bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of platelet function by catecholamines in the cerebral vasculature of the rabbit
Authors: Emerson Michael , Paul William , Page Clive P 
Published: January 2005

111In‐labelled platelets were monitored continuously in the cerebral and pulmonary vascular beds of anaesthetized rabbits. Dopamine can, depending upon the concentration, either potentiate or inhibit thrombin‐induced platelet accumulation in the cerebral vasculature of rabbits by unknown mechanisms. The effects of specific adrenergic and dopaminergic receptor antagonists were tested upon dopamine's actions on intracarotid (i.c.) thrombin‐induced (80 u kg−1) platelet accumulation in the cerebral vasculature. The effect of adrenaline on the response to thrombin in this vascular bed was also investigated.
Thrombin‐induced platelet accumulation was significantly (P<0.01) potentiated by dopamine (100 μg kg−1 min−1, i.c.) and this effect was significantly inhibited by infusion of the α‐adrenoceptor antagonist, phentolamine.
A higher dose of dopamine (2 mg kg−1 min−1, i.c.) inhibited thrombin‐induced platelet accumulation. The β‐adrenoceptor antagonist, propranolol, did not significantly alter this inhibitory effect whereas it was abolished by the dopamine D1 selective antagonist, SCH23390.
Adrenaline (when administered i.c. by bolus injection or infusion) had no significant effect on thrombin‐induced accumulation at any of the doses tested.
Potentiation of in vivo platelet accumulation by dopamine therefore seems to occur via α‐adrenergic receptors. However, the inhibitory effect of dopamine appears to be exerted via the activation of dopamine D1 receptors and not via β‐adrenergic receptors. Our findings confirm that dopamine, but not adrenaline, can modify platelet function in the cerebral vasculature and these observations may have implications for current and potential therapeutic uses of dopamine and selective dopaminergic compounds.

British Journal of Pharmacology (1999) 127, 1652–1656; doi:10.1038/sj.bjp.0702671
Comparison of the functional potencies of ropinirole and other dopamine receptor agonists at human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells
Authors: Coldwell Martyn C , Boyfield Izzy , Brown Tony , Hagan Jim J , Middlemiss Derek N 
Published: January 2005

The aim of the present study was to characterize functional responses to ropinirole, its major metabolites in man (SKF‐104557 (4‐[2‐(propylamino)ethyl]‐2‐(3H) indolone), SKF‐97930 (4‐carboxy‐2‐(3H) indolone)) and other dopamine receptor agonists at human dopamine D2(long) (hD2), D3 (hD3) and D4.4 (hD4) receptors separately expressed in Chinese hamster ovary cells using microphysiometry.
All the receptor agonists tested (ropinirole, SKF‐104557, SKF‐97930, bromocriptine, lisuride, pergolide, pramipexole, talipexole, dopamine) increased extracellular acidification rate in Chinese hamster ovary clones expressing the human D2, D3 or D4 receptor. The pEC50s of ropinirole at hD2, hD3 and hD4 receptors were 7.4, 8.4 and 6.8, respectively. Ropinirole is therefore at least 10 fold selective for the human dopamine D3 receptor over the other D2 receptor family members.
At the hD2 and hD3 dopamine receptors all the compounds tested were full agonists as compared to quinpirole. Talipexole and the ropinirole metabolite, SKF‐104557, were partial agonists at the hD4 receptor.
Bromocriptine and lisuride had a slow onset of agonist action which precluded determination of EC50s.
The rank order of agonist potencies was dissimilar to the rank order of radioligand binding affinities at each of the dopamine receptor subtypes. Functional selectivities of the dopamine receptor agonists, as measured in the microphysiometer, were less than radioligand binding selectivities.
The results show that ropinirole is a full agonist at human D2, D3 and D4 dopamine receptors. SKF‐104557 the major human metabolite of ropinirole, had similar radioligand binding affinities to, but lower functional potencies than, the parent compound.

British Journal of Pharmacology (1999) 127, 1696–1702; doi:10.1038/sj.bjp.0702673
Calcium antagonistic properties of the cyclooxygenase‐2 inhibitor nimesulide in human myometrial myocytes
Authors: Knock Gregory A , Aaronson Philip I 
Published: January 2005

The non‐steroidal anti‐inflammatory drug nimesulide is a selective inhibitor of cyclooxygenase‐2 which relaxes spontaneously contracting human myometrium in vivo and is potentially a useful tocolytic drug. Part of the relaxant action of nimesulide may be via block of myometrial Ca2+ channels. Here, we describe the Ca2+ channel blocking properties of nimesulide in freshly dispersed human term‐pregnant myometrial smooth muscle cells (HMSMCs).
Both L‐ and T‐components of the whole cell Ca2+ channel current were inhibited by 100 μM nimesulide (38±3 and 35±1% block, respectively). At physiological pH inside and outside the cell (pHo/pHi=7.4/7.2), this block did not depend on the holding or test potential, although a degree of use‐dependence was observed during high frequency stimulation at a higher concentration of drug (300 μM).
At pHo/pHi=6.8, under which condition the concentration of the non‐ionized form of the drug is increased 3 fold compared to pH 7.4, nimesulide blocked the L‐type current more potently (58±3% inhibition at 100 μM, P<0.01) compared to physiological pH. Nimesulide caused a 7 mV leftward shift in the availability curve of the current at pH 6.8, suggesting that the affinity of the drug for the inactivated channel is approximately 4 fold higher than its affinity for the closed channel. We speculate that acidification and depolarization of the myometrium during the intense and prolonged contractions of labour might increase the potency of nimesulide as a Ca2+ channel antagonist, promoting its action as a tocolytic agent.

British Journal of Pharmacology (1999) 127, 1470–1478; doi:10.1038/sj.bjp.0702685
Differential effects of adenine nucleotide analogues on shape change and aggregation induced by adenosine 5′‐diphosphate (ADP) in human platelets
Authors: Park Hye‐Seong , Hourani Susanna M O 
Published: January 2005

Adenosine 5′‐diphosphate (ADP) induces human blood platelets to aggregate and change shape, and it has been suggested that these two responses are mediated by more than one subtype of ADP receptor.
The structure‐activity relationships for several analogues of adenine nucleotides in causing aggregation and shape change were measured and compared in washed platelets using an aggregometer. ADP and its analogues 2‐methylthioadenosine 5′‐diphosphate (2‐methylthio‐ADP), adenosine 5′(α,β‐methylene)diphosphonate (AMPCP), SP‐adenosine 5′‐O‐(1‐thiodiphosphate) (AD‐PαS) and adenosine 5′‐O‐(2‐thiodiphosphate) (ADPβS) were used as agonists. Adenosine 5′‐triphosphate (ATP) and its analogues, P1, P5‐diadenosine pentaphosphate (Ap5A), adenosine (5′‐(α,β‐methylene)triphosphonate (AMPCPP), 2‐methylthioadenosine 5′‐triphosphate (2‐methylthio‐ATP) and uridine 5′‐triphosphate (UTP), as well as the trypanocidal drug suramin, were used as antagonists.
In general, the structure‐activity relationships for both responses were similar, but for some analogues differences were observed. ADPαS and ADPβS were much more potent agonists relative to ADP for shape change than for aggregation and indeed ADPαS antagonized ADP‐induced aggregation with an apparent pKB value of 5.5±0.1. 2‐Methylthio‐ATP also had different effects in aggregation and shape change, being a much higher affinity antagonist of aggregation than of shape change with an apparent pKB value of 7.0±0.2 for aggregation and 5.2±0.2 for shape change.
These results support the suggestion that these two responses are mediated by multiple ADP receptors on human platelets, and are consistent with shape change being mediated via one receptor (the P2Y1 receptor) with aggregation requiring the activation of two receptors (the P2Y1 and another P2Y receptor).

British Journal of Pharmacology (1999) 127, 1359–1366; doi:10.1038/sj.bjp.0702690
The ether lipid ET‐18‐OCH3 increases cytosolic Ca2+ concentrations in Madin Darby canine kidney cells
Authors: Jan Chung‐Ren , Wu Sheng‐Nan , Tseng Ching‐Jiunn 
Published: January 2005

The effect of the ether lipid 1‐O‐octadecyl‐2‐O‐methyl‐sn‐glycero‐3‐phosphorylcholine (ET‐18‐OCH3) on the intracellular free Ca2+ concentration ([Ca2+]i) in Madin Darby canine kidney (MDCK) cells was studied using fura‐2 as the Ca2+ probe. In Ca2+ medium, ET‐18‐OCH3 induced a significant rise in [Ca2+]i at concentrations between 10–100 μM with a concentration‐dependent delay of 45–175 s. The [Ca2+]i signal was composed of a gradual rise and a sustained plateau.
In Ca2+‐free medium, ET‐18‐OCH3 (10–100 μM) induced a Ca2+ release from internal Ca2+ stores with a concentration‐dependent delay of 45–175 s. This discharge of internal Ca2+ triggered capacitative Ca2+ entry in a concentration‐dependent manner. This capacitative Ca2+ entry was not inhibited by econazole (25 μM), 1‐[β‐[3‐(4‐methoxyphenyl)propoxy]‐4‐methoxyphenethyl]‐1H‐imidazole hydrochloride (SKF96365; 50 μM), nifedipine (10 μM), verapamil (10 μM), diltiazem (10 μM) and cadmium (0.5 μM).
Methyl 2‐(phenylthio)ethyl‐1,4‐dihydro‐2,4,6‐trimethylpyridine‐3,5‐dicarboxylate (PCA‐4248), a platelet‐activating factor (PAF) receptor antagonist, inhibited 25 μM ET‐18‐OCH3‐induced [Ca2+]i rise in a concentration‐dependent manner between 1–20 μM, with 20 μM exerting a complete block.
The [Ca2+]i rise induced by ET‐18‐OCH3 (25 μM) was not altered when the production of inositol 1,4,5‐trisphosphate (IP3) was suppressed by the phospholipase C inhibitor U73122 (2 μM), but was partly inhibited by the phospholipase D inhibitor propranolol (0.1 mM) or the phospholipase A2 inhibitor aristolochic acid (20–40 μM).
In Ca2+‐free medium, pretreatment with 25 μM ET‐18‐OCH3 completely depleted the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin‐sensitive Ca2+ store. In contrast, pretreatment with thapsigargin abolished 0.1 mM ATP‐induced [Ca2+]i rise without altering the ET‐18‐OCH3‐induced [Ca2+]i rise. This suggests that ET‐18‐OCH3 depleted thapsigargin‐sensitive Ca2+ stores and also released Ca2+ from thapsigargin‐insensitive stores. The thapsigargin‐insensitive stores involve mitochondria because the mitochondria uncoupler carbonylcyanide m‐chlorophenylhydrazone (CCCP; 2 μM) induced a release of mitochondrial Ca2+ which was abolished by pretreatment with 25 μM ET‐18‐OCH3.
ET‐18‐OCH3 (25 μM) induced a significant Mn2+ quench of fura‐2 fluorescence at 360 nm excitation wavelength confirming that ET‐18‐OCH3 induced capacitative Ca2+ entry. La3+ (0.1 mM) or Gd3+ (50 μM) abolished the ET‐18‐OCH3‐induced Mn2+ quench and [Ca2+]i rise.
Our data imply that ET‐18‐OCH3 induced a [Ca2+]i rise in MDCK cells by activating PAF receptors leading to an internal Ca2+ release followed by capacitative Ca2+ entry. Phospholipase D and phospholipase A2, but not phospholipase C, might be involved in mediating the capacitative Ca2+ entry. La3+ abolished the ET‐18‐OCH3‐induced [Ca2+]i rise presumably by inhibiting PAF receptors.

British Journal of Pharmacology (1999) 127, 1502–1510; doi:10.1038/sj.bjp.0702691
GABAB, opioid and α2 receptor inhibition of calcium channels in acutely‐dissociated locus coeruleus neurones
Authors: Chieng B , Bekkers J M 
Published: January 2005

The effects of GABAB, opioid and α2 receptor activation on different subtypes of calcium channels in acutely‐dissociated rat locus coeruleus (LC) neurones were investigated using whole‐cell patch clamping.
Barium currents through calcium channels could be fractionated into four classes: L‐type (nimodipine‐sensitive), N‐type (ω‐conotoxin GVIA‐sensitive), P/Q‐type (ω‐agatoxin IVA‐sensitive) and R‐type (remaining in the presence of all three blockers). The percentage of each was, respectively, 25±2, 34±1, 28±3 and 12±1% (mean±s.e.mean, n=4).
The GABAB receptor agonist, baclofen, and the opioid receptor agonist, enkephalin, partially inhibited the total barium current in a concentration‐dependent manner with EC50 values of 2 and 0.3 μM, respectively. Maximal inhibition was 17±1% (n=38) for baclofen and 30±2% (n=20) for enkephalin. The α2‐adrenoceptor agonist, UK14304 (10 μM), also inhibited barium current in these neurones (28±2%, n=11). The agonists did not shift the current‐voltage relationship along the voltage axis.
Maximal baclofen inhibition of different calcium channel subtypes was 9±7% (L‐type, n=4), 11±8% (N‐type, n=4), 26±6% (P/Q‐type, n=4), and 6±5% (R‐type, n=5). The corresponding values for enkephalin inhibition were 5±9% (L‐type), 30±11% (N‐type), 37±9% (P/Q‐type), and 17±8% (R‐type).
In the presence of a saturating concentration of enkephalin, baclofen produced additional inhibition of the barium current. In contrast, in the presence of a saturating concentration of enkephalin, UK14304 produced no further inhibition of the barium current.
These results indicate that neuromodulation of calcium channels in LC neurones involves a complex pattern of overlapping and distinct second messenger pathways. Regulation of LC neuronal firing activity by the modulation of calcium channels may be important for LC‐mediated behaviour such as alertness and vigilance.

British Journal of Pharmacology (1999) 127, 1533–1538; doi:10.1038/sj.bjp.0702693
Pacing‐induced delayed protection against arrhythmias is attenuated by aminoguanidine, an inhibitor of nitric oxide synthase
Authors: Kis Adrienn , Végh Agnes , Papp Julius , Parratt James 
Published: January 2005

Cardiac pacing, in anaesthetized dogs, protects against ischaemia and reperfusion‐induced ventricular arrhythmias when this is initiated 24 h after the pacing stimulus. Now we have examined whether this delayed cardioprotection afforded by cardiac pacing is mediated through nitric oxide.
Twenty‐two dogs were paced (4×5 min periods at 220 beats min−1) by way of the right ventricle, 24 h prior to a 25 min period of coronary artery occlusion. Nine of these dogs were given the inhibitor of induced nitric oxide synthase, aminoguanidine (50 mg kg−1 i.v.), 0.5 h prior to coronary artery occlusion. Sham‐operated non‐paced dogs with and without aminoguanidine treatment served as controls.
Pacing markedly (P<0.05) reduced arrhythmia severity (ventricular fibrillation, VF, during occlusion 15%; survival from the combined ischaemia‐reperfusion insult 62%) compared to control, sham‐operated, unpaced dogs (VF during occlusion 58%; survival 17%). This protection was attenuated by the administration of aminoguanidine prior to coronary artery occlusion (survival from the combined ischaemia‐reperfusion insult 11%, which was significantly (P<0.05) less than in the paced dogs not given aminoguanidine and similar to the controls). Aminoguanidine had no significant effects on coronary artery occlusion when given to dogs that had not been paced. In the dose used aminoguanadine transiently elevated systemic arterial pressure by a mean of 20 mmHg and reduced heart rate by a mean of 22 beats min−1.
These results suggest that nitric oxide, probably derived from induced nitric oxide synthase, contributes significantly to the delayed cardioprotection afforded by cardiac pacing.

British Journal of Pharmacology (1999) 127, 1545–1550; doi:10.1038/sj.bjp.0702695
Bronchodilator and anti‐inflammatory activities of glaucine: In vitro studies in human airway smooth muscle and polymorphonuclear leukocytes
Authors: Cortijo J , Villagrasa V , Pons R , Berto L , Martí‐Cabrera M , Martinez‐Losa M , Domenech T , Beleta J , Morcillo E J 
Published: January 2005

Selective phosphodiesterase 4 (PDE4) inhibitors are of potential interest in the treatment of asthma. We examined the effects of the alkaloid S‐(+)‐glaucine, a PDE4 inhibitor, on human isolated bronchus and granulocyte function.
Glaucine selectively inhibited PDE4 from human bronchus and polymorphonuclear leukocytes (PMN) in a non‐competitive manner (Ki=3.4 μM). Glaucine displaced [3H]‐rolipram from its high‐affinity binding sites in rat brain cortex membranes (IC50∼100 μM).
Glaucine inhibited the spontaneous and histamine‐induced tone in human isolated bronchus (pD2∼4.5). Glaucine (10 μM) did not potentiate the isoprenaline‐induced relaxation but augmented cyclic AMP accumulation by isoprenaline. The glaucine‐induced relaxation was resistant to H‐89, a protein kinase A inhibitor. Glaucine depressed the contractile responses to Ca2+ (pD'2∼3.62) and reduced the sustained rise of [Ca2+]i produced by histamine in cultured human airway smooth muscle cells (−log IC50∼4.3).
Glaucine augmented cyclic AMP levels in human polymorphonuclear leukocytes challenged with N‐formyl‐Met‐Leu‐Phe (FMLP) or isoprenaline, and inhibited FMLP‐induced superoxide generation, elastase release, leukotriene B4 production, [Ca2+]i signal and platelet aggregation as well as opsonized zymosan‐, phorbol myristate acetate‐, and A23187‐induced superoxide release. The inhibitory effect of glaucine on superoxide generation by FMLP was reduced by H‐89.
In conclusion, Ca2+ channel antagonism by glaucine appears mainly responsible for the relaxant effect of glaucine in human isolated bronchus while PDE4 inhibition contributes to the inhibitory effects of glaucine in human granulocytes. The very low PDE4/binding site ratio found for glaucine makes this compound attractive for further structure‐activity studies.

British Journal of Pharmacology (1999) 127, 1641–1651; doi:10.1038/sj.bjp.0702702
Active intestinal elimination of ciprofloxacin in rats: modulation by different substrates
Authors: Dautrey S , Felice K , Petiet A , Lacour B , Carbon C , Farinotti R 
Published: January 2005

Two in vivo models, in the rat, were used to investigate, in the presence of different substrates, the overall and net intestinal elimination of ciprofloxacin: an open‐intestinal perfusion model and an intestinal loop model respectively.
In the presence of quinidine, verapamil and cyclosporin (substrates of the P‐glycoprotein (P‐gp)), plasma AUCs of ciprofloxacin were 1.5–2 fold increased, while biliary clearance (1.5–2 fold), intestinal overall and net clearances (2–4 fold and 1.5–8 fold respectively) decreased. The weak effect obtained with cyclosporin as compared to verapamil and especially quinidine, suggests, for ciprofloxacin, the existence of transport systems distinct from the P‐gp, as the OCT1 transporter which could be inhibited by quinidine.
With cephalexin and azlocillin, two β‐lactam antibiotics, plasma AUCs of ciprofloxacin increased and biliary and intestinal overall clearances decreased in a similar fashion (1.3–2 fold), suggesting the involvement of organic anion and/or cation transporters.
In the presence of structural analogues, the effect was dependent on the compound administered: Sparfloxacin had no effect on intestinal clearance of ciprofloxacin. In contrast, with pefloxacin, overall intestinal clearance of ciprofloxacin was decreased and net intestinal clearance increased.
The specificity of ciprofloxacin intestinal transport appears to be different from P‐gp as outlined by the lack of competition with sparfloxacin, a P‐gp substrate. Ciprofloxacin intestinal elimination seems to be mediated by organic anion and/or cation transporters and a mechanism sensitive to quinidine and verapamil.

British Journal of Pharmacology (1999) 127, 1728–1734; doi:10.1038/sj.bjp.0702703
An inhibitor of poly (ADP‐ribose) synthetase activity reduces contractile dysfunction and preserves high energy phosphate levels during reperfusion of the ischaemic rat heart
Authors: Docherty John C , Kuzio Bozena , Silvester Jocelyn A , Bowes Joanne , Thiemermann Christoph 
Published: January 2005

The cardioprotective properties of inhibition of poly (ADP‐ribose) synthetase (PARS) were investigated in the isolated perfused heart of the rat. Hearts were perfused in the Langendorff mode and subjected to 23 min total global ischaemia and reperfused for 60 min.
Left ventricular function was assessed by means of an intra‐ventricular balloon. High energy phosphates were measured by 31P‐NMR spectroscopy. Intracellular levels of NAD were measured by capillary electrophoresis of perchloric acid extracts of hearts at the end of reperfusion.
Reperfusion in the presence of the PARS inhibitor 1,5 didroxyisoquinoline (ISO, 100 μM) attenuated the mechanical dysfunction observed following 1 h of reperfusion; 27±13 and 65±8% recovery of preischaemic rate pressure product for control and 100 μM ISO, respectively.
This cardioprotection was accompanied by a preservation of intracellular high‐energy phosphates during reperfusion; 38±2 vs 58±4% (P<0.05) of preischaemic levels of phosphocreatine (PCr) for control and 100 μM ISO respectively and 23±1 vs 31±3% (P<0.05) of preischaemic levels of ATP for control and 100 μM ISO respectively.
Cellular levels of NAD were higher in ISO treated hearts at the end of reperfusion; 2.56±0.45 vs 4.76±1.12 μmoles g−1 dry weight (P<0.05) for control and ISO treated.
These results demonstrate that the cardioprotection afforded by inhibition of PARS activity with ISO is accompanied by a preservation of high‐energy phosphates and cellular NAD levels and suggest that the mechanism responsible for this cardioprotection may involve prevention of intracellular ATP depletion.

British Journal of Pharmacology (1999) 127, 1518–1524; doi:10.1038/sj.bjp.0702705
Maitotoxin‐induced nerve growth factor production accompanied by the activation of a voltage‐insensitive Ca2+ channel in C6‐BU‐1 glioma cells
Authors: Obara Yutaro , Takahashi Masami , Nakahata Norimichi , Ohizumi Yasushi 
Published: January 2005

The aim of the present study was to determine the effects of maitotoxin on nerve growth factor production and the Ca2+ influx in clonal rat glioma cells (C6‐BU‐1).
Maitotoxin (1–10 ng ml−1) induced a profound increase in 45Ca2+ influx in an extracellular Ca2+‐dependent manner. However, high KCl had no effect at all. These effects were supported by the results from the analysis of intracellular Ca2+ concentration using fura 2.
The maitotoxin‐induced 45Ca2+ influx was inhibited by inorganic Ca2+ antagonists, such as Mg2+, Mn2+ and Co2+. The inhibitory effect of Co2+ was antagonized by increasing the extracellular Ca2+ concentrations.
Maitotoxin (3 ng ml−1) as well as A‐23187 (1 μM) and dibutyryl cyclic AMP (0.5 mM) caused an acceleration of nerve growth factor (NGF) production in C6‐BU‐1 cells, as determined by NGF enzyme immunoassay.
Reverse transcription polymerase chain reaction (RT–PCR) analysis showed that maitotoxin (10 ng ml−1) enhanced the expression of NGF mRNA, which was abolished by the removal of extracellular Ca2+. A‐23187 also accelerated its expression.
These results suggest that maitotoxin activates a voltage‐insensitive Ca2+ channel and accelerates NGF production mediated through a Ca2+ signalling pathway in C6‐BU‐1 glioma cells.

British Journal of Pharmacology (1999) 127, 1577–1582; doi:10.1038/sj.bjp.0702706