bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of serum, cerebrospinal fluid and brain extracellular fluid pharmacokinetics of lamotrigine
Authors: Walker M C , Tong X , Perry H , Alavijeh M S , Patsalos P N 
Published: January 2005

We investigated the rate of penetration into and the intra‐relationship between the serum, cerebrospinal fluid (CSF) and regional brain extracellular fluid (bECF) compartments following systemic administration of lamotrigine in rat.
The serum pharmacokinetics were biphasic with an initial distribution phase, (half‐life approximately 3 h), and then a prolonged elimination phase of over 30 h. The serum pharmacokinetics were linear over the range 10–40 mg kg−1.
Using direct sampling of CSF with concomitant serum sampling, the calculated penetration half‐time into CSF was 0.42±0.15 h. At equilibrium, the CSF to total serum concentration ratio (0.61±0.02) was greater than the free to total serum concentration (0.39±0.01).
Using in vivo recovery corrected microdialysis sampling in frontal cortex and hippocampus with concomitant serum sampling, the calculated penetration half‐time of lamotrigine into bECF, 0.51±0.11 h, was similar to that for CSF and was not area or dose dependent. At equilibrium, the bECF to total serum concentration ratio (0.40±0.04) was similar to the free to total serum concentration (0.39±0.01), and did not differ between hippocampus and frontal cortex.
The species specific serum kinetics can explain the prolonged action of lamotrigine in rat seizure models. Lamotrigine has a relatively slow penetration into both CSF and bECF compartments compared with antiepileptic drugs used in acute seizures. Furthermore, the free serum drug concentration is not the sole contributor to the CSF compartment, and the CSF concentration is an overestimate of the bECF concentration of lamotrigine.

British Journal of Pharmacology (2000) 130, 242–248; doi:10.1038/sj.bjp.0703337
Conditions permitting suppression of stretch‐induced and vasoconstrictor tone by basal nitric oxide activity in porcine cerebral artery
Authors: Wallis Sarah J , Martin William 
Published: January 2005

This study examined the ability of basal nitric oxide activity to suppress intrinsic and vasoconstrictor tone in isolated rings of porcine cerebral artery.
Following stretch of approximately 1 g, NG‐nitro‐L‐arginine methyl ester (L‐NAME, 100 μM) produced a rise in tone in endothelium‐containing but not endothelium‐denuded rings. Thus, intrinsic tone was present and was powerfully suppressed by basal nitric oxide activity.
Nevertheless, when concentration‐response curves were constructed to U46619 and 5‐hydroxytryptamine (5‐HT), no endothelium‐dependent depression of vasoconstriction was observed. It therefore appeared that basal nitric oxide activity was able to suppress intrinsic but not vasoconstrictor tone in these vessels.
Stretch‐tension curves generated following the application of stretch over the range 0–5.5 g on endothelium‐denuded rings showed that tension was stretch‐induced. Experiments conducted in the presence of L‐NAME (100 μM) revealed that the level of tone present in endothelium‐containing rings was substantially higher than in endothelium‐denuded rings across the entire range of stretch.
When endothelium‐containing and endothelium‐denuded rings were set at similar levels of stretch‐induced tone, rather than similar levels of stretch, the presence of the endothelium now depressed significantly vasoconstrictor responses to U46619 and 5‐HT.
Thus, when endothelium‐containing and endothelium‐denuded rings of porcine cerebral artery are set at similar points along their respective stretch‐tension curves, rather than at similar levels of stretch, basal nitric oxide activity can be seen to inhibit both stretch‐induced and vasoconstrictor tone.

British Journal of Pharmacology (2000) 130, 567–574; doi:10.1038/sj.bjp.0703351
Involvement of tyrosine phosphorylation in the positive inotropic effect produced by H1‐receptors with histamine in guinea‐pig left atrium
Authors: Akaishi Yasuhiro , Hattori Yuichi , Yoshimoto Kimihiro , Kitabatake Akira , Yasuda Keishu , Kanno Morio 
Published: January 2005

We investigated the effect of stimulation of H1‐receptors with histamine on protein tyrosine phosphorylation levels in guinea‐pig left atrium and evaluated the influences of tyrosine kinase inhibitors on the positive inotropic effect mediated by H1‐receptors in this tissue.
Histamine induced an increase in tyrosine phosphorylation in four main clusters of proteins with apparent molecular weights of 25, 35, 65 and 150 kDa. Tyrosine phosphorylation of these proteins attained a peak around 2–3 min following histamine stimulation and then declined to or below basal levels. Histamine‐induced protein tyrosine phosphorylation was antagonized by the H1‐receptor antagonists mepyramine (1 μM) and chlorpheniramine (1 μM), but not by the H2‐receptor antagonist cimetidine (10 μM).
The positive inotropic effect of histamine was depressed in a concentration‐dependent manner by the tyrosine kinase inhibitors tyrphostin A25 (50 to 100 μM) and genistein (10 to 50 μM) but not by the inactive genistein analogue daidzein (50 μM). The positive inotropic effect of isoprenaline was unchanged by tyrphostin A25 and genistein.
At a concentration of 1 μM histamine produced a dual‐component positive inotropic response composed of an initial increasing phase and a second and late developing, greater positive inotropic phase. Treatment with tyrphostin A25 (100 μM) and genistein (50 μM), but not daidzein (50 μM), significantly attenuated the two components of the inotropic response, although genistein suppressed the initial component more markedly than the late component.
We conclude that increased protein tyrosine phosphorylation may play an important role in initiating at least some part of the positive inotropic effect of H1‐receptor stimulation in guinea‐pig left atrium.

British Journal of Pharmacology (2000) 130, 907–915; doi:10.1038/sj.bjp.0703355
Characterization of SB‐269970‐A, a selective 5‐HT7 receptor antagonist
Authors: Hagan Jim J , Price Gary W , Jeffrey Phillip , Deeks Nigel J , Stean Tania , Piper David , Smith Martin I , Upton Neil , Medhurst Andrew D , Middlemiss Derek N , Riley Graham J , Lovell Peter J , Bromidge Steven M , Thomas David R 
Published: January 2005

The novel 5‐HT7 receptor antagonist, SB‐269970‐A, potently displaced [3H]‐5‐CT from human 5‐HT7(a) (pKi 8.9±0.1) and 5‐HT7 receptors in guinea‐pig cortex (pKi 8.3±0.2).
5‐CT stimulated adenylyl cyclase activity in 5‐HT7(a)/HEK293 membranes (pEC50 7.5±0.1) and SB‐269970‐A (0.03–1 μM) inhibited the 5‐CT concentration‐response with no significant alteration in the maximal response. The pA2 (8.5±0.2) for SB‐269970‐A agreed well with the pKi determined from [3H]‐5‐CT binding studies.
5‐CT‐stimulated adenylyl cyclase activity in guinea‐pig hippocampal membranes (pEC50 of 8.4±0.2) was inhibited by SB‐269970‐A (0.3 μM) with a pKB (8.3±0.1) in good agreement with its antagonist potency at the human cloned 5‐HT7(a) receptor and its binding affinity at guinea‐pig cortical membranes.
5‐HT7 receptor mRNA was highly expressed in human hypothalamus, amygdala, thalamus, hippocampus and testis.
SB‐269970‐A was CNS penetrant (steady‐state brain : blood ratio of ca. 0.83 : 1 in rats) but was rapidly cleared from the blood (CLb=ca. 140 ml min−1 kg−1). Following a single dose (3 mg kg−1) SB‐269970 was detectable in rat brain at 30 (87 nM) and 60 min (58 nM). In guinea‐pigs, brain levels averaged 31 and 51 nM respectively at 30 and 60 min after dosing, although the compound was undetectable in one of the three animals tested.
5‐CT (0.3 mg kg−1 i.p.) induced hypothermia in guinea‐pigs was blocked by SB‐269970‐A (ED50 2.96 mg kg−1 i.p.) and the non‐selective 5‐HT7 receptor antagonist metergoline (0.3–3 mg kg−1 s.c.), suggesting a role for 5‐HT7 receptor stimulation in 5‐CT induced hypothermia in guinea‐pigs.
SB‐269970‐A (30 mg kg−1) administered at the start of the sleep period, significantly reduced time spent in Paradoxical Sleep (PS) during the first 3  h of EEG recording in conscious rats.

British Journal of Pharmacology (2000) 130, 539–548; doi:10.1038/sj.bjp.0703357
Specific inhibition of stretch‐induced increase in L‐type calcium channel currents by herbimycin A in canine basilar arterial myocytes
Authors: Kimura Makoto , Obara Kazuo , Sasase Tomohiko , Ishikawa Tomohisa , Tanabe Yoshiyuki , Nakayama Koichi 
Published: January 2005

The effects of protein‐tyrosine kinase (PTK) and protein‐tyrosine phosphatase (PTP) inhibitors on voltage‐activated barium currents (IBa) through L‐type calcium channels increased by hypotonic solution were investigated in canine basilar arterial myocytes by the whole‐cell patch‐clamp technique.
IBa was elicited by depolarizing step from a holding potential of −80 to +10 mV and identified by using an L‐type calcium channel agonist, Bay K 8644 (100 nM), and an L‐type calcium channel blocker, nicardipine (1 μM).
Hypotonic superfusate induced cell swelling and acted as a stretch stimulus, which reversibly increased peak IBa amplitude at +10 mV. IBa was also decreased by nicardipine (1 μM) under the hypotonic condition.
PTK inhibitors such as herbimycin A (30 nM), genistein (10 μM), and lavendustin A (10 μM) decreased IBa enhanced by hypotonic solution. Genistein also decreased IBa in a concentration‐dependent manner under the isotonic condition. The inactive genistein analogue daidzein (10 μM) had no effect on IBa under either the isotonic or hypotonic condition. By contrast, herbimycin A did not decrease IBa under the isotonic condition. Sodium orthovanadate (10 μM), a PTP inhibitor, increased IBa under both conditions.
The present results suggest that cell swelling by hypotonic solution increases the L‐type calcium channel currents in canine basilar artery and that herbimycin‐sensitive PTK activity is primarily involved in the enhancement of calcium channel currents.

British Journal of Pharmacology (2000) 130, 923–931; doi:10.1038/sj.bjp.0703360
Insulin modulation of intracellular free magnesium in heart: involvement of protein kinase C
Authors: Amano Tetsuya , Matsubara Tatsuaki , Watanabe Junji , Nakayama Shinsuke , Hotta Nigishi 
Published: January 2005

In the present study of rat heart using 31P‐nuclear magnetic resonance, we examined the interaction between β‐adrenergic and insulin receptors in terms of the intracellular free Mg2+ concentration ([Mg2+]i) regulation.
[Mg2+]i was estimated from the separation of the chemical shifts of the α‐ and β‐adenosine triphosphate (ATP) peaks, using the dissociation constant of MgATP 87 μM (established recently). In normal (phosphate‐free Krebs‐Henseleit) solution, [Mg2+]i was approximately 1.02 mM.
Insulin at physiological and pathological concentrations increased [Mg2+]i and contractility in a dose‐dependent manner.
Insulin (more than 100 μu ml−1) suppressed the decrease in [Mg2+]i caused by isoprenaline (100 nM), and these effects of insulin on [Mg2+]i and contractility were blocked by LY333531 (macrocyclic bis (indolyl) maleimide, 100 nM), a protein kinase C (PKC) inhibitor.
The isoprenaline‐induced decrease in the concentrations of ATP ([ATP]) with insulin application was significantly smaller than that without insulin.
Insulin modulates [Mg2+]i and haemodynamics, presumably via activation of PKC, thereby antagonizing the reduction of [Mg2+]i induced by β‐adrenoceptor stimulation.

British Journal of Pharmacology (2000) 130, 731–738; doi:10.1038/sj.bjp.0703361
Flibanserin has anxiolytic effects without locomotor side effects in the infant rat ultrasonic vocalization model of anxiety
Authors: Podhorna J , Brown R E 
Published: January 2005

This study compared the effects of flibanserin, a novel 5‐HT1A agonist/5‐HT2A antagonist; diazepam, a traditional anxiolytic; and imipramine, a traditional antidepressant, on separation‐induced ultrasonic vocalizations (USVs), locomotor behaviour, negative geotaxis and body temperature of 7–8‐day‐old rat pups.
Flibanserin (5, 10, 25 and 50 mg kg−1 s.c.) reduced USVs but had no effects on locomotor behaviour or negative geotaxis. Lower doses of flibanserin (0.5, 1, 2 and 4 mg kg−1 s.c.) had no effect on any behaviour. Diazepam (0.25, 0.5, 1 and 2 mg kg−1 s.c.) not only reduced the USVs but also increased rolling and increased the latency of the negative geotaxic response. Imipramine (10, 15, 20 and 30 mg kg−1 s.c.) reduced USVs, increased total locomotor activity and rolling but had no effect on negative geotaxis. None of the drugs altered body temperature.
Our data showed that flibanserin is as effective in reducing the USVs as diazepam and imipramine but has a lower incidence of motor side effects. This suggests that flibanserin might be effective for the treatment of mood disturbances such as anxiety.

British Journal of Pharmacology (2000) 130, 739–746; doi:10.1038/sj.bjp.0703364
Tissue angiotensin II and endothelin‐1 modulate differently the response to flow in mesenteric resistance arteries of normotensive and spontaneously hypertensive rats
Authors: Matrougui Khalid , Lévy Bernard I , Henrion Daniel 
Published: January 2005

In resistance arteries pressure‐induced (myogenic) tone (MT) and flow (shear stress)‐induced dilation (FD) are potent determinant of vascular resistance. We investigated the role of angiotensin II and endothelin‐1 in FD and MT in resistance arteries and their potential change in hypertension.
Flow–diameter–pressure relationship was established in situ, under anaesthesia, in two daughter branches of a mesenteric resistance artery (180 μM, n=7 per group) from spontaneously hypertensive (SHR) or normotensive (WKY) rats. One artery was ligated distally, so that it was submitted to pressure only, while the other was submitted to pressure and flow. Drugs were added to the preparation and external diameter, pressure and flow measured continuously.
External diameter (with flow) ranged from 150±3 to 191±7 μM in WKY (n=28) rats and from 168±6 to 186±6 μM in SHR (n=28). Flow induced a dilation of the non‐ligated arteries which was lower in SHR (13±5–31±4 μM vs WKY: 5±5–44±4 μM). In the ligated artery, the diameter did not significantly change, due to MT.
In the vessels submitted to flow angiotensin converting enzyme inhibition (perindopril, 10 μmol L−1) increased the diameter in SHR (+11±2 μM) significantly more than in WKY (+2±1 μM). Angiotensin type 1 receptor (AT1R) blockade (losartan, 10 μmol L−1) increased the diameter in the vessels with flow in SHR only (+6±1 μM). Angiotensin type 2 receptor (AT2R) blockade (PD 123319, 1 μmol L−1) decreased arterial diameter in WKY only (9±2). Endothelin‐1 type A receptor (ETAR) blockade (LU135252, 0.1 μmol L−1) increased the diameter only in SHR in the artery submitted to flow (by 6±1 μM).
Thus FD was counteracted by a flow‐dependent AT1 and ETA receptors‐activation in SHR whereas in WKY FD AT2‐dependent dilation is involved.

British Journal of Pharmacology (2000) 130, 521–526; doi:10.1038/sj.bjp.0703371
Pyrimidinoceptor potentiation of macrophage PGE2 release involved in the induction of nitric oxide synthase
Authors: Chen Bing‐C , Lin Wan‐W 
Published: January 2005

We have previously demonstrated that Ca2+/calmodulin‐dependent protein kinase (CaMK) mediates pyrimidinoceptor potentiation of LPS‐elicited inducible nitric oxide synthase (iNOS) induction in murine J774 macrophages. In the present paper, we have explored the role of cyclo‐oxygenase (COX)‐dependent prostaglandin E2 (PGE2) formation in this event.
In J774 macrophages predominantly expressing P2Y6 receptors, the simultaneous addition of UTP and lipopolysaccharide (LPS) resulted in potentiated increase in PGE2 release.
UTP‐induced increased PGE2 release was demonstrated by a concomitant increase in COX‐2 protein expression, and was decreased by inhibitors specific for phosphatidylinositide‐phospholipase C (PI‐PLC), CaMK, protein kinase C (PKC), nuclear factor‐kappa B (NF‐κB) or COX‐2.
NS‐398 (a selective COX‐2 inhibitor) reduced LPS plus UTP‐elicited iNOS induction and nitrite accumulation, supporting for the positive regulation of iNOS gene expression by endogenous PGE2.
Moreover, the cyclic AMP/PKA‐dependent up‐regulation of iNOS expression mediated by PGE2 was drawn from the inhibitory effects of 2′,5′‐dideoxyadenosine, KT5720 and H‐89. Exogenous PGE2 induced NF‐κB activation and potentiated nitrite accumulation in response to LPS.
In addition to COX‐2 induction, arachidonic acid (AA) release and steady‐state mRNA levels of type V secretory phospholipase A2 (sPLA2) and Ca2+‐independent PLA2 (iPLA2) were also increased in the presence of LPS and UTP; the LPS‐induced increase in iPLA2 activity was also potentiated by UTP.
Taken together, we conclude that UTP‐mediated COX‐2 and iPLA2 potentiation and PGE2 formation contribute to the iNOS induction, and that CaMK activation is the primary step in the UTP enhancement of COX‐2 induction.

British Journal of Pharmacology (2000) 130, 777–786; doi:10.1038/sj.bjp.0703375
Effects of chronic fluoxetine treatment in the presence and absence of (±)pindolol: a microdialysis study
Authors: Dawson L A , Nguyen H Q , Smith D I , Schechter L E 
Published: January 2005

Using in vivo microdialysis in the frontal cortex of the freely moving rat we evaluated the effects of chronic treatment with the serotonin specific reuptake inhibitor (SSRI) fluoxetine in the presence and absence of the 5‐HT1A/β‐adrenergic antagonist (±)pindolol.
Chronic vehicle treated animals produced no significant response to a challenge with fluoxetine (10 mg kg−1) on day 8 and 15. Alternatively, a significant (P<0.05) decrease in extracellular 5‐HT was observed in control animals upon challenge with the 5‐HT1A agonist 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT; 0.03 and 0.1 mg kg−1).
Conversely, animals treated with fluoxetine (10 mg kg−1 o.d.) for 7 and 14 days produced a significant (P<0.05) 2 fold increase in extracellular 5‐HT when challenged with fluoxetine (10 mg kg−1) on day 8 and 15. Moreover, no significant decrease in extracellular 5‐HT was observed upon challenge with either dose of 8‐OH‐DPAT.
Animals chronically treated with (±)pindolol (10 or 20 mg kg−1 b.i.d.) produced a significant dose‐related increase in extracellular 5‐HT upon challenge with fluoxetine on day 15 only. Furthermore, both doses produced a significantly blunted response to the low dose challenge of 8‐OH‐DPAT (0.03 mg kg−1). In addition, 20 mg kg−1 (±)pindolol treated animals also had no response to the higher 0.1 mg kg−1 dose of 8‐OH‐DPAT.
Animals treated for 14 days with a combination of (±)pindolol (10 or 20 mg kg−1) and fluoxetine were not significantly different from vehicle treated animals when challenged with fluoxetine or 8‐OH‐DPAT.
Taken together it would therefore appear that although (±)pindolol alone has sufficient intrinsic activity to produce a desensitization of the 5‐HT1A receptor, when given in combination with fluoxetine it is able to prevent the desensitization induced by not only fluoxetine but also itself. This may suggest that the clinical augmentation of antidepressant action by pindolol, when co‐administered with a SSRI, is via antagonism of the 5‐HT1A receptor.

British Journal of Pharmacology (2000) 130, 797–804; doi:10.1038/sj.bjp.0703378
Manganese increases L‐DOPA auto‐oxidation in the striatum of the freely moving rat: potential implications to L‐DOPA long‐term therapy of Parkinson's disease
Authors: Serra Pier Andrea , Esposito Giovanni , Enrico Paolo , Mura Maria A , Migheli Rossana , Delogu M Rosaria , Miele Maddalena , Desole Maria S , Grella Giuseppe , Miele Egidio 
Published: January 2005

We have previously shown that manganese enhances L‐dihydroxyphenylanine (L‐DOPA) toxicity to PC12 cells in vitro. The supposed mechanism of manganese enhancing effect [an increase in L‐DOPA and dopamine (DA) auto‐oxidation] was studied using microdialysis in the striatum of freely moving rats.
Systemic L‐DOPA [25 mg kg−1 intraperitoneally (i.p.) twice in a 12 h interval] significantly increased baseline dialysate concentrations of L‐DOPA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and uric acid, compared to controls. Conversely, DA and ascorbic acid concentrations were significantly decreased.
A L‐DOPA oxidation product, presumptively identified as L‐DOPA semiquinone, was detected in the dialysate. The L‐DOPA semiquinone was detected also following intrastriatal infusion of L‐DOPA.
In rats given L‐DOPA i.p., intrastriatal infusion of N‐acetylcysteine (NAC) significantly increased DA and L‐DOPA dialysate concentrations and lowered those of L‐DOPA semiquinone; in addition, NAC decreased DOPAC+HVA and uric acid dialysate concentrations.
In rats given L‐DOPA either systemically or intrastriatally, intrastriatal infusion of manganese decreased L‐DOPA dialysate concentrations and greatly increased those of L‐DOPA semiquinone. These changes were inhibited by NAC infusion.
These findings demonstrate that auto‐oxidation of exogenous L‐DOPA occurs in vivo in the rat striatum. The consequent reactive oxygen species generation may account for the decrease in dialysate DA and ascorbic acid concentrations and increase in enzymatic oxidation of xanthine and DA. L‐DOPA auto‐oxidation is inhibited by NAC and enhanced by manganese. These results may be of relevance to the L‐DOPA long‐term therapy of Parkinson's disease.

British Journal of Pharmacology (2000) 130, 937–945; doi:10.1038/sj.bjp.0703379
Taurine blocks ATP‐sensitive potassium channels of rat skeletal muscle fibres interfering with the sulphonylurea receptor
Authors: Tricarico Domenico , Barbieri Mariagrazia , Camerino Diana Conte 
Published: January 2005

Taurine is a sulphonic aminoacid present in high amounts in various tissues including cardiac and skeletal muscles showing different properties such as antioxidative, antimyotonic and anti‐schaemic effects. The cellular mechanism of action of taurine is under investigation and appears to involve the interaction of the sulphonic aminoacid with several ion channels.
Using the patch‐clamp technique we studied the effects of taurine in rat skeletal muscle fibres on ATP‐sensitive K+ channel (KATP) immediately after excision and on channels that underwent rundown.
The cytoplasmic application of 20 mM of taurine reduced the KATP current; this effect was reverted by washout of the drug solution. In this experimental condition the IC50 was 20.1 mM. After rundown, taurine inhibited the KATP current with similar efficacy. Competition experiments showed that taurine shifted the dose‐response inhibition curve of glybenclamide to the left on the log‐dose axis without significantly affecting those of ATP or Ca2+ ion.
Single channel recording revealed that taurine affects the close state of the channel prolonging it and reducing the bursts duration.
Our data indicate that taurine inhibits the muscular KATP channel interfering with the glybenclamide site on the sulphonylurea receptor of the channel or on the site allosterically coupled to it. During ischaemia and hypoxia, the skeletal and heart muscles undergo several changes; for example, the activation of KATP channels and loss of the intracellular taurine content. The depletion of taurine during ischaemia would contribute to the early activation of KATP channels and salvage the intracellular ATP content.

British Journal of Pharmacology (2000) 130, 827–834; doi:10.1038/sj.bjp.0703385