bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of the selective 5‐HT1A agonists alnespirone (S‐20499) and 8‐OH‐DPAT on extracellular 5‐hydroxytryptamine in different regions of rat brain
Authors: Casanovas J. M. , Lésourd M. , Artigas F. 
Published: January 2005

We have examined the effects of the systemic administration of the selective 5‐HT1A agonist alnespirone (S‐20499) on in vivo 5‐hydroxytryptamine (5‐HT) release in the dorsal raphe nucleus, the median raphe nucleus and four forebrain areas innervated differentially by both (dorsal striatum, frontal cortex, ventral hippocampus and dorsal hippocampus).
Alnespirone (0.1–3 mg kg−1, s.c.) dose‐dependently reduced extracellular 5‐HT in the six areas examined. In forebrain, the maximal reductions occurred in striatum and frontal cortex (maximal reduction to 23 and 29% of baseline, respectively). Those in dorsal and ventral hippocampus were more moderate (to ca 65% of baseline). In contrast, the decrease in 5‐HT elicited in the median raphe nucleus was more marked than that in the dorsal raphe nucleus (to ca 30 and 60% of baseline, respectively). The selective 5‐HT1A antagonist WAY‐100635 (0.5 mg kg−1, s.c.) prevented the decrease in 5‐HT induced by alnespirone (0.3 mg kg−1, s.c.) in frontal cortex.
8‐OH‐DPAT (0.025, 0.1 and 0.3 mg kg−1, s.c.) also reduced extracellular 5‐HT in a regionally‐selective manner (e.g., to 32% of baseline in striatum and to 69% in dorsal hippocampus at 0.1 mg kg−1, s.c.). In midbrain, 8‐OH‐DPAT reduced the dialysate 5‐HT slightly more in the median than in the dorsal raphe nucleus at all doses examined.
Doses of both compounds close to their respective ED50 values (0.3 mg kg−1 alnespirone, 0.025 mg kg−1 8‐OH‐DPAT) reduced 5‐HT to a comparable extent in all regions examined. However, the reductions attained at higher doses were more pronounced for 8‐OH‐DPAT.
These data show that the reduction of 5‐HT release elicited by alnespirone and 8‐OH‐DPAT is more important in forebrain areas innervated by 5‐hydroxytryptaminergic neurones of the dorsal raphe nucleus. This regional selectivity seems unlikely to be accounted for by differences in the sensitivity of 5‐HT1A autoreceptors controlling 5‐HT release, given the dissimilar effects of these two 5‐HT1A agonists in regions rich in cell bodies and nerve terminals. This suggests the presence of complex mechanisms of control of 5‐HT release by 5‐HT1A receptors.

British Journal of Pharmacology (1997) 122, 733–741; doi:10.1038/sj.bjp.0701420
Local neurogenic regulation of rat hindlimb circulation: CO2‐induced release of calcitonin gene‐related peptide from sensory nerves
Authors: Yamada Masami , Ishikawa Tomohisa , Yamanaka Akihiro , Fujimori Akira , Goto Katsutoshi 
Published: January 2005

The mechanism of release of calcitonin gene‐related peptide (CGRP) from sensory nerves in response to skeletal muscle contraction was investigated in the rat hindlimb in vivo and in vitro.
In the anaesthetized rat, sciatic nerve stimulation at 10 Hz for 1 min caused a hyperaemic response in the hindlimb. During the response, partial pressure of CO2 in the venous blood effluent from the hindlimb significantly increased from 43±3 to 73±8 mmHg, whereas a small decrease in pH and no appreciable change in partial pressure of O2 were observed.
An intra‐arterial bolus injection of NaHCO3 (titrated to pH 7.2 with HCl), which elevated PCO2 of the venous blood, caused a sustained increase in regional blood flow of the iliac artery. Capsaicin (0.33 μmol kg−1, i.a.) and a specific calcitonin gene‐related peptide (CGRP) receptor antagonist, CGRP(8–37), (100 nmol kg−1 min−1, i.v.) significantly suppressed the hyperaemic response to NaHCO3. Neither NDΩ‐nitro‐L‐arginine methyl ester (1 μmol kg−1 min−1, i.v.) nor indomethacin (5 mg kg−1, i.v.) affected the response.
The serum level of CGRP‐like immunoreactivity in the venous blood was significantly increased by a bolus injection of NaHCO3 (pH=7.2) from 50±4 to 196±16 fmol ml−1.
In the isolated hindlimb perfused with Krebs‐Ringer solution, a bolus injection of NaHCO3 (pH=7.2) caused a decrease in perfusion pressure which was composed of two responses, i.e., an initial transient response and a slowly‐developing long‐lasting one. CGRP(8–37) significantly inhibited the latter response by 73%.
These results suggest that CO2 liberated from exercising skeletal muscle activates capsaicin‐sensitive perivascular sensory nerves locally, which results in the release of CGRP from their peripheral endings, and then the released peptide causes local vasodilatation.

British Journal of Pharmacology (1997) 122, 710–714; doi:10.1038/sj.bjp.0701423
The effect of glibenclamide on the production of interstitial adenosine by inhibiting ecto‐5′‐nucleotidase in rat hearts
Authors: Sato Toshiaki , Obata Toshio , Yamanaka Yasumitsu , Arita Makoto 
Published: January 2005

Adenosine exerts cardioprotective effects on the ischaemic myocardium. The production of adenosine in the ischaemic myocardium is attributed primarily to the enzymatic dephosphorylation of adenosine 5′‐monophosphate (AMP) by 5′‐nucleotidase. We determined the activity of 5′‐nucleotidase in rat hearts. The objective of the study was to determine the effects of ATP‐sensitive K+ (KATP) channel antagonists (glibenclamide and 5‐hydroxydecanoate) on the production of adenosine, by use of a flexibly mounted microdialysis technique.
Rats were anaesthetized and the microdialysis probe was implanted in the left ventricular myocardium, followed by perfusion with Tyrode solution. The baseline level of dialysate adenosine was 0.51±0.09 μM (n=16). Introduction of AMP (100 μM) through the probe increased the dialysate adenosine markedly to 9.79±0.43 μM (n=12, P<0.001 vs baseline), and this increase was inhibited by the ecto‐5′‐nucleotidase inhibitor, α,β‐methyleneadenosine 5′‐diphosphate (100 μM), to 0.76±0.12 μM (n=8). Thus, the dialysate adenosine noted during the perfusion of AMP originated from dephosphorylation of AMP by ecto‐5′‐nucleotidase, and the dialysate level of adenosine attained reflects the ecto‐5′‐nucleotidase activity in the tissue in situ.
Glibenclamide (0.1–100 μM) decreased the adenosine concentration measured during the perfusion of AMP (100 μM) in a concentration‐dependent manner (IC50=10.5 μM). In contrast, 5‐hydroxydecanoate (10–100 μM) did not affect the concentrations of dialysate adenosine, measured in the presence of AMP (100 μM). These results suggest that glibenclamide inhibits the activity of endogenous ecto‐5′‐nucleotidase and decreases the concentration of adenosine in the interstitial space of rat ventricular muscles in situ.

British Journal of Pharmacology (1997) 122, 611–618; doi:10.1038/sj.bjp.0701424
Calcium‐independent NO‐synthase activity and nitrites/nitrates production in transient focal cerebral ischaemia in mice
Authors: Grandati M. , Verrecchia C. , Revaud M. L. , Allix M. , Boulu R. G. , Plotkine M. 
Published: January 2005

The temporal changes in constitutive NO‐synthase (cNOS) and in calcium‐independent NO‐synthase activities were studied in mice subjected to 2 h of transient focal cerebral ischaemia. The changes in brain nitrites/nitrates (NOx) content were also studied.
NOS activities were measured by the conversion of L‐[14C]‐arginine to L‐[14C]‐citrulline. Brain NOx contents were investigated by the Griess colourimetric method.
cNOS activity in the infarcted cortical area was significantly reduced after 6 h of reperfusion and this activity remained attenuated for up to 10 days after ischaemia. A calcium‐independent NOS activity began to increase 48 h after reperfusion, reached a maximum at 7 days and returned to baseline at 10 days.
There was a significant increase of brain NOx content beginning after 3 days of reperfusion. This increase was maximal at 7 days and returned to baseline at 10 days.
Thus, ischaemia followed by recirculation leads to a rapid, prolonged drop in cNOS activity in the infarcted cortex. There is also a substantial appearance of calcium‐independent NOS activity in the later phase of transient ischaemia, leading to an important increase of NOx production.

British Journal of Pharmacology (1997) 122, 625–630; doi:10.1038/sj.bjp.0701427
The multi‐drug resistance reversal agent SR33557 and modulation of vinca alkaloid binding to P‐glycoprotein by an allosteric interaction
Authors: Martin Catherine , Berridge Georgina , Higgins Christopher F. , Callaghan Richard 
Published: January 2005

The interaction of the indolizin sulfone SR33557 with the multidrug resistance P‐glycoprotein (P‐gp), was used to explore the nature of drug binding site(s) on this transporter. The steady‐state accumulation of [3H]‐vinblastine in P‐gp expressing CHrB30 cells was increased by SR33557 with greater potency than verapamil. Furthermore, SR33557 potentiated the affinity of verapamil to modulate vinblastine transport when added simultaneously.
Verapamil elicited a 1.5 to 2.5 fold stimulation of basal ATPase activity in CHrB30 membranes, whereas SR33557 and vinblastine inhibited activity, but only at relatively high concentrations. However, SR33557 and vinblastine decreased the Vmax but not the Km for verapamil stimulation of ATPase activity. This is indicative of a non‐competitive interaction, most likely at distinct sites.
The specific [3H]‐vinblastine binding to P‐gp in CHrB30 cell membranes was displaced by SR33557 with an IC50 of 8.3±4.5 nM. Moreover, SR33557 caused a 3 fold increase in the dissociation rate of vinblastine binding to P‐gp indicating a negative allosteric effect on the vinca alkaloid acceptor site.
These results demonstrate that SR33557 interacts with a site on P‐gp which is distinct from, but allosterically linked to the vinca alkaloid site. The apparent broad substrate specificity displayed by P‐gp may be explained by a multiple drug binding site model.

British Journal of Pharmacology (1997) 122, 765–771; doi:10.1038/sj.bjp.0701429
Effects of dopamine and selective dopamine agonists upon platelet accumulation in the cerebral and pulmonary vasculature of the rabbit
Authors: Emerson Michael , Paul William , Ferlenga Pierpaolo , Semeraro Claudio , Page Clive 
Published: January 2005

A selection of novel compounds were shown to exhibit dopaminergic activity in vitro.
111Indium‐labelled platelets were continuously monitored in the cerebral and pulmonary vasculature of anaesthetized rabbits. The effects of dopamine and selective dopamine receptor agonists on ADP and thrombin induced platelet accumulation were recorded.
Pretreatment with dopamine (2 mg kg−1 min−1, i.v.) significantly reduced ADP (20 μg kg−1, i.v.) induced platelet accumulation in the pulmonary vasculature whereas lower doses had no effect.
Dopamine (100 μg kg−1 min−1 intra‐carotid, i.c.) potentiated thrombin (90 u kg−1, i.c.) induced platelet accumulation in the cerebral vasculature whereas higher doses (1–2 mg kg−1 min−1) inhibited accumulation.
The selective dopamine receptor agonists tested did not significantly inhibit platelet accumulation induced by ADP or thrombin. Two of these selective agonists, at doses higher than the intended therapeutic doses, induced thrombocytopaenia and an associated increase in platelet accumulation in the lung in response to thrombin.
These results extend previous in vitro studies regarding the dual actions of dopamine upon platelets and show for the first time the effects of selective dopamine receptor agonists upon platelet aggregation in vivo.

British Journal of Pharmacology (1997) 122, 682–686; doi:10.1038/sj.bjp.0701432
Purification of 5‐hydroxytryptamine3 receptors from porcine brain
Authors: Fletcher Stephanie , Barnes Nicholas M. 
Published: January 2005

We demonstrate, for the first time, the purification of the 5‐hydroxytryptamine3 (5‐HT3) receptor from a native tissue source, pig cerebral cortex.
From a range of detergents, the non‐ionic detergent Triton X‐100 was demonstrated to exhibit the least inhibition of [3H]‐(S)‐zacopride binding to membrane bound 5‐HT3 receptors from pig cerebral cortex at concentrations above its critical micellular concentration (CMC). This detergent was therefore selected to solubilize 5‐HT3 binding sites from homogenates of pig cerebral cortex. Maximum yield (43.8±3.7%, mean±s.e.mean, n=13) was obtained with Triton X‐100 at 0.4% (22.1×CMC). Radioligand binding studies with [3H]‐(S)‐zacopride indicated that the solubilized 5‐HT3 receptor displayed near identical pharmacology to the membrane bound receptor (the correlation coefficient (r) between the pKi values of structurally unrelated compounds competing for [3H]‐(S)‐zacopride binding in the membrane bound and solubilized 5‐HT3 receptor preparations was 0.99, Bmax=20.7±4.2 fmol mg−1 protein, Kd=1.57±0.53 nM, mean±s.e.mean, n=6).
Solubilized (0.4% Triton X‐100) 5‐HT3 receptors were affinity purified using Affi‐Gel 15 coupled to the high affinity 5‐HT3 receptor ligand GR119566X. Radioligand binding studies indicated that the pharmacological profile of the affinity purified 5‐HT3 receptor, assessed using ligands with a range of affinities spanning 3 orders of magnitude, was similar to that in both crude homogenates (r=0.85) and solubilized 5‐HT3 receptor sites (r=0.85) from pig brain. The specific activity for the purified 5‐HT3 receptor overlapped the theoretical specific activity of the receptor (Bmax=3.27±1.41 and 5.35±2.33 nmol mg−1 protein, assessed by saturation and competition studies respectively, mean±s.e.mean, n=3–4), which indicated a 60 000–100 000 fold purification of the membrane bound receptor.
Under non‐reducing conditions, samples of the affinity purified protein failed to enter a 10% separating gel in SDS–PAGE analysis, indicating a molecular mass for the receptor complex of >200 kDa. Further investigation of the non‐reduced purified protein with a 7.5% separating gel gave a mass for the complex of ∼279 kDa. Under reducing conditions, SDS–PAGE analysis of the affinity purified 5‐HT3 receptor resulted in 3–6 silver stained bands at apparent molecular masses of 37, 44–50, 52, 57–61, 63 and 65–71 kDa (n=12). Unlike protein bands at 45, 50, 60 and 66 kDa, the bands corresponding to proteins of 52, 57, 63 and 71 kDa consistently gave no reaction with an antiserum specific for the cloned A subunit of the 5‐HT3 receptor in both a modified dot blot procedure and a Western blot procedure (n=2–5).
We conclude that we have purified the 5‐HT3 receptor from pig brain to homogeneity and suggest this may contain non‐5‐HT3‐A receptor subunit(s).

British Journal of Pharmacology (1997) 122, 655–662; doi:10.1038/sj.bjp.0701439
Trifluoperazine and dibucaine‐induced inhibition of glutamate‐induced mitochondrial depolarization in rat cultured forebrain neurones
Authors: Hoyt Kari R. , Sharma Terre A. , Reynolds Ian J. 
Published: January 2005

Glutamate receptor activation has been previously shown to result in mitochondrial depolarization and activation of the mitochondrial permeability transition pore in cultured neurones. In this study, we characterized the effects of two putative permeability transition inhibitors, namely trifluoperazine and dibucaine, on mitochondrial depolarization in rat intact, cultured forebrain neurones.
Permeability transition was monitored by following mitochondrial depolarization in neurones loaded with the mitochondrial membrane potential‐sensitive fluorescent indicator, JC‐1. Trifluoperazine (10–20 μM) and dibucaine (50–100 μM) inhibited or delayed the onset of glutamate‐induced permeability transition.
We also investigated the effects of trifluoperazine and dibucaine on neuronal recovery from glutamate‐induced Ca2+ loads. Trifluoperazine affected Ca2+ recovery in a manner similar to the mitochondrial Na+/Ca2+ exchange inhibitor, CGP‐37157, while dibucaine had no apparent effect on Ca2+ recovery. Therefore, inhibition of permeability transition does not appear to be involved in Ca2+ recovery from glutamate‐induced Ca2+ loads.
Trifluoperazine and dibucaine did not inhibit [3H]‐dizocilpine binding at the concentrations that prevented mitochondrial depolarization.
These studies suggest that trifluoperazine and dibucaine inhibit permeability transition in intact neurones. Trifluoperazine also appears to inhibit mitochondrial Na+/Ca2+ exchange. These drugs should prove to be valuable tools in the further study of the role of mitochondrial permeability transition in glutamate‐induced neuronal death.

British Journal of Pharmacology (1997) 122, 803–808; doi:10.1038/sj.bjp.0701442
Somatostatin sst5 inhibition of receptor mediated regeneration of rat aortic vascular smooth muscle cells
Authors: Lauder H. , Sellers L. A. , Fan T. ‐P D. , Feniuk W. , Humphrey P. P. A. 
Published: January 2005

The aim of the present study was to determine the effect of somatostatin (SRIF) on mitogen‐induced regeneration of rat aortic vascular smooth muscle cells (VSMC) and for comparison Chinese hamster ovary (CHO)‐K1 cells expressing human recombinant sst5 receptors (CHOsst5), following partial denudation of a confluent cell monolayer. Regeneration was assessed by measuring areas of recovery into the denuded area and by counting total cell numbers.
In VSMC, SRIF (0.1 nM–1 μM) had no effect on the basal levels of regeneration but caused a concentration‐dependent inhibition (pIC50 8.0–8.6) of the stimulated regeneration induced by sub‐maximal concentrations of basic fibroblast growth factor (bFGF, 10 ng ml−1), platelet‐derived growth factor‐BB (PDGF, 5 ng ml−1) or endothelin‐1 (ET‐1, 100 nM). SRIF (pIC50 8.8) also inhibited bFGF‐induced regeneration of CHOsst5 cells.
In VSMC, the inhibitory action of SRIF on the regeneration induced by bFGF (10 ng ml−1) was due to an anti‐proliferative effect, rather than an effect on cell migration, as SRIF (0.1 nM–1 μM) abolished bFGF‐induced increases in total cell numbers. The bFGF‐induced increase in cell numbers was also abolished by actinomycin D (0.1 μg ml−1).
The sst5 receptor‐selective agonist, L‐362,855 (pIC50 10.5), was about 100 times more potent than SRIF at inhibiting bFGF‐induced regeneration of both VSMC and CHOsst5 cells whilst the sst2 receptor‐selective agonist, BIM‐23027 (pIC50 6.8), was approximately 20 times weaker than SRIF.
The sst5 receptor antagonist, BIM‐23056 (100 nM), antagonized SRIF‐induced inhibition of bFGF‐induced regeneration in both VSMC and CHOsst5 cells (estimated pKB values 8.8 and 8.3, respectively).
SRIF‐induced inhibition of bFGF‐induced regeneration of VSMC and CHOsst5 cells was abolished by pretreating cells with pertussis toxin (100 ng ml−1) for 20 h.
These findings suggest that SRIF‐induced inhibition of the proliferation of rat aortic VSMC is mediated via activation of receptors which are similar to human sst5 receptors. Furthermore this inhibitory effect is transduced via pertussis toxin‐sensitive Gi/Go proteins.

British Journal of Pharmacology (1997) 122, 663–670; doi:10.1038/sj.bjp.0701443
Vascular actions of octreotide in the portal hypertensive rat
Authors: Aboud R. W. , Connolly C. , McCormick P. A. , Docherty J. R. 
Published: January 2005

We have investigated the actions of the somatostatin analogue octreotide in the portal hypertensive Wistar rat in vivo and in rat small mesenteric artery and aorta in vitro.
In small mesenteric artery, octreotide (0.1–0.3 μM) failed to produce any direct contraction, nor did it affect contractions to noradrenaline (NA, 10 μM) or endothelium‐dependent relaxations to acetylcholine.
In rat aorta, octreotide (0.3 μM) and somatostatin (1 μM) failed to affect contractions to NA (1 μM), or concentration‐contractile response curves to NA.
In rat vas deferens, octreotide and somatostatin significantly reduced contractile responses to electrical stimulation with pD2 values (−log IC50) of 8.19±0.10 (n=4) and 8.16±0.26 (n=4), respectively. Hence, the lack of effect of these agents in aorta or mesenteric artery was not due to lack of efficacy or inappropriate choice of concentration.
In the anaesthetized portal hypertensive rat, intravenous injection of octreotide (1–100 μg kg−1) did not significantly affect systemic blood pressure, nor did it affect mesenteric vascular conductance as measured by laser doppler flow probes. However, octreotide (100 μg kg−1) significantly reduced vascular conductance to 74.2±7.7% of control (n=6) in porto‐systemic shunt vessels as measured by laser doppler flow probes.
Phenylephrine (1 μg kg−1) significantly raised blood pressure and significantly decreased vascular conductance in both mesenteric (66.6±3.7% of control) and porto‐systemic shunt vessels (58.7±10.0% of control).
It was concluded that octreotide has selective effects on porto‐systemic shunt vessles in vivo in the portal hypertensive rat.

British Journal of Pharmacology (1997) 122, 698–702; doi:10.1038/sj.bjp.0701444
Antinociceptive activity of CP‐101,606, an NMDA receptor NR2B subunit antagonist
Authors: Taniguchi Kana , Shinjo Katsuhiro , Mizutani Mayumi , Shimada Kaoru , Ishikawa Toshihisa , Menniti Frank S. , Nagahisa Atsushi 
Published: January 2005

The analgesic activity of CP‐101,606, an NR2B subunit‐selective N‐methyl‐D‐aspartate (NMDA) receptor antagonist, was examined in carrageenan‐induced hyperalgesia, capsaicin‐ and 4β‐phorbol‐12‐myristate‐13‐acetate (PMA)‐induced nociceptive tests in the rat.
CP‐101,606 30 mg kg−1, s.c., at 0.5 and 2.5 h after carrageenan challenge suppressed mechanical hyperalgesia without any apparant alternations in motor coordination or behaviour in the rat.
CP‐101,606 also inhibited capsaicin‐ and PMA‐induced nociceptive responses (licking behaviour) with ED50 values of 7.5 and 5.7 mg kg−1, s.c., respectively.
These results suggest that inhibition of the NR2B subunit of the NMDA receptor is effective in vivo at modulating nociception and hyperalgesia responses without causing the behavioural side effects often observed with currently available NMDA receptor antagonists.

British Journal of Pharmacology (1997) 122, 809–812; doi:10.1038/sj.bjp.0701445
Positive inotropic effect of exogenous and endogenous NO in hypertrophic rat hearts
Authors: Kojda Georg , Kottenberg Karin , Stasch Johannes‐Peter , Schrör Karsten , Noack Eike 
Published: January 2005

Recent evidence suggests that nitric oxide (NO) modulates the contractile force of isolated cardiomyocytes in a biphasic manner. We sought to examine whether myocardial hypertrophy induced by long‐term hypertension changes the effects of NO on myocardial contractility.
We used constant flow perfused non‐paced Langendorff preparations of hearts of 3 months old Wistar rats (WIS, n=23) and of stroke‐prone spontaneously hypertensive rats (SHR) at the age of 10 months (SHR10, n=16) and 15 months (SHR15, n=8). Changes of left ventricular peak pressure (LVP), +dP/dtmax, −dP/dtmax, coronary perfusion pressure (CPP) and heart rate (HR) were recorded after infusion of noradrenaline (NA, 0.1 μmol  l−1), glyceryl trinitrate (GTN, 1–100 μmol 1−1), S‐nitroso‐N‐acetyl‐D, L‐penicillamine (SNAP, 1–10 μmol 1−1) and Nω‐nitro‐L‐arginine (L‐NOARG, 0.1–1 mmol 1−1).
Long‐term hypertension induced myocardial hypertrophy and an abnormal response to NA. The relative heart weight (in mg kg−1) increased from 2.95±0.04 (WIS) to 6.67±0.34 (SHR15), while the increase in +dP/dtmax induced by NA was absent in SHR15. Hearts of SHR10 showed an intermediate response.
Both SNAP and GTN significantly increased LVP, +dP/dtmax and −dP/dtmax in hearts of WIS and of SHR. In WIS but not in SHR10, SNAP also increased HR. In SHR10 the lowest concentration of SNAP (1 μmol 1−1) showed no effect on contractility but a significantly diminished reduction of CPP suggesting inactivation of extracellularly released NO in the coronary circulation of SHR.
L‐NOARG significantly reduced contractility in hearts of WIS and of SHR to a similar extent. At a concentration of 1 mmol 1−1 L‐NOARG also reduced HR.
These results suggests that positive inotropic effects of exogenous and endogenous NO are not changed in hypertension induced myocardial hypertrophy.

British Journal of Pharmacology (1997) 122, 813–820; doi:10.1038/sj.bjp.0701446