‐matched animals. Tetrodotoxin (10−6 M) completely blocked the frequency‐dependent contractions in all groups.
The purinergic component of the parasympathetic neurotransmission was not affected in hibernating and cold‐exposed animals while the cholinergic component was increased with respect to age‐matched animals. The neurogenic response to EFS, still present after incubation with atropine (10−6 M) and suramin (10−4 M), was attenuated by indomethacin (10−6 M) and blocked by tetrodotoxin (10−6 M).
Exogenous administration of α,β‐methylene ATP elicited a significantly reduced contraction in strips from hibernating and cold‐exposed hamsters relative to age‐matched animals. The contractile response to exogenous acetylcholine was greater in the detrusors from hibernating hamsters than in cold‐exposed and age‐matched animals. Substance K elicited reduced contractions in preparations from hibernating animals compared with cold‐exposed and control animals. Calcitonin gene‐related peptide, vasoactive intestinal polypeptide, substance P and capsaicin did not elicit any relaxant or contractile response either at resting tone or in carbachol (5×10−7 M)‐precontracted tissues.
In summary, our findings indicate that 4 weeks of hibernation can significantly increase neurogenic responses in the hamster urinary bladder. This appears to be due to an increase in postjunctional responses to acetylcholine. In contrast, there was a decrease of the postjunctional responses to the parasympathetic cotransmitter ATP and also to the sensory‐motor neurotransmitter substance K.

British Journal of Pharmacology (1998) 123, 1281–1287; doi:10.1038/sj.bjp.0701734
Effect of the triaminopyridine flupirtine on calcium uptake, membrane potential and ATP synthesis in rat heart mitochondria
Authors: Zimmer Guido , Balakirev Maxim , Zwicker Klaus , Hofmann Michael , Woodcock Barry G. , Pergande Gabriela 
Published: January 2005

Flupirtine is an analgesic agent which exhibits neuronal cytoprotective activity and may have value in the treatment of conditions involving cell injury and apoptosis. Since flupirtine has no action on known receptor sites we have investigated the effect of this drug on mitochondrial membrane potential, and the changes in intramitochondrial calcium concentration in particular.
The findings show that flupirtine increases Ca2+ uptake in mitochondria in vitro. At clinically relevant flupirtine concentrations, corresponding to flupirtine levels in vitro of 0.2 to 10 nmol mg−1 mitochondrial protein, there was a 2 to 3 fold increase in mitochondrial calcium levels (P<0.01). At supra‐physiological flupirtine concentrations of 20 nmol mg−1 mitochondrial protein and above, the mitochondrial calcium concentrations were indistinguishable from those in untreated mitochondria.
Mitochondrial membrane potential closely paralleled the changes in mitochondrial calcium levels showing a 20% (P<0.01) increase when the flupirtine concentration was raised from 0.2 nmol to 10 nmol mg−1 mitochondrial protein and a return to control values at 20 nmol mg−1 protein.
The increase in mitochondrial calcium uptake and membrane potential were accompanied by an increase in mitochondrial ATP synthesis (30%; P<0.05) and a similar percentage reduction in mitochondrial volume.
Calcium at 80 and 160 nmol mg−1 mitochondrial protein decreased ATP synthesis by 20–25% (P<0.001). This decrease was prevented or diminished if flupirtine at 10 nmol mg−1 protein was added before the addition of calcium.
Since intracellular levels of flupirtine in intact cells never exceeded 10 nmol mg−1 mitochondrial protein, these findings are supportive evidence for an in vivo cytoprotective action of flupirtine at the mitochondrial level.

British Journal of Pharmacology (1998) 123, 1154–1158; doi:10.1038/sj.bjp.0701736
Nitric oxide‐related cyclic GMP‐independent relaxing effect of N‐acetylcysteine in lipopolysaccharide‐treated rat aorta
Authors: Muller Bernard , Kleschyov Andrei L. , Malblanc Sophie , Stoclet Jean‐Claude 
Published: January 2005

We have recently demonstrated the formation of protein‐bound dinitrosyl‐iron complexes (DNIC) in rat aortic rings exposed to lipopolysaccharide (LPS) and shown that N‐acetylcysteine (NAC) can promote vasorelaxation in these arteries, possibly via the release of nitric oxide (NO) as low molecular weight DNIC from these storage sites. The aim of the present study was to investigate further the mechanism of the relaxation induced by NAC in LPS‐treated vessels.
In rings incubated with LPS (10 μg ml−1 for 18 h) and precontracted with noradrenaline (NA, 3 μM) plus Nω‐nitro‐L‐arginine methylester (L‐NAME, 3 mM), the relaxation evoked by NAC (0.1 to 10 mM) was abolished by 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ, 1 μM, a selective inhibitor of soluble guanylyl cyclase) but not affected by Rp‐8‐bromoguanosine 3′5′‐cyclic monophosphorothioate (Rp‐8BrcGMPS, 60 μM a selective inhibitor of cyclic GMP‐dependent protein kinase). Tetrabutylammonium (TBA, 3 mM, as a non selective K+ channels blocker) or elevated concentration of external KCl (25 or 50 mM) significantly attenuated the NAC‐induced relaxation. Selective K+ channels blockers (10 μM glibenclamide, 0.1 μM charybdotoxin, 0.5 μM apamin or 3 mM 4‐aminopyridine) did not affect the NAC‐induced relaxation. The relaxing effect of NAC (10 mM) was not associated with an elevation of guanosine 3′ : 5′ cyclic monophosphate (cyclic GMP) in LPS‐treated rings.
In aortic rings precontracted with NA (0.1 μM), low molecular weight DNIC (with thiosulphate as ligand, 1 nM to 10 μM) evoked a concentration‐dependent relaxation which was antagonized by ODQ (1 μM) and Rp‐8BrcGMPS (150 μM) but not significantly affected by TBA (3 mM) or by the use of KCl (50 mM) as preconstricting agent. The relaxation produced by DNIC (0.1 μM) was associated with an 11 fold increase in aortic cyclic GMP content, which was completely abolished by ODQ (1 μM).
Taken together with our previous data, the main finding of the present study is that the vascular relaxation induced by NAC in LPS‐treated aorta, although probably related to NO through an interaction via preformed NO stores, was not mediated by activation of the cyclic GMP pathway. It may involve the activation of TBA‐sensitive K+ channels. The differences in the mechanism of relaxation induced by NAC and by exogenous DNIC suggest that the generation of low molecular weight DNIC from protein‐bound species does not play a major role in the NAC‐induced relaxation observed in LPS‐treated rat aorta. In addition, it is suggested that ODQ may display other properties than the inhibition of soluble guanylyl cyclase.

British Journal of Pharmacology (1998) 123, 1221–1229; doi:10.1038/sj.bjp.0701737
Role of nitric oxide in the development and partial reversal of allergen‐induced airway hyperreactivity in conscious, unrestrained guinea‐pigs
Authors: Schuiling Martin , Zuidhof Annet B. , Bonouvrie Monique A. A. , Venema Nicolette , Zaagsma Johan , Meurs Herman 
Published: January 2005

Using a conscious, unrestrained guinea‐pig model of allergic asthma, we investigated the role of endogenous nitric oxide (NO) in the regulation of airway (hyper)reactivity to histamine before and after the allergen‐induced early and late asthmatic reactions, by examining the effect of inhalation of the NO synthase inhibitor Nω‐nitro‐l‐arginine methyl ester (l‐NAME, 12 mm, 15 min) on the histamine‐induced airway obstruction of ovalbumin‐sensitized guinea‐pigs before, and at 5.5 h and 23.5 h after allergen challenge.
Before allergen challenge, inhaled l‐NAME caused a significant 2.02±0.25 fold increase (P<0.01) in airway reactivity to histamine; this effect was reversed within 2.5 to 6 h after administration.
After the allergen‐induced early asthmatic reaction at 5 h after ovalbumin provocation, a significant 3.73±0.67 fold increase (P<0.01) of the airway reactivity to histamine was observed; subsequent inhalation of l‐NAME at 5.5 h had no effect on the airway hyperreactivity, reassessed at 6 h.
After the late asthmatic reaction, at 23 h after ovalbumin provocation, a reduced, but still significant airway hyperreactivity to histamine (2.18±0.40 fold; P<0.05) was observed. Subsequent inhalation of l‐NAME now significantly potentiated the partially reduced airway hyperreactivity 1.57±0.19 fold (P<0.05) to the level observed after the early asthmatic reaction.
When administered 30 min before allergen exposure, l‐NAME significantly enhanced the allergen‐induced early asthmatic reaction. However, when administered at 5.5 h after allergen provocation, l‐NAME did not affect the subsequent late asthmatic reaction.
These results indicate that endogenous NO is involved the regulation of histamine‐ and allergen‐induced bronchoconstriction and that a deficiency of cNOS‐derived NO contributes to the allergen‐induced airway hyperreactivity to histamine after the early asthmatic reaction, while a recovery of NO deficiency may account for the partial reversal of the allergen‐induced airway hyperreactivity after the late asthmatic reaction.

British Journal of Pharmacology (1998) 123, 1450–1456; doi:10.1038/sj.bjp.0701738
The expression of functional postsynaptic α2‐adrenoceptors in the corpus cavernosum smooth muscle
Authors: Gupta Sandeep , Moreland Robert B. , Yang Stone , Gallant Cynthia M. , Goldstein Irwin , Traish Abdulmaged 
Published: January 2005

The purpose of this study was to determine if corpus cavernosum smooth muscle expresses functional postsynaptic α2‐adrenoceptors (AR).
The α2‐adrenoceptor agonist UK 14,304 elicited concentration‐dependent contractions in rabbit corpus cavernosum smooth muscle (CCSM). The half‐maximal response occurred at 0.32±0.03 μM and the maximum contraction at 10 μM UK 14,304.
Pretreatment of CCSM strips with selective α2‐adrenoceptor antagonists, rauwolscine and RS‐15385, produced rightward shifts in the dose‐response curves to UK 14,304 (pA2 values 7.1 and 8.5, respectively). In contrast, these antagonists did not alter contraction induced by the α1‐adrenoceptor agonist phenylephrine (PE) or oxymetazoline. UK 14,304‐induced contractions were also inhibited by prazosin (pA2=9.08).
UK 14,304‐induced contractions, unlike those to PE, were highly dependent on the presence of extracellular Ca2+.
[3H]‐rauwolscine bound to CCSM membranes with high affinity (Kd=1.5 nM). [3H]‐rauwolscine binding was displaced by unlabelled rauwolscine, RS‐15385, UK 14,304 and prazosin, but not by PE.
UK 14,304 inhibited forskolin and prostaglandin E1 (PGE1)‐induced increases in intracellular cyclic AMP concentration in primary cultures of rabbit CCSM cells.
These results demonstrate that CCSM expresses Gi‐coupled postsynaptic α2‐adrenoceptors, and activation of these receptors causes contraction of trabecular smooth muscle.

British Journal of Pharmacology (1998) 123, 1237–1245; doi:10.1038/sj.bjp.0701739
Antidepressant‐like effects of endogenous histamine and of two histamine H1 receptor agonists in the mouse forced swim test
Authors: Lamberti Claudia , Ipponi Alessandro , Bartolini Alessandro , Schunack Walter , Malmberg‐Aiello Petra 
Published: January 2005

Effects of substances which are able to alter brain histamine levels and two histamine H1 receptor agonists were investigated in mice by means of an animal model of depression, the forced swim test.
Imipramine (10 and 30 mg kg−1, i.p.) and amitriptyline (5 and 15 mg kg−1, i.p.) were used as positive controls. Their effects were not affected by pretreatment with the histamine H3 receptor agonist, (R)‐α‐methylhistamine, at a dose (10 mg kg−1, i.p.) which did not modify the cumulative time of immobility.
The histamine H3 receptor antagonist, thioperamide (2–20 mg kg−1, s.c.), showed an antidepressant‐like effect, with a maximum at the dose of 5 mg kg−1, which was completely prevented by (R)‐α‐methylhistamine.
The histamine‐N‐methyltransferase inhibitor, metoprine (2–20 mg kg−1, s.c.), was effective with an ED50 of 4.02 (2.71–5.96) mg kg−1; its effect was prevented by (R)‐α‐methylhistamine.
The histamine precursor, l‐histidine (100–1000 mg kg−1, i.p.), dose‐dependently decreased the time of immobility [ED30 587 (499–712) mg kg−1]. The effect of 500 mg kg−1 l‐histidine was completely prevented by the selective histidine decarboxylase inhibitor, (S)‐α‐fluoromethylhistidine (50 mg kg−1, i.p.), administered 15 h before.
The highly selective histamine H1 receptor agonist, 2‐(3‐trifluoromethylphenyl)histamine (0.3–6.5 μg per mouse, i.c.v.), and the better known H1 agonist, 2‐thiazolylethylamine (0.1–1 μg per mouse, i.c.v.), were both dose‐dependently effective in decreasing the time of immobility [ED50 3.6 (1.53–8.48) and 1.34 (0.084–21.5) μg per mouse, respectively].
None of the substances tested affected mouse performance in the rota rod test at the doses used in the forced swim test.
It was concluded that endogenous histamine reduces the time of immobility in this test, suggesting an antidepressant‐like effect, via activation of H1 receptors.

British Journal of Pharmacology (1998) 123, 1331–1336; doi:10.1038/sj.bjp.0701740
Involvement of bradykinin B1 and B2 receptors in relaxation of mouse isolated trachea
Authors: Li Liang , Vaali Kirsi , Paakkari Ilari , Vapaatalo Heikki 
Published: January 2005

The aim of the present study was to investigate the effects of bradykinin and [des‐Arg9]‐bradykinin and their relaxant mechanisms in the mouse isolated trachea.
In the resting tracheal preparations with intact epithelium, bradykinin and [des‐Arg9]‐bradykinin (each drug, 0.01–10 μm) induced neither contraction nor relaxation. In contrast, bradykinin (0.01–10 μm) induced concentration‐dependent relaxation when the tracheal preparations were precontracted with methacholine (1 μm). The relaxation induced by bradykinin was inhibited by the B2 receptor antagonist, d‐Arg0‐[Hyp3,Thi5,d‐Tic7,Oic8]‐bradykinin (Hoe 140, 0.01–1 μm) in a concentration‐dependent manner whereas the B1 receptor antagonist, [des‐Arg9,Leu8]‐bradykinin (0.01–1 μm), had no inhibitory effect on bradykinin‐induced relaxation. [des‐Arg9]‐bradykinin (0.01–10 μm) also caused concentration‐dependent relaxation after precontraction with methacholine. The relaxation induced by [des‐Arg9]‐bradykinin was concentration‐dependently inhibited by the B1 receptor antagonist, [des‐Arg9,Leu8]‐bradykinin (0.01–1 μm), whereas the B2 receptor antagonist, Hoe 140 (0.01–1 μm) was without effect.
In the presence of the cyclo‐oxygenase inhibitor, indomethacin (0.01–1 μm), the relaxations induced by bradykinin and [des‐Arg9]‐bradykinin were inhibited concentration‐dependently.
Two nitric oxide (NO) biosynthesis inhibitors NG‐nitro‐l‐arginine methyl ester (l‐NAME, 100 μm) and NG‐nitro‐l‐arginine (l‐NOARG, 100 μm) had no inhibitory effects on the relaxations induced by bradykinin and [des‐Arg9]‐bradykinin. Neither did the selective inhibitor of the soluble guanylate cyclase, 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ, 10 μm) inhibit the relaxations induced by bradykinin and [des‐Arg9]‐bradykinin.
Prostaglandin E2 (PGE2, 0.01–33 μm) caused concentration‐dependent relaxation of the tracheal preparations precontracted with methacholine. Indomethacin (1 μm) and ODQ (10 μm) exerted no inhibitory effects on the relaxation induced by PGE2.
The NO‐donor, sodium nitroprusside (SNP; 0.01–100 μm) also caused concentration‐dependent relaxation of the tracheal preparations precontracted with methacholine. ODQ (0.1–1 μm) concentration‐dependently inhibited the relaxation induced by SNP.
These data demonstrate that bradykinin and [des‐Arg9]‐bradykinin relax the mouse trachea precontracted with methacholine by the activation of bradykinin B2‐receptors and B1‐receptors, respectively. The stimulation of bradykinin receptors induces activation of the cyclo‐oxygenase pathway, leading to the production of relaxing prostaglandins. The NO pathway is not involved in the bradykinin‐induced relaxation. The relaxation caused by NO‐donors in the mouse trachea is likely to be mediated via activation of soluble guanylate cyclase.

British Journal of Pharmacology (1998) 123, 1337–1342; doi:10.1038/sj.bjp.0701741
Validation of Furchgott's method to determine agonist‐dependent A1‐adenosine receptor reserve in guinea‐pig atrium
Authors: Morey Timothy E. , Belardinelli Luiz , Dennis Donn M. 
Published: January 2005

The ubiquitous distribution of A1‐adenosine receptors (A1AdoR) represents an impediment to achieve organ and/or response selectivity of A1AdoR agonists. Differential receptor reserve may be exploited to overcome this problem. We hypothesize that A1AdoR reserve is agonist‐dependent and can be accurately estimated with Furchgott's method.
Concentration‐response curves were constructed from measurement of the atrial monophasic action potential duration in guinea‐pig, isolated hearts treated with R(−) N6‐(2‐phenylisopropyl)adenosine (R‐PIA) or 2‐chloro‐N6‐cyclopentyl‐adenosine (CCPA) before and after treatment with the selective, irreversible A1AdoR antagonist 8‐cyclopentyl‐3‐[3‐[[4‐(fluorosulphonyl)benzoyl]oxy]propyl]‐1‐propyl‐xanthine (FSCPX). Using Furchgott's method, we determined the equilibrium dissociation constant (KA) of R‐PIA and CCPA, and the fraction of non‐inactivated A1AdoRs remaining after FSCPX treatment (qfunctional). Values of qfunctional were correlated to the fraction of specific binding sites after FSCPX treatment labelled by [3H]‐8‐cyclopentyl‐1,3‐dipropylxanthine ([3H]‐CPX) derived from saturation binding normalized to control (qbinding).
Both R‐PIA and CCPA are full A1AdoR agonists, but have significantly different potencies (pD2 [EC50]=6.84±0.04 [145 nm] vs 7.36±0.04 [44 nm], respectively), receptor affinities (pKA [KA]= 6.54±0.10 [288 nm] vs 6.13±0.03 [734 nm]), and pharmacological shift ratios defined as KA/EC50 (2.2±0.6 vs 15.9±1.5). Values for qfunctional and qbinding were highly correlated (r2=0.96). The ratio between the intrinsic efficacies of CCPA and R‐PIA derived from Furchgott's analysis was 5.9, a value similar to the ratio of 6.2–6.6 calculated from previously obtained binding data.
Radioligand binding studies validated the use of Furchgott's method to estimate A1AdoR reserve. A1AdoR reserve was agonist‐dependent. CCPA was shown to be a high intrinsic efficacy, low affinity agonist, whereas R‐PIA was found to be a low intrinsic efficacy, high affinity agonist.

British Journal of Pharmacology (1998) 123, 1425–1433; doi:10.1038/sj.bjp.0701747