bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biphasic effects of cyclosporin A on formyl‐methionyl‐leucyl‐phenylalanine stimulated responses in HL‐60 cells differentiated into neutrophils
Authors: Nguyen Nathalie S D , Pulido Silvia M , Rüegg Urs T 
Published: January 2005

The immunosuppressive drug cyclosporin A (CsA) depresses neutrophil oxidative burst which may lead to an increased susceptibility to infection in transplant patients. Using specific CsA analogues we investigated the mechanism of inhibition of the oxidative burst and evaluated short and long‐term effects of CsA on dimethylsulphoxide‐differentiated HL‐60 neutrophils.
A biphasic pattern was observed: a 4 h pre‐treatment with CsA (1 μM) diminished the fMLP induced [Ca2+]c rise, reactive oxygen species (ROS) production, and β‐glucuronidase release by about 40%, whereas a 20 h pre‐treatment increased these responses by about 1.5 fold.
[MeVal4]CsA, which binds with high affinity to cyclophilin but inhibits the interaction of the CsA‐cyclophilin complex with calcineurin, blocked the stimulation observed with CsA after a 20 h incubation but did not alter the CsA effects after a 4 h pre‐treatment.
PSC 833 (1 μM), a potent multi drug resistance transporter (MDR) inhibitor, diminished ROS production to the same extent as a 4 h CsA incubation but was ineffective after a 20 h pre‐treatment. An involvement of MDR as a basis for CsA or PSC 833 action was ruled out based on the results of the calcein retention assay.
[3H]CsA uptake showed that CsA and [MeVal4]CsA, but not CsH or PSC 833 were strongly taken up and retained by the cells.
In conclusion, the reduction of the responses after 4 h appear to be due to a primary reduction of calcium signalling, while the enhanced responses after 20 h may be due to calcineurin inhibition.

British Journal of Pharmacology (1998) 124, 1774–1780; doi:10.1038/sj.bjp.0702020
Direct dopamine D2‐receptor‐mediated modulation of arachidonic acid release in transfected CHO cells without the concomitant administration of a Ca2+‐mobilizing agent
Authors: Nilsson Christer L , Hellstrand Monika , Ekman Agneta , Eriksson Elias 
Published: January 2005

In CHO cells transfected with the rat dopamine D2 receptor (long isoform), administration of dopamine per se elicited a concentration‐dependent increase in arachidonic acid (AA) release. The maximal effect was 197% of controls (EC50=25 nM). The partial D2 receptor agonist, (−)‐(3‐hydroxyphenyl)‐N‐n‐propylpiperidine [(−)‐3‐PPP], also induced AA release, but with somewhat lower efficacy (maximal effect: 165%; EC50=91 nM).
The AA‐releasing effect of dopamine was counteracted by pertussis toxin, by the inhibitor of intracellular Ca2+ release, 8‐(N N‐diethylamino)octyl‐3,4,5‐trimethoxybenzoate (TMB‐8), by excluding calcium from the medium, by the phospholipase A2 (PLA2) inhibitor, quinacrine, and by long‐term pretreatment with the phorbol ester, 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA). In addition, it was antagonized by the D2 antagonists, raclopride and (−)‐sulpiride–but not by (+)‐sulpiride–and absent in sham‐transfected CHO cells devoid of D2 receptors.
The results obtained contrast to the previous notion that dopamine and other D2 receptor agonists require the concomitant administration of calcium‐mobilizing agents such as ATP, ionophore A‐23187 (calcimycin), thrombin, and TRH, to influence AA release from various cell lines.

British Journal of Pharmacology (1998) 124, 1651–1658; doi:10.1038/sj.bjp.0702025
ATP‐sensitive K+ channels in smooth muscle cells of guinea‐pig mesenteric lymphatics: role in nitric oxide and β‐adrenoceptor agonist‐induced hyperpolarizations
Authors: von der Weid Pierre‐Yves 
Published: January 2005

Intracellular microelectrode recordings were performed to investigate the membrane K+ conductances involved in smooth muscle hyperpolarization of lymphatic vessels in the guinea‐pig mesentery.
Nitric oxide (NO), released either by the endothelium after acetylcholine (ACh; 10 μM) stimulation or by sodium nitroprusside (SNP; 50–100 μM), hyperpolarized lymphatic smooth muscle. These responses were inhibited with the guanylyl cyclase inhibitor 1H‐[1,2,4]oxadiazole [4,3‐a]quinoxalin‐1‐one (ODQ, 10 μM).
ACh and SNP‐induced hyperpolarizations were inhibited (by about 90%) upon application of the ATP‐sensitive K+(KATP) channel blocker, glibenclamide (10 μM), or with 4‐aminopyridine (2.5 mM), but were not affected by the Ca2+‐activated K+ channels blocker, penitrem A (100 nM).
Hyperpolarization caused by the K+ channel opener, cromakalim (0.1–10 μM), isoprenaline (0.1 μM) or forskolin (0.5 μM) were all significantly blocked by glibenclamide.
Hyperpolarization evoked by ACh and SNP were inhibited with N‐[2‐(p‐bromociannamylamino)‐ethyl]‐5‐isoquinolinesulfonamide‐dichloride (H89, 10 μM), suggesting the involvement of cyclic AMP dependent protein kinase (PKA).
These results suggest that KATP channels play a central role in lymphatic smooth muscle hyperpolarization evoked by a NO‐induced increase in cyclic GMP synthesis, as well as by β‐adrenoceptor‐mediated production of cyclic AMP. Interestingly, both pathways lead to KATP channels opening through the activation of PKA.

British Journal of Pharmacology (1998) 125, 17–22; doi:10.1038/sj.bjp.0702026
Citalopram‐induced hypophagia is enhanced by blockade of 5‐HT1A receptors: role of 5‐HT2C receptors
Authors: Grignaschi G , Invernizzi R W , Fanelli E , Fracasso C , Caccia S , Samanin R 
Published: January 2005

The selective 5‐hydroxytryptamine reuptake inhibitor citalopram (10 and 20 mg kg−1, i.p.) significantly reduced food intake in male rats (CD‐COBS) habituated to eat their daily food during a 4‐h period.
The 5‐HT1A receptor antagonist WAY100635 (0.3 mg kg−1) administered systemically did not modify feeding but significantly potentiated the reduction in food intake caused by 10 mg kg−1 i.p. citalopram. The dose of 5 mg kg−1 i.p. citalopram was not active in animals pretreated with vehicle but significantly reduced feeding in animals pretreated with WAY100635.
WAY100635 (0.1 μg 0.5 μl−1) injected into the dorsal raphe significantly potentiated the hypophagic effect of 10 mg kg−1 citalopram.
WAY100635 (1.0 μg 0.5 μl−1) injected into the median raphe did not modify feeding or the hypophagic effect of 10 mg kg−1 citalopram.
The 5‐HT2B/2C receptor antagonist SB206553 (10 mg kg−1, p.o.) slightly reduced feeding by itself but partially antagonized the effect of WAY100635 administered systemically (0.3 mg kg−1, s.c.) or into the dorsal raphe (0.1 μg 0.5 μl−1) in combination with 10 mg kg−1 i.p. citalopram. The hypophagic effect of 10 mg kg−1 i.p. citalopram alone was not significantly modified by SB206553.
Brain concentrations of citalopram and its metabolite desmethylcitalopram in rats pretreated with SB206553, WAY100635 and their combination were comparable to those of vehicle‐pretreated rats, 90 min after citalopram injection.
The hypophagic effect of citalopram was potentiated by blocking 5‐HT1A receptors. Only the effect of the WAY100635/citalopram combination seemed to be partially mediated by central 5‐HT2C receptors.

British Journal of Pharmacology (1998) 124, 1781–1787; doi:10.1038/sj.bjp.0702028
Frequency dependence of muscarinic facilitation of transmitter release in urinary bladder strips from neurally intact or chronic spinal cord transected rats
Authors: Somogyi G T , Zernova G V , Yoshiyama M , Yamamoto T , de Groat W C 
Published: January 2005

Electrical stimulation evoked release of 3H‐noradrenaline (NA) and 14C‐acetylcholine (ACh), as well as neurally evoked contractions were measured at various (1–40 Hz, 100 shocks) stimulation frequencies in bladder strips from neurally intact (NI) and spinal cord transected (SCT) rats.
The frequency response curves for ACh and NA release were shifted to the left in SCT bladder strips as compared to NI bladder strips.
Atropine (1 μM) depressed ACh release in NI bladder strips at high frequency stimulation (10 and 40 Hz) but not at low frequency stimulation (2–5 Hz). However, in SCT bladders, atropine depressed ACh release both at low and high frequencies of stimulation, indicating that muscarinic facilitation occurs at lower frequencies.
Atropine depressed the release of NA in NI bladders at only 40 Hz stimulation, but depressed release at all frequencies in SCT bladders.
The amplitude of neurally evoked contractions of bladder strips from NI rats was enhanced as the frequency of stimulation was increased from 1 to 40 Hz (80 shocks). The frequency response curve was shifted to the left in SCT bladders. Atropine blocked the neurally evoked contractions in SCT bladder strips to a greater extent than the contractions in NI strips indicating a cholinergic dominance in the SCT bladders.
Maximal contractile force of SCT bladder strips evoked by neural stimulation at 20 Hz 10 shocks and 80 shocks was significantly lower than that of NI bladder strips, whereas the release of ACh was significantly higher in SCT than NI bladders indicating a postjunctional defect in the SCT preparations.
It is suggested that presynaptic muscarinic facilitatory mechanisms are upregulated in the cholinergic and adrenergic nerve terminals in SCT bladders leading to a larger relative contractile response at lower frequencies of stimulation (2–5 Hz). Thus the hyperreflexic bladder occurring after spinal cord injury may be due in part to an enhancement of transmitter release at bladder postganglionic nerve terminals.

British Journal of Pharmacology (1998) 125, 241–246; doi:10.1038/sj.bjp.0702041
Inhibition by nitric oxide‐releasing compounds of prostacyclin production in human endothelial cells
Authors: Kosonen Outi , Kankaanranta Hannu , Malo‐Ranta Ulla , Ristimäki Ari , Moilanen Eeva 
Published: January 2005

The effects of two chemically unrelated nitric oxide (NO)‐releasing compounds were studied on prostacyclin production in lipopolysaccharide (LPS)‐stimulated human umbilical vein endothelial cells (HUVECs). The cells expressed cyclooxygenase‐2 (COX‐2) protein and produced prostacyclin by NS‐398‐sensitive manner suggesting that prostacyclin production derives principally by COX‐2 pathway.
A novel NO‐releasing oxatriazole derivative GEA 3175 (1–30 μM) inhibited LPS‐induced production of prostacyclin in HUVECs in a dose‐dependent manner being more potent than the earlier known NO‐donor S‐nitroso‐N‐acetylpenicillamine (SNAP).
The effects of the two NO‐donors on prostacyclin synthesis were reversed when red blood cells were added into the culture indicating that the effects are due to NO released from the compounds.
Addition of exogenous arachidonic acid into the culture did not alter the inhibitory action of NO‐donors suggesting that phospholipases are not the target of action of NO.
The NO‐donors did not inhibit prostacyclin production in the presence of a selective COX‐2 inhibitor NS‐398. These data suggest that NO affects COX‐2 pathway rather than has an overall effect on cyclooxygenases.
NO‐releasing compounds did not alter the level of COX‐2 protein expression in LPS‐treated HUVECs as measured by Western blot analysis.
The results suggest that NO‐donors inhibit the activity of COX‐2 in human endothelial cells. A link between NO and the regulation of eicosanoid synthesis could represent an important mechanism in controlling vascular and inflammatory responses in pathophysiological states and during treatment with nitrovasodilators.

British Journal of Pharmacology (1998) 125, 247–254; doi:10.1038/sj.bjp.0702042
Inhibition of serum and transforming growth factor beta (TGF‐β1)‐induced DNA synthesis in confluent airway smooth muscle by heparin
Authors: Okona‐Mensah K B , Shittu E , Page C , Costello J , Kilfeather S A 
Published: January 2005

Airway remodelling occurs in asthma and involves an increase in airway smooth muscle mass through cell proliferation and hypertrophy. Increased eosinophil density in the airways is a feature of asthma. Eosinophils exhibiting activation in the airways of asthmatics also exhibit increased expression of transforming growth factor beta (TGF‐β1). We have examined the capacity of TGF‐β1 and epidermal growth factor (EGF) to influence airway smooth muscle division and the effect of heparin on TGF‐β1, EGF and serum‐induced smooth muscle DNA synthesis in confluent airway smooth muscle cells (ASMC) as an indication of entry into S phase preceding mitogenesis.
ASMC were obtained from cell populations growing out from explanted bovine trachealis muscle sections. Cell division was monitored in sparse plated cells by direct cell counting following nuclear staining. Cell DNA synthesis in confluent cells was monitored by uptake of [3H]‐thymidine.
TGF‐β1 (100 pM) inhibited FBS (10%)‐induced smooth muscle division in sparsely plated cells (40%). TGF‐β1 (100 pM) increased cell DNA synthesis (200%) in confluent cells in the presence of bovine serum albumin (BSA, 0.25%). EGF (0.7 nM) also increased airway smooth muscle DNA synthesis (69%) in the presence of BSA (0.25%). The facilitatory effect of TGF‐β1 was observed between 1–100 pM, while that of EGF was observed between 20–200 pM.
Heparin inhibited serum and TGF‐β1‐induced DNA synthesis in confluent ASMC (55%), consistent with our previous observation of inhibition of division in sparsely populated ASMC (Kilfeather et al., 1995a). This action of heparin was observed between concentrations of 1–100 μg ml−1. Heparin did not inhibit DNA synthesis in response to EGF. An anti‐mitogenic effect of heparin was also observed against responses to combined exposure to TGF‐β1 and EGF.
There was a clear inhibitory effect of heparin in absolute terms against serum‐induced division in cells plated at 10, 20 and 45×103 cells cm−2. The inhibitory effect of heparin was also observed at a plating density of 45,000 cells cm−2 when responses to serum were expressed as fold‐stimulation of basal DNA synthesis.
These findings demonstrate a potential role of TGF‐β1, EGF and heparin‐related molecules in regulation of airway smooth muscle division.

British Journal of Pharmacology (1998) 125, 599–606; doi:10.1038/sj.bjp.0702046
Effects of mitogen‐activated protein kinase kinase inhibitor PD 098059 on antigen challenge of guinea‐pig airways in vitro
Authors: Tsang F , Koh A H M , Ting W L , Wong P T H , Wong W S F 
Published: January 2005

It has been shown that activation of protein tyrosine kinases is the earliest detectable signalling response to FcεRI cross‐linking on mast cell. Following tyrosine kinase activation, a family of mitogen‐activated protein kinases (MAPKs) was found to be activated as well. The present study examined the role of MAPK signalling cascade in in vitro model of allergic asthma using a specific MAPK kinase inhibitor PD 098059.
Guinea‐pigs were passively sensitized with IgG antibody raised against ovalbumin (OA). Effects of PD 098059 on OA‐induced anaphylactic contraction of isolated bronchi and release of histamine and peptidoleukotrienes from chopped lung preparations were studied.
PD 098059 (10–50 μM) produced only minor reduction of maximal OA‐induced bronchial contraction. In contrast, the rate of relaxation of OA‐induced bronchial contraction was markedly faster in the presence of PD 098059 than the vehicle control in a concentration‐dependent manner.
These observations corroborate well with the inability of PD 098059 (5–50 μM) to substantially block the OA‐induced release of histamine and with marked inhibition of OA‐induced release of peptidoleukotrienes from lung fragments in the presence of PD 098059. Exogenous arachidonic acid‐induced release of peptidoleukotrienes from lung fragments was not blocked by PD 098059.
In immunoblotting study, we found that p42MAPK was constitutively expressed in guinea‐pig bronchi. However, treatment with OA, histamine or LTD4 did not cause activation of p42MAPK. These findings together with the lack of inhibitory effects of PD 098059 on bronchial contraction induced by histamine or LTD4 suggest that histamine‐ and LTD4‐induced bronchial contractions are not mediated by p42MAPK activation.
Taken together, our findings show that inhibition of MAPK signalling cascade by PD 098059 significantly reduced the OA‐triggered release of peptidoleukotrienes leading to rapid relaxation of anaphylactic bronchial contraction. On the other hand, p42MAPK did not play a role in histamine‐ or LTD4‐induced bronchial smooth muscle contraction suggesting that PD 098059 exerts its inhibitory effects on OA‐induced bronchial contraction primarily through inhibition of peptidoleukotrienes release from mast cells.

British Journal of Pharmacology (1998) 125, 61–68; doi:10.1038/sj.bjp.0702049
Relaxant effects of L‐citrulline in rabbit vascular smooth muscle
Authors: Ruiz E , Tejerina T 
Published: January 2005

Vascular endothelium plays a pivotal role in the control of vascular tone through the release of vasoactive factors such as EDRF (NO).
The aim of this study was to investigate whether the addition of exogenous L‐citrulline, the byproduct of the NO‐synthesis, could relax vascular smooth muscle.
L‐citrulline relaxed both endothelium‐denuded and endothelium‐intact rabbit aortic rings precontracted with noradrenaline 10−6 M (maximum relaxations induced by L‐citrulline 10−8 M were 74.1±5.2% vs 51.3±2.8% in endothelium‐denuded and endothelium‐intact arteries, respectively).
This relaxant effect was enhanced by zaprinast (a phosphodiesterase type 5 inhibitor) and inhibited by HS‐142‐1 (a particulate guanylate cyclase inhibitor) and by apamin (a KCa‐channel blocker).
L‐citrulline (10−13–10−8 M) increased cGMP levels in aortic rings (maximum value with L‐citrulline 10−8 M was 0.165±0.010 pmol cGMP mg−1 of tissue vs 0.038±0.009 pmol mg−1 of tissue in basal).
L‐citrulline as well as NO were released from endothelial cells in culture stimulated with ACh. The values were 6.50±0.50 μM vs 2.30±0.20 μM (stimulated with ACh and basal respectively) for L‐citrulline and 4.22±0.10 μM vs 0.87±0.26 μM (stimulated with ACh and basal respectively) for NO.
These results suggest that L‐citrulline could be released together with NO from endothelium and may have actions complementary to those of NO in the control of vascular smooth muscle relaxation.

British Journal of Pharmacology (1998) 125, 186–192; doi:10.1038/sj.bjp.0702051
Role of transforming growth factor‐β pathway in the mechanism of wound healing by saponin from Ginseng Radix rubra
Authors: Kanzaki Tetsuto , Morisaki Nobuhiro , Shiina Ritsuko , Saito Yasushi 
Published: January 2005

The effects of saponin from Ginseng Radix rubra on extracellular matrix metabolism, the activation and synthesis of TGF‐β1, and the modification of TGF‐β receptor in fibroblasts were examined to elucidate the contribution of the TGF‐β pathway to the mechanism of wound healing by saponin.
Fibronectin synthesis was analysed by the immunoprecipitation method. Activation and synthesis of TGF‐β1 were measured by ELISA. The expressions of TGF‐β receptors in fibroblasts were examined at protein and mRNA levels by the cross‐linking method and Northern blot analysis, respectively.
The fibronectin synthesis increased 2.3‐ and 3.9‐fold at fibroblasts treated with 1 and 10 μg ml−1 of saponin, respectively, compared with that in non‐treated cells. Fibronectin synthesis stimulated with 10 μg ml−1 of saponin was inhibited with 69% by 5 μg ml−1 of an anti‐TGF‐β1 antibody. mRNA of TGF‐β type I receptor increased 4.8‐ and 4.4‐fold at fibroblasts treated with 1 and 10 μg ml−1 of saponin, respectively, and that of TGF‐β type II receptor also increased 3.4‐ and 3.2‐fold at fibroblasts treated with 1 and 10 μg ml−1 of saponin, respectively. The significant increases of TGF‐β type I and II receptors and of fibronectin synthesis were observed at the same concentrations of saponin. TGF‐β1 content increased 1.74‐ and 1.87‐fold at conditioned medium of fibroblasts treated with 100 and 250 μg ml−1 of saponin, respectively, higher concentrations than those which accelerated fibronectin synthesis. Furthermore, the active TGF‐β1 content was below 10% of total TGF‐β1 at each concentration of saponin.
These results indicate that saponin stimulates fibronectin synthesis through the changes of TGF‐β receptor expressions in fibroblasts.

British Journal of Pharmacology (1998) 125, 255–262; doi:10.1038/sj.bjp.0702052
Peripheral and/or central effects of racemic‐, S(+)‐ and R(−)‐flurbiprofen on inflammatory nociceptive processes: a c‐Fos protein study in the rat spinal cord
Authors: Buritova Jaroslava , Besson Jean‐Marie 
Published: January 2005

We have evaluated the effects of intravenous or intraplantar racemic‐, S(+)‐ and R(−)‐flurbiprofen on both the carrageenan‐evoked peripheral oedema and spinal c‐Fos immunoreactivity, an indirect index of neurons involved in spinal nociceptive processes.
Three hours after intraplantar injection of carrageenan (6 mg in 150 μl of saline) in awake rats, a peripheral oedema and numerous c‐Fos protein‐like immunoreactive (c‐Fos‐LI) neurons in L4–L5 segments were observed. c‐Fos‐LI neurons were essentially located in the superficial (I–II) and deep (V–VI) laminae of the dorsal horn.
Intravenous racemic‐flurbiprofen (0.3, 3 and 9  mg kg−1) dose‐relatedly reduced the carrageenan‐evoked oedema and spinal c‐Fos expression (r=0.64, r=0.88 and r=0.84 for paw diameter, ankle diameter and number of c‐Fos‐LI neurons; P<0.05, P<0.001 and P<0.001 respectively).
Similar effects to those of intravenous racemic‐flurbiprofen were obtained with intravenous S(+)‐flurbiprofen (0.3, 3 and 9 mg kg−1) which dose‐relatedly reduced the number of c‐Fos‐LI neurons (r=0.69, P<0.01) and diameters of paw and ankle (r=0.56 and r=0.52 respectively, P<0.05 for both).
For the dose of 0.3 mg kg−1 i.v., R(−)‐flurbiprofen did not modify the number of c‐Fos‐LI neurons and produced a weak reduction of oedema at only the ankle level (23±12% reduction, P<0.05). However, a ten times higher dose of R(−)‐flurbiprofen (3 mg kg−1 i.v.) was necessary to obtain effects comparable to those of S(+)‐ or racemic‐flurbiprofen (0.3 mg kg−1 i.v.).
Intraplantar racemic‐flurbiprofen (1, 10 and 30 μg) dose‐relatedly reduced the carrageenan‐enhanced ankle diameter (r=0.81, P<0.001) and the number of c‐Fos‐LI neurons in L4–L5 segments (r=0.83, P<0.001), with a 60±3% reduction of the number of c‐Fos‐LI neurons (P<0.001), and 30±3 and 67±7% reduction of paw and ankle diameter respectively (P<0.001 for both) for the dose of 30 μg.
For intraplantar S(+)‐flurbiprofen (1, 10 and 30  μg) the dose‐related effects (r=0.77, r=0.60 and r=0.59 for c‐Fos‐LI neurons, paw and ankle diameters respectively, P<0.001, P<0.01 and P<0.01) were similar to those of racemic‐flurbiprofen. In contrast, intraplantar R(−)‐flurbiprofen (1, 10 and 30 μg) did not have detectable effects on all studied parameters.
The present study provides clear evidence for potent anti‐inflammatory and antinociceptive effects of both intravenous or intraplantar racemic‐ and S(+)‐flurbiprofen. These results further demonstrate marked anti‐inflammatory and antinociceptive effects of intravenous, but not intraplantar, R(−)‐flurbiprofen. These results suggest that the main site of action of racemic‐ and S(+)‐flurbiprofen is in the periphery and indicate that the site of action of R(−)‐flurbiprofen is mainly of central origin.

British Journal of Pharmacology (1998) 125, 87–101; doi:10.1038/sj.bjp.0702053