bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose‐dependent effects of chronic ethanol on mouse adipose tissue lipase activity and cyclic AMP accumulation
Authors: Shih Mei‐Fen , Taberner Peter V. 
Published: August 2006

The effects of two chronic ethanol treatment schedules, which produce different plasma ethanol concentrations, on the specific activities of adipose tissue lipoprotein lipase (LPL) and hormone‐sensitive lipase (HSL) have been investigated in brown and white fat.
Mice provided with 20% ethanol solution as sole drinking fluid for 28 days consumed between 13 and 15 g ethanol kg−1 body weight day−1 over days 22–28. The mean plasma ethanol concentration was 4.94± 1.4 mM (n = 8) at 09 h 00 min on day 28 when the lipase assays were performed. Mice given ethanol in a liquid diet for 7 days consumed between 15 and 18 g ethanol day−1 over days 3–7. The mean plasma ethanol concentration was 15.9 ± 4.7 mM (n = 8) at 09 h 00 min on day 7. These concentrations of ethanol had no effect on the activity of either LPL or HSL in vitro.
LPL activity in white and brown fat (expressed as nmol fatty acids released h−1. mg−1 acetone powder) was unaltered 60 min following an acute injection of ethanol (2.5 g kg−1, i.p.) which produced a mean blood ethanol level of 37.5 ± 6.7 mM. HSL activity in white fat (expressed as nmol fatty acid released h−1 mg−1 protein) was also unaffected by this acute dose of ethanol, but the activity in brown fat was significantly reduced: 3.07 ± 0.30 (n = 8) after ethanol compared to 4.36 + 0.25 (n = 12) in controls (P<0.01).
LPL activity in white fat was little altered by either of the chronic ethanol treatment schedules whilst LPL activity in the brown fat from the same animals was significantly increased compared to the respective control values: 0.27±0.03 (ethanol drinking), control: 0.16±0.01; 0.79±0.14 (ethanol liquid diet), control: 0.39 ±0.05.
HSL activity in white fat was significantly increased by the chronic drinking treatment (7.7 ± 0.5; control: 3.78 ± 0.17, n = 8) at the same time that the activity in brown fat was reduced (3.76 ± 0.2; control: 4.74 ± 0.16). The ethanol liquid diet also reduced HSL activity in brown fat but had negligible effect in white fat.
The effects of the two chronic ethanol treatments on adenosine 3′: 5′‐cyclic monophosphate (cyclic AMP) accumulation in brown and white fat were very similar, both qualitatively and quantitatively, to the effects on HSL.
It has been shown that brown and white adipose tissues respond differently to the presence of chronic ethanol and that the response is dependent both upon the concentration of ethanol and the nature of the diet with which the ethanol is administered. The effects of ethanol on adipose tissue HSL activity appear to be mediated via changes in the tissue cyclic AMP level and, in this respect, brown fat is more sensitive to ethanol than white fat.
Stimulation by extracellular ATP and UTP of the stress‐activated protein kinase cascade in rat renal mesangial cells
Authors: Huwiler Andrea , Van Rossum Gerda , Wartmann Markus , Pfeilschifter Josef 
Published: August 2006

Extracellular adenosine 5′‐triphosphate (ATP) and uridine 5′‐triphosphate (UTP) have been shown to activate a nucleotide receptor (P2U receptor) in rat mesangial cells that mediates phosphoinositide and phosphatidylcholine hydrolysis by phospholipases C and D, respectively. This is followed by an increased activity of the mitogen‐activated protein kinase cascade and cell proliferation. Here we show that ATP and UTP potently stimulate the stress‐activated protein kinase pathway and phosphorylation of the transcription factor c‐Jun.
Both nucleotides stimulated a rapid (within 5 min) and concentration‐dependent activation of stress‐activated protein kinases as measured by the phosphorylation of c‐Jun in a solid phase kinase assay.
When added at 100 μm the rank order of potency of a series of nucleotide analogues for stimulation of c‐Jun phosphorylation was UTP>ATP=UDP=ATPγS>2‐methylthio‐ATP>βγ‐imido‐ATP= ADP>AMP=UMP=adenosine=uridine. Activation of stress‐activated protein kinase activity by ATP and UTP was dose‐dependently attenuated by suramin.
Down‐regulation of protein kinase C‐α, ‐δ and ‐ε isoenzymes by 24 h treatment of the cells with 12‐O‐tetradecanoylphorbol 13‐acetate did not inhibit ATP‐ and UTP‐induced activation of c‐Jun phosphorylation. Furthermore, the specific protein kinase C inhibitors, CGP 41251 and Ro 31–8220, did not inhibit nucleotide‐stimulated c‐Jun phosphorylation, suggesting that protein kinase C is not involved in ATP‐ and UTP‐triggered stress‐activated protein kinase activation.
Pretreatment of the cells with pertussis toxin or the tyrosine kinase inhibitor, genistein, strongly attenuated ATP‐ and UTP‐induced c‐Jun phosphorylation. Furthermore, N‐acetyl‐cysteine completely blocked the activation of stress‐activated protein kinase in response to extracellular nucleotide stimulation.
In summary, these results suggest that ATP and UTP trigger the activation of the stress‐activated protein kinase module in mesangial cells by a pathway independent of protein kinase C but requiring a pertussis toxin – sensitive G‐protein and tyrosine kinase activation.

British Journal of Pharmacology (1997) 120, 807–812; doi:10.1038/sj.bjp.0700979
The duration of action of non‐β2‐adrenoceptor mediated responses to salmeterol
Authors: Nials A T , Coleman R A , Johnson M , Vardey C J 
Published: August 2006

To investigate further the mechanism of the long duration of action of the selective β2‐adrenoceptor agonist, salmeterol, we have determined the duration of action of some responses to salmeterol which are not mediated throughβ2‐adrenoceptors.
In the presence of propranolol (1 μm), salmeterol (1–30 μm) caused concentration‐related relaxation of superfused, pre‐contracted strips of guinea‐pig gastric fundus. On washing the tissues, these relaxant responses were rapidly lost, the time to 50% recovery being approximately 30 min.
In human neutrophils, salmeterol (1–100 μm) caused concentration‐related inhibition of FMLP‐induced O2− release. Propranolol (1 μm) had little or no effect on the inhibitory activity of salmeterol. Washing the cells twice over a 40 min period caused a marked reduction of the inhibitory activity of salmeterol.
In guinea‐pig superfused trachea, in the absence of propranolol, infusions of (RS)‐salmeterol (10–30 nm) and the less potent (S)‐enantiomer of salmeterol (300–3000 nm) inhibited electrically‐induced contractile responses. When the infusion was stopped, there was no recovery from the inhibitory responses within 200 min. In the presence of propranolol (1 μm), infusions of (RS)‐salmeterol (10 μm) and (S)‐salmeterol (10–100 μm) also inhibited the contractile responses, but, in contrast, on stopping the infusions differences were observed in recovery times. Thus no appreciable recovery was observed from the responses to (RS)‐salmeterol, whereas a rapid loss of inhibition was observed on stopping the infusion of (S)‐salmeterol, the time to 50% recovery being 30–35 min.
These relatively short‐lasting effects of salmeterol which are not mediated through β2‐adrenoceptors, contrast with the persistence of the responses which are mediated through β2‐adrenoceptors seen in a variety of tissues, but are similar to the rate of dissociation of salmeterol observed from artificial membranes. These observations suggest that the sustained agonist activity of salmeterol is peculiar to responses mediated by β2‐adrenoceptors.

British Journal of Pharmacology (1997) 120, 961–967; doi:10.1038/sj.bjp.0700986
The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes
Authors: Suessbrich H , Schönherr R , Heinemann S H , Attali B , Lang F , Busch A E 
Published: August 2006

The antipsychotic drug haloperidol can induce a marked QT prolongation and polymorphic ventricular arrhythmias. In this study, we expressed several cloned cardiac K+ channels, including the human ether‐a‐go‐go related gene (HERG) channels, in Xenopus oocytes and tested them for their haloperidol sensitivity.
Haloperidol had only little effects on the delayed rectifier channels Kv1.1, Kv1.2, Kv1.5 and IsK, the A‐type channel Kv1.4 and the inward rectifier channel Kir2.1 (inhibition <6% at 3 μm haloperidol).
In contrast, haloperidol blocked HERG channels potently with an IC50 value of approximately 1 μm. Reduced haloperidol, the primary metabolite of haloperidol, produced a block with an IC50 value of 2.6 μm.
Haloperidol block was use‐ and voltage‐dependent, suggesting that it binds preferentially to either open or inactivated HERG channels. As haloperidol increased the degree and rate of HERG inactivation, binding to inactivated HERG channels is suggested.
The channel mutant HERG S631A has been shown to exhibit greatly reduced C‐type inactivation which occurs only at potentials greater than 0 mV. Haloperidol block of HERG S631A at 0 mV was four fold weaker than for HERG wild‐type channels. Haloperidol affinity for HERG S631A was increased four fold at +40 mV compared to 0 mV.
In summary, the data suggest that HERG channel blockade is involved in the arrhythmogenic side effects of haloperidol. The mechanism of haloperidol block involves binding to inactivated HERG channels.

British Journal of Pharmacology (1997) 120, 968–974; doi:10.1038/sj.bjp.0700989
The induction of nitric oxide‐mediated relaxation of human isolated pulmonary arteries by PACAP
Authors: Cardell Lars Olaf , Hjert Ola , Uddman Rolf 
Published: August 2006

The effects of pituitary adenylate cyclase‐activating peptide (PACAP) and vasoactive intestinal peptide (VIP) were analysed in human isolated circular segments of pulmonary arteries. Guinea‐pig pulmonary arteries were used for comparison. The responses obtained were analysed in relation to the vascular endothelium and the nitric oxide (NO) synthase inhibitor NG‐monomethyl l‐arginine (l‐NMMA).
PACAP and VIP induced concentration‐dependent relaxations of precontracted pulmonary arteries. The maximal dilator response (Imax,%) and the potency (pEC50 value) were the same for both peptides, and there were no differences in the effects obtained on human and guinea‐pig segments. PACAP and VIP were both more potent that acetylcholine (ACh).
Removal of the vascular endothelium abolished the PACAP induced dilator response in pulmonary arteries from both species. The VIP induced dilatation was unaffected, whereas the response to ACh was abolished. l‐NMMA given before PACAP inhibited the dilatation. Furthermore, l‐NMMA also reversed the dilatation already induced by PACAP and excess concentrations of l‐arginine restored the dilator response of the l‐NMMA treated arteries.
PACAP is a potent dilator of human pulmonary arteries. Although the dilator effect seems to be similar in amplitude to the one induced by VIP, the present results suggest differences in the underlying mechanisms of action (endothelium‐dependency) between the two peptides.

British Journal of Pharmacology (1997) 120, 1096–1100; doi:10.1038/sj.bjp.0700992
Differential block of nicotinic synapses on B versus C neurones in sympathetic ganglia of frog by α‐conotoxins MII and ImI
Authors: Tavazoie Sohail F , Tavazoie Masoud F , McIntosh J Michael , Olivera Baldomero M , Yoshikami Doju 
Published: August 2006

The effects of two new acetylcholine receptor antagonists, α‐conotoxin MII and α‐conotoxin ImI, on nicotinic synaptic transmission in the 10th paravertebral sympathetic ganglion of the leopard frog (Rana pipiens) were examined. The preganglionic nerve was electrically stimulated (at low frequency, 1 min−1, to avoid use‐dependent changes) while compound action potentials of B and C neurones were monitored from the postganglionic nerve.
α‐Conotoxins MII and ImI, at low micromolar concentrations, reversibly blocked both B and C waves. α‐Conotoxin MII blocked the C wave more effectively than the B wave, whereas the potency of α‐conotoxin ImI was opposite that of MII. The observation that nicotinic antagonists can differentially block synaptic transmission of B versus C neurones with opposite selectivities strongly suggests that these neurones possess distinct nicotinic receptors.
In addition to fast and slow B waves described by others, C waves with two temporally distinguishable components were present in our recordings. Each α‐conotoxin affected fast and slow B waves similarly. Likewise, toxins did not discriminate between the two components of C waves. This suggests that all neurones within each major class (B or C) may have the same nicotinic receptors.
Synthetic forms of α‐conotoxins MII and ImI were used in the present study. Their ease of synthesis and their specificities should make these toxins useful probes to investigate the various subtypes of neuronal nicotinic acetylcholine receptors.

British Journal of Pharmacology (1997) 120, 995–1000; doi:10.1038/sj.bjp.0700993
Mechanism of nitric oxide‐induced contraction in the rat isolated small intestine
Authors: Lefebvre R A , Barthó L 
Published: August 2006

The contractile response to nitric oxide (NO) in ral ileal myenteric plexus‐longitudinal muscle strips was pharmacologically analysed.
NO (10−7 m) induced only contraction while 10−6 m NO induced contraction followed by relaxation. Methylene blue (up to 10−4 m) did not affect the NO‐induced contractions but significantly reduced the relaxation evoked by 10−6 m NO. Administration of 8‐bromo‐cyclic GMP (10−6–10−4 m) only induced relaxation.
Sodium nitroprusside (SNP; 10−7–10−5 m) induced concentration‐dependent contractions per se; the contractile response to NO, administered within 10 min after SNP, was concentration‐dependently reduced. The guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) content of the tissues was not increased during contractions with 10−8 m NO and 10−6 m SNP; it was increased by a factor of 2 during contraction with 10−7 m NO, and by a factor of 12 during relaxation with 3×10−6 m NO.
The NO‐induced contractions were not affected by ryanodine (3×10−5 m) but were concentration‐dependently reduced by nifedipine (10−8–10−7 m) and apamin (3×10−9–3×10−8 m).
These results suggest that cyclic GMP is not involved in the NO‐induced contraction in the rat small intestine. The NO‐induced contraction is related to extracellular Ca2+ influx through L‐type Ca2+ channels, that might be activated in response to the closure of Ca2+‐dependent K+ channels.

British Journal of Pharmacology (1997) 120, 975–981; doi:10.1038/sj.bjp.0700996
Attenuation of morphine withdrawal symptoms by subtype‐selective metabotropic glutamate receptor antagonists
Authors: Fundytus Marian E , Ritchie Jennifer , Coderre Terence J 
Published: August 2006

We have previously shown that chronic antagonism of group I metabotropic glutamate receptors (mGluRs), in the brain, attenuates the precipitated morphine withdrawal syndrome in rats. In the present investigation we assessed the effects of chronic antagonism of group II and III mGluRs on the severity of withdrawal symptoms in rats treated chronically with subcutaneous (s.c.) morphine.
Concurrently with s.c. morphine we infused intracerebroventricularly (i.c.v.) one of a series of phenylglycine derivatives selective for specific mGluR subtypes. Group II mGluRs (mGluR2,3), which are negatively coupled to adenosine 3′: 5′‐cyclic monophosphate (cyclic AMP) production, were selectively antagonized with 2s, 1′s, 2′s‐2‐methyl‐2‐(2′‐carboxycyclopropyl) glycine (MCCG). Group III mGluRs (mGluR4,6,7 and 8), which are also negatively linked to cyclic AMP production, were selectively antagonized with α‐methyl‐l‐amino‐4‐phosphonobutanoate (MAP4). The effects of MCCG and MAP4 were compared with α‐methyl‐4‐carboxyphenylglycine (MCPG), which non‐selectively antagonizes group II mGluRs, as well as group I mGluRs (mGluR1,5) which are positively coupled to phosphatidylinositol (PI) hydrolysis.
Chronic i.c.v. administration of both MCCG and MAP4 significantly decreased the time spent in withdrawal, MCPG and MCCG reduced the frequency of jumps and wet dog shakes and attenuated the severity of agitation.
Acute i.c.v. injection of mGluR antagonists just before the precipitation of withdrawal failed to decrease the severity of abstinence symptoms. Rather, acute i.c.v. injection of MCCG significantly increased the time spent in withdrawal.
Our results suggest that the development of opioid dependence is affected by mGluR‐mediated PI hydrolysis and mGluR‐regulated cyclic AMP production.

British Journal of Pharmacology (1997) 120, 1015–1020; doi:10.1038/sj.bjp.0701000
Tachykinin receptors in the guinea‐pig isolated oesophagus: a complex system
Authors: Kerr K P , Mitchelson F , Coupar I M 
Published: August 2006

The tachykinin receptors mediating contraction of isolated longitudinal strips of the guinea‐pig oesophageal body were characterized with substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) as well as the analogues, [Sar9,Met(O2)11]SP, [Nle10]NKA(4–10) and [MePhe7]NKB, selective for NK1, NK2 and NK3, receptors, respectively. Experiments were performed both in the absence and presence of a cocktail of peptidase inhibitors, captopril (1 μm), thiorphan (1 μm) and amastatin (20 μm), in order to determine whether membrane bound proteases are important in the metabolism of tachykinins in this preparation.
All agonists produced concentration‐dependent contractile effects. The presence of the peptidase inhibitors shifted the concentration‐response curves of SP, [Nle10]NKA(4–10) and [MePhe7]NKB significantly leftwards and the concentration‐response curve of NKB was shifted significantly rightwards. However, the EC50 values were significantly different only for [Nle10]NKA(4–10) and NKB.
In the presence of the peptidase inhibitors, the EC50 values of the selective agonists, [MePhe7]NKB (0.6 nm) and [Nle10]NKA(4–10) (66 nm) indicated the presence of both tachykinin NK3 and NK2 receptors. [MePhe7]NKB produced less than 50% of the maximal response obtained with the other agonists. Since [Sar9,Met(O2)11]SP produced a small response in the nanomolar concentration range in about 30% of the preparations tested, it is possible that some NK1 receptors were also present.
Assuming competitive antagonism, the NK2‐selective antagonist SR 48,968 (30 nm) gave apparent pKB values of 8.13 and 8.65 for [Nle10]NKA(4–10) in the absence and presence of peptidase inhibitors, respectively, supporting the presence of NK2 receptors.
The NK3‐selective antagonist SR 142,801 (0.1 μm), suppressed responses to low (0.1–10 nm) concentrations of [MePhe7]NKB. These contractile responses to [MePhe7]NKB were also abolished by atropine (0.6 μm) suggesting that this response was mediated via cholinergic nerves.
It is concluded that the guinea‐pig oesophagus is a complex system which has both NK2 and NK3 receptors and possibly some NK1 receptors as well.

British Journal of Pharmacology (1997) 120, 1021–1028; doi:10.1038/sj.bjp.0701001
Enhancement of the response to purinergic agonists in P2Y1 transfected 1321N1 cells by antagonists suramin and PPADS
Authors: Brown Colin A , Charlton Steven J , Boarder Michael R 
Published: August 2006

We have previously shown that both suramin and pyridoxal‐phosphate‐6‐azophenyl‐2′, 4′ disulphonic acid (PPADS) act as antagonists at transfected P2Y1 receptors. Here we show that under certain experimental conditions these two P2 antagonists can enhance the response to agonists acting at these receptors.
The expression of either P2Y1 or P2Y2 receptors in 1321N1 human astrocytoma cells results, on a change of medium, in an elevation of basal (no added agonist) accumulation of [3H]‐inositol(poly)phosphates([3H]‐InsPx) compared to cells not expressing these receptors. This elevation is much greater in P2Y1 transfectants than in P2Y2 transfectants.
Both PPADS and suramin reduced this basal level of [3H]‐InsPx accumulation in the P2Y1 expressing cells.
When a protocol was used which required changing the culture medium, antagonists were added at a concentration which reduced the basal accumulation by about 50%, there was a significant stimulation in response to increasing concentrations of 2‐methylthioadenosine 5′‐triphosphate (2MeSATP), in the absence of antagonists there was no significant effect of the agonist.
However, when 2MeSATP was added in the absence of a change of medium and with no antagonist present, there was a several fold increase in [3H]‐InsPx accumulation. These results show that a release of endogenous agonist activity (possibly ATP/ADP) from the P2Y1 expressing cells can create conditions in which a response to an agonist such as 2MeSATP can only be seen in the presence of a competitive antagonist.

British Journal of Pharmacology (1997) 120, 1049–1052; doi:10.1038/sj.bjp.0701010
The effect of the selectin binding polysaccharide fucoidin on eosinophil recruitment in vivo
Authors: Teixeira Mauro M , Hellewell Paul G 
Published: August 2006

In order to accumulate at sites of inflammation, leukocytes initially roll on endothelial cells of post‐capillary venules before becoming firmly attached. This process of rolling is mediated by selectins which bind to carbohydrate counter‐ligands present on the surface of both leukocytes and endothelial cells. The polysaccharide fucoidin has been previously shown to inhibit leukocyte rolling in the mesenteric circulation and to reduce neutrophil accumulation in the skin and meninges in experimental inflammation.
In the present study we have assessed the effects of fucoidin on eosinophil function in vitro and eosinophil accumulation at sites of inflammation in guinea‐pig skin.
At concentrations of up to 1200 μg ml−1, fucoidin inhibited phorbol myristate acetate (PMA)‐induced eosinophil homotypic aggregation by up to 60% but had no inhibitory effect on PMA‐induced eosinophil adhesion to serum‐coated plates.
Fucoidin effectively reduced the binding of the anti‐L‐selectin mAb MEL‐14 to guinea‐pig eosinophils. Binding of a P‐selectin‐IgG chimera to eosinophils was also partially inhibited by fucoidin, but binding of an anti‐CD18 or an anti‐VLA‐4 mAb were unaffected.
When given systemically to guinea‐pigs, fucoidin suppressed 111In‐labelled eosinophil recruitment to sites of allergic inflammation. 111In‐labelled eosinophil accumulation induced by platelet‐activating factor (PAF) and zymosan‐activated plasma (as a source of C5a des Arg) was also inhibited.
These results demonstrate a role for fucoidin‐sensitive selectins in mediating eosinophil recruitment in vivo.

British Journal of Pharmacology (1997) 120, 1059–1066; doi:10.1038/sj.bjp.0701024