bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancement of glycine receptor function by ethanol: role of phosphorylation
Authors: Paola Mascia Maria , Wick Marilee J , Martinez Larry D , Harris R Adron 
Published: January 2005

The effects of several kinase inhibitors (staurosporine, GF 109203X, H89, KN62, genistein) and of the phosphatase inhibitor calyculin A were studied on the ethanol potentiation and on the function of homomeric α1 glycine receptor expressed in Xenopus oocytes using a two electrode voltage clamp recording technique.
The function of the homomeric α1 glycine receptor was not modified in Xenopus oocytes pretreated with kinase inhibitors or with the phosphatase inhibitor calyculin A.
The potentiation of the glycine receptor function induced by ethanol (10–200 mM) was significantly reduced in Xenopus oocytes pretreated with the PKC inhibitors staurosporine or GF 109203X.
No differences in propofol (2.5 μM) or halothane (250 μM) actions were found after exposure of Xenopus oocytes to staurosporine.
No differences in ethanol sensitivity were found after exposure of Xenopus oocytes expressing glycine α1 receptors to H89, KN62, genistein or to the phosphatase inhibitor calyculin A.
The mutant α1 (S391A), in which the PKC phosphorylation site at serine 391 was mutated to alanine, was less sensitive to the effects of ethanol than was the α1 wild type receptor. Moreover, the ethanol potentiation of the glycine receptor function was not affected by treatment with staurosporine in oocytes expressing α1 (S391A).
The splice variant of the α1 glycine receptor subunit, α1ins, containing eight additional amino acids and a potential phosphorylation site for PKA, did not differ from wild type for sensitivity to ethanol.
These results indicate that phosphorylation by PKC of the homomeric α1 glycine receptor subunit modulates ethanol potentiation, but not the function of the glycine receptor.

British Journal of Pharmacology (1998) 125, 263–270; doi:10.1038/sj.bjp.0702054
5‐Hydroxytryptamine receptors mediating vasoconstriction and vasodilation in perinatal and adult rabbit small pulmonary arteries
Authors: Morecroft Ian , MacLean Margaret R 
Published: January 2005

Vasoconstrictor responses to 5‐HT, 5‐carboxamidotryptamine (5‐CT, 5‐HT1 receptor agonist), α‐methyl‐5‐HT (5‐HT2 receptor agonist) and sumatriptan (5‐HT1D/1B receptor agonist) were studied in fetal, 0–24 h, 4 day, 7 day and adult rabbit pulmonary resistance arteries (PRAs), alone and in the presence of the NO synthase inhibitor Nω‐nitro‐L‐arginine methylester (L‐NAME). The effect of the selective 5‐HT receptor antagonists ketanserin (5‐HT2A receptor) and GR55562 (5‐HT1B/1D receptor) on vasoconstrictor responses to 5‐HT were studied in the presence of L‐NAME. Vasodilator responses to 5‐CT were also studied in pre‐contracted PRAs.
5‐HT and α‐methyl‐5‐HT were equipotent in causing contraction in the PRAs at each age (e.g. pEC50s for 5‐HT and α‐methyl‐5‐HT were 6.74±0.13 and 6.63±0.22 respectively in adult vessels). In the perinatal PRAs, sumatriptan and 5‐CT produced negligible contractions, but in adult PRAs, 5‐CT and sumatriptan were potent agonists with pEC50s of 6.05±0.3 and 5.70±0.20 respectively.
L‐NAME markedly increased the maximum response to 5‐HT in the 0–24 h, 4 day and 7 day vessels and increased 5‐HT potency in the 4‐, 7‐day‐old and adult rabbit vessels.
In perinatal vessels, responses to 5‐HT, with L‐NAME present, were antagonized by ketanserin (30 nM and 0.1 μM) but not GR55562 (1 μM). A small ketanserin‐resistant, GR55562‐sensitive component was observed at 0–24 h. In adult vessels, both ketanserin and GR55562 inhibited 5‐HT‐induced responses.
Vasodilator responses to 5‐CT were observed in pre‐contracted PRAs from 4‐ and 7‐day‐old rabbits but not in the fetus, 0–24 h old or adult rabbit vessels. At 4 days the vasodilator response was inhibited both by L‐NAME and GR55562. At 7 days the response was only partly blocked by L‐NAME and resistant to GR55562. The L‐NAME resistant component was antagonized by the 5‐HT7 receptor antagonist spiperone (1 μM).
The results suggest that 5‐HT2A‐receptors mediate vasoconstriction in perinatal vessels whilst the 5‐HT1D or 5‐HT1B receptor contributes in adult rabbit vessels. The 5‐HT1D or 5‐HT1B receptor mediates NO‐dependent vasodilation in vessels from rabbits at 4 days of age whilst 5‐HT7 receptors mediate NO‐independent vasodilation by 7 days.

British Journal of Pharmacology (1998) 125, 69–78; doi:10.1038/sj.bjp.0702055
Prostanoid receptors of the EP3 subtype mediate inhibition of evoked [3H]acetylcholine release from isolated human bronchi
Authors: Reinheimer Torsten , Harnack Eva , Racke Kurt , Wessler Ignaz 
Published: January 2005

The release of neuronal [3H]acetylcholine (ACh) from isolated human bronchi after labelling with [3H]choline was measured to investigate the effects of prostanoids.
A first period of electrical field stimulation (S1) caused a [3H]ACh release of 320±70 and 200±40 Becquerel (Bq) g−1 in epithelium‐denuded and epithelium‐containing bronchi respectively (P>0.05). Subsequent periods of electrical stimulation (Sn, n=2, 3, and 4) released less [3H]ACh, i.e. decreasing Sn/S1 values were obtained (0.76±0.09, 0.68±0.07 and 0.40±0.04, respectively).
Cumulative concentrations (1–1000 nM) of EP‐receptor agonists like prostaglandin E2, nocloprost, and sulprostone (EP1 and EP3 selective) inhibited evoked [3H]ACh release in a concentration dependent manner with IC50 values between 4–14 nM and maximal inhibition of about 70%.
The inhibition of evoked [3H]ACh release by prostaglandin E2, nocloprost and sulprostone was not affected by the DP‐, EP1‐ and EP2‐receptor antagonist AH6809 at a concentration of 3 μM, i.e. a 3–30 times greater concentration than its affinity (pA2 values) at the respective receptors.
Circaprost (IP‐receptor agonist; 1–100 nM), iloprost (IP‐ and EP1‐receptor agonist; 10‐1000 nM) and U‐46619 (TP‐receptor agonist; 100–1000 nM) did not significantly affect [3H]ACh release.
Blockade of cyclooxygenase by 3 μM indomethacin did not significantly modulate evoked [3H]ACh release in epithelium‐containing and epithelium‐denuded bronchi. Likewise, the combined cyclo‐ and lipoxygenase inhibitor BW‐755C (20 μM) did not affect evoked [3H]ACh release.
In conclusion, applied prostanoids appear to inhibit [3H]ACh release in epithelium‐denuded human bronchi under the present in vitro conditions, most likely via prejunctional prostanoid receptors of the EP3 subtype.

British Journal of Pharmacology (1998) 125, 271–276; doi:10.1038/sj.bjp.0702057
Augmented myocardial ischaemia by nicotine – Mechanisms and their possible significance
Authors: Schrör Karsten , Zimmermann Katja C , Tannhäuser Roman 
Published: January 2005

To study the effect of nicotine on the severity of experimental myocardial ischaemia, Langendorff hearts of rabbits (n=7–12 per group) were subjected to 2 h of low‐flow ischaemia followed by 1 h of reperfusion.
Infusion of nicotine (100 ng ml−1) caused only minor changes in non‐ischaemic conditions but a significant (P<0.05) increase in end‐diastolic pressure (LVEDP), loss of creatine kinase (CK) and troponin (TnT) as well as increase in noradrenaline (NA) overflow in reperfused ischaemic hearts.
RT–PCR was done on total RNA for mRNA expression of the constitutive (COX‐1) and inducible cyclooxygenase (COX‐2). There was no COX‐2 in non‐ischaemic hearts but a significant expression in ischaemia (n=5) which was further increased by nicotine. These data were confirmed at the protein level by Western blotting and additionally shown that COX‐1 remained unchanged.
There was a marked increase in prostacyclin (PGI2) and a 2 fold increase in NA overflow which were both stimulated by nicotine.
The aggravating effects of nicotine on myocardial ischaemia (CK release) as well as the expression of COX‐2 mRNA were prevented by pretreatment with the β‐blocker pindolol (1 μM).
The data demonstrate marked deleterious actions of nicotine in reperfused ischaemic hearts. These actions are probably related to the increase in catecholamine overflow, are β‐receptor‐mediated and involve enhanced gene expression of COX‐2.

British Journal of Pharmacology (1998) 125, 79–86; doi:10.1038/sj.bjp.0702061
Glycine induces a novel form of long‐term potentiation in the superficial layers of the superior colliculus
Authors: Platt Bettina , Bate Joanne R , von Linstow Roloff Eva , Withington Deborah J 
Published: January 2005

The mammalian superior colliculus (SC) is a midbrain nucleus containing space maps of different sensory modalities which show various forms of age‐ and activity‐dependent plasticity in vivo and in vitro. In the present study, we aimed to characterize the role of glycine (Gly) receptors in the SC, and we observed that application of glycine (Gly; 500 μM and 3 mM) for 7 min to SC slices of adult guinea‐pigs caused a novel form of long‐term potentiation (termed LTPgly) of evoked excitatory postsynaptic potentials recorded in the superficial layers.
The strength of potentiation was found to be concentration‐dependent and partially independent from synaptic stimulation.
LTPgly did not involve NMDA receptor activation as proven by the lack of inhibition by 100 μM D,L‐2‐amino‐5‐phosphonovaleric acid (APV) and 10 μM MK‐801.
LTPgly could only be masked but not prevented by strychnine (100 μM) and remained undisturbed in the presence of picrotoxin (100 μM).
Inhibition of carbonic anhydrase by acetazolamide (20 μM) had no effect on LTPgly suggesting that the excitatory action of Gly is not due to a differential breakdown of the Cl−/HCO3− gradients.
As indicated by the inhibition of LTPgly of the fEPSP slope by the L‐type calcium channel blocker nifedipine (20 μM), voltage‐dependent calcium channels are the source for Ca2+ elevation as the intracellular trigger.
Our data provide the first evidence for a role of Gly in SC synaptic transmission. They illustrate a so far unknown action of Gly which can lead to long‐lasting changes of synaptic efficacy and which is not mediated via NMDA‐related or strychnine‐sensitive binding sites.

British Journal of Pharmacology (1998) 125, 293–300; doi:10.1038/sj.bjp.0702062
Catecholamine transport by the organic cation transporter type 1 (OCT1)
Authors: Breidert Tilo , Spitzenberger Folker , Gründemann Dirk , Schömig Edgar 
Published: January 2005

Liver and kidney extract adrenaline and noradrenaline from the circulation by a mechanism which does not seem to be one of the classical catecholamine transporters. The hypothesis that OCT1 is involved–the organic cation transporter type 1 which exists in rat kidney and liver–was tested.
Based on human embryonic kidney cells (293), we constructed a cell line which stably expresses OCT1r (293OCT1r cells). Transfection with OCT1 resulted in a transport activity not only for prototypical known substrates of OCT1 such as 3H‐1‐methyl‐4‐phenylpyridinium and 14C‐tetraethylammonium but also for the catecholamines 3H‐adrenaline, 3H‐noradrenaline (3H‐NA) and 3H‐dopamine (3H‐DA), the indoleamine 3H‐5‐hydroxytryptamine (3H‐5HT) as well as the indirect sympathomimetic 14C‐tyramine.
For 3H‐DA, 3H‐5HT and 3H‐NA, at non‐saturating concentrations, the rate constants for inwardly directed substrate flux (kin) were 6.9±0.8, 3.1±0.2, and 1.2±0.1 μl min−1 mg protein−1. In wild type cells (293WT) the corresponding kin's were considerably lower, being 0.94±0.40, 0.47±0.08 and 0.23±0.05 μl min−1 mg protein−1 (n=12). The indirectly determined half‐saturating concentrations of DA, 5HT, and NA were 1.1 (95% c.i.: 0.8, 1.4), 0.65 (0.49, 0.86), and 2.8 (2.1, 3.7) mmol l−1 (n=3).
Specific 3H‐DA uptake in 293OCT1r cells was resistant to cocaine (1 μmol l−1), 3H‐5HT uptake was resistant to citalopram (300 nmol l−1) and 3H‐NA uptake was resistant to desipramine (100 nmoll−1), corticosterone (1 μmol l−1), and reserpine (10 nmol l−1) which rules out the involvement of classical transporters for biogenic amines.
The findings demonstrate that OCT1 efficiently transports catecholamines and other biogenic amines and support the hypothesis that OCT1 is responsible for hepatic and renal inactivation of circulating catecholamines.

British Journal of Pharmacology (1998) 125, 218–224; doi:10.1038/sj.bjp.0702065
Actions of novel antidiabetic thiazolidinedione, T‐174, in animal models of non‐insulin‐dependent diabetes mellitus (NIDDM) and in cultured muscle cells
Authors: Arakawa Kenji , Ishihara Tomomi , Aoto Masamichi , Inamasu Masanori , Saito Akira , Ikezawa Katsuo 
Published: January 2005

The antihyperglycaemic effect and the possible mechanism of action of T‐174, a novel thiazolidinedione derivative, was determined in vivo and in vitro.
Oral administration of T‐174 markedly improved hyperglycaemia, hyperinsulinaemia, hyperlipidaemia, and glucose intolerance in genetically obese and diabetic yellow KK (KK‐Ay) mice (0.2–15.5 mg kg−1 day−1, for 7 days) and Zucker fatty rats (1.4–11.4 mg kg−1 day−1, for 6 days). The ED50 values for the glucose lowering action of T‐174 and pioglitazone, another thiazolidinedione antidiabetic, were 1.8 and 29 mg kg−1 day−1, respectively in KK‐Ay mice; T‐174 was about 16 times more potent than pioglitazone.
The hypoglycaemic effect of exogenous insulin in KK‐Ay mice was enhanced after the administration of T‐174. A hyperinsulinaemic euglycaemic clamp study in Zucker fatty rats showed an amelioration of whole‐body insulin resistance by the T‐174 treatment.
Insulin‐stimulated glucose metabolism was enhanced in adipocytes from KK‐Ay mice treated with T‐174. The insulin receptor number of the adipocytes was increased without a change in the affinity of the receptor.
The hypomagnesaemia in KK‐Ay mice was completely restored by T‐174.
In cultured L6 myotubes, glucose consumption and [3H]‐2‐deoxy‐glucose transport were enhanced by T‐174 (EC50; 6 and 4 μM, respectively). Combination of insulin with T‐174 was additive to stimulate glucose disposal.
These results suggest that the antihyperglycaemic effect of T‐174 was mediated by enhanced insulin action. This was associated with amelioration of the hypomagnesaemia and T‐174 directly increased basal and insulin‐stimulated glucose utilization by cultured muscle cells.

British Journal of Pharmacology (1998) 125, 429–436; doi:10.1038/sj.bjp.0702066
Nociceptin inhibits non‐adrenergic non‐cholinergic contraction in guinea‐pig airway
Authors: Shah S , Page C P , Spina D 
Published: January 2005

Electrical field stimulation (EFS) of guinea‐pig isolated main bronchi induced a non‐adrenergic non‐cholinergic (NANC) contractile response. Nociceptin (0.01–1 μM) significantly inhibited the contractile response to EFS (P<0.01), but not to capsaicin (P>0.05).
The μ‐, δ‐ and κ‐opioid receptor antagonists, naloxone (0.3 μM), naltrindole (3 μM) and nor‐binaltorphimine (1 μM), respectively, did not significantly affect the inhibitory effect of nociceptin (0.03 μM; P>0.05).
The novel nociceptin antagonist, [Phe1ψ(CH2‐NH)Gly2]nociceptin(1–13)NH2 (0.03–1 μM); the σ ligands, carbetapentane (30 μM), 3‐phenylpiperidine (30–100 μM) and (+)‐cyclazocine (10–100 μM) significantly reversed the inhibitory effect of nociceptin (0.03 μM, P<0.05). In contrast, rimcazole, did not significantly reverse the inhibitory effect of nociceptin (0.03 μM) at any concentration tested (P>0.05).
EFS of guinea‐pig bronchial preparations significantly increased SP‐LI release above basal SP‐LI (P<0.05). In the presence of nociceptin (1 μM), EFS induced a significant increase in SP‐LI release above basal SP‐LI release (P<0.05). Nociceptin caused a 59±11% (n=5) inhibition of EFS‐induced release of SP‐LI.
Nociceptin reduces the release of sensory neuropeptides induced by EFS, but not capsaicin, from guinea‐pig airways. These experiments provide further evidence for a role for nociceptin in regulating the release of sensory neuropeptides in response to EFS.

British Journal of Pharmacology (1998) 125, 510–516; doi:10.1038/sj.bjp.0702068
Investigation of the functional role played by the chemokine monocyte chemoattractant protein‐1 in interleukin‐1‐induced murine peritonitis
Authors: Ajuebor Maureen N , Gibbs Linda , Flower Roderick J , Das Anuk M , Perretti Mauro 
Published: January 2005

Intraperitoneal (i.p.) injection of murine recombinant IL‐1β (mrIL‐1β) produced a dose‐dependent (0.5–50 ng) and time‐related (0.5–2 h) secretion of murine monocyte chemoattractant protein‐1 (mMCP‐1; 3–4 ng per cavity) in the lavage fluids. MCP‐1 mRNA could also be detected in the cell pellets by reverse transcriptase‐polymerase chain reaction (RT‐PCR).
MCP‐1 levels were reduced by more than 90% by co‐administration of IL‐1 receptor antagonist (10 μg) (n=6, P<0.05). In contrast, an IL‐1 mutant with low affinity for IL‐1 receptor type I, termed yIL‐1βΔ4 (50 ng), produced only a modest release of the chemokine. Treatment of mice with dexamethasone (DEX) (∼1 mg kg−1 s.c.) reduced mrIL‐1β‐induced mMCP‐1 gene expression (apparent total inhibition) and protein release in the lavage fluids (∼40% reduction; n=10; P<0.05). Drastic reductions in the numbers of residential macrophages or mast cells did not modify the levels of mMCP‐1 recovered in the lavage fluids.
Injection of mrIL‐1β produced neutrophil accumulation into the peritoneal cavities (maximal at 4 h with 1.42±0.15×106 cells per mouse). Co‐injection of a specific polyclonal antibody against mMCP‐1 reduced this process by more than 50% (n=6; P<0.05). In conclusion, we studied the mechanisms leading to the specific release of the CC chemokine mMCP‐1 after in vivo administration of mrIL‐1β.

British Journal of Pharmacology (1998) 125, 319–326; doi:10.1038/sj.bjp.0702071
Inhibitory effects of mesoionic 3‐aryl substituted oxatriazole‐5‐imine derivatives on vascular smooth muscle cell mitogenesis and proliferation in vitro
Authors: Lähteenmäki Tuula , Sievi Eeva , Vapaatalo Heikki 
Published: January 2005

The effects of oxatriazole‐type (GEA 3162 and GEA 5624) nitric oxide (NO) donors on mitogenesis and proliferation were studied in vascular smooth muscle cell (VSMC) culture. The effects of the GEA‐compounds were compared with well‐known NO‐donors 3‐morpholinosydnonimine (SIN‐1) and S‐nitroso‐N‐acetylpenicillamine (SNAP).
All NO‐donors released NO and increased the production of cyclic GMP concentration‐dependently. The production of cyclic GMP was inhibited by the guanylate cyclase inhibitor, ODQ (1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one).
The NO‐donors inhibited basal and serum‐induced DNA synthesis concentration‐dependently. The GEA‐compounds were needed in concentrations 10 times lower than SIN‐1 and SNAP. GEA 3162, SIN‐1 and SNAP were also able to inhibit serum‐induced cell proliferation. GEA 5624 was ineffective. The antimitogenic effect of NO‐donors was not reduced by inhibiting the guanylate cyclase.
These results suggest that NO inhibits serum‐induced DNA synthesis and proliferation of VSMC by a cyclic GMP‐independent mechanism. The oxatriazole‐type NO‐donor GEA 3162 was found to be a more potent inhibitor of mitogenesis and cell proliferation than SIN‐1 and SNAP.

British Journal of Pharmacology (1998) 125, 402–408; doi:10.1038/sj.bjp.0702076
Inhibition of the gap junctional component of endothelium‐dependent relaxations in rabbit iliac artery by 18‐α glycyrrhetinic acid
Authors: Taylor Hannah J , Chaytor Andrew T , Evans W Howard , Griffith Tudor M 
Published: January 2005

The gap junction inhibitor 18‐α‐glycyrrhetinic acid (α‐GA, 100 μM) attenuated endothelium‐dependent relaxations to acetylcholine and cyclopiazonic acid by ∼20% in rings of pre‐constricted rabbit iliac artery. The nitric oxide synthase inhibitor NG‐nitro‐L‐arginine methyl ester (L‐NAME, 300 μM) inhibited relaxations to both agents by ∼65% and these were further attenuated by α‐GA to <10% of control. In endothelium‐denuded preparations, relaxations to sodium nitroprusside were not affected by α‐GA. Heterocellular gap junctional communication may therefore account for nitric oxide‐independent relaxations evoked both by receptor‐dependent and ‐independent mechanisms in rabbit iliac artery.British Journal of Pharmacology (1998) 125, 1–3; doi:10.1038/sj.bjp.0702078
Enhanced expression of G protein‐coupled receptor kinase 2 selectively increases the sensitivity of A2A adenosine receptors to agonist‐induced desensitization
Authors: Mundell Stuart J , Luty Jason S , Willets Jon , Benovic Jeffrey L , Kelly Eamonn 
Published: January 2005

G protein‐coupled receptor kinases (GRKs) are thought to be important in mediating the agonist‐induced phosphorylation and consequent desensitization of G protein‐coupled receptor (GPCR) responses. We have previously shown that stable expression of a dominant negative mutant G protein‐ coupled receptor kinase 2 (GRK2) construct in NG108‐15 mouse neuroblastoma × rat glioma cells suppresses the agonist‐induced desensitization of A2A and A2B adenosine receptor‐stimulated adenylyl cyclase activity (Mundell et al., 1997). To further determine the role of GRK2 in agonist‐induced desensitization of these adenosine receptors, we stably overexpressed wild type GRK2 in NG108‐15 cells.
In homogenates prepared from cells overexpressing GRK2, the acute stimulation of adenylyl cyclase by activation of A2A and A2B adenosine receptors was markedly reduced, but could be reversed by pretreating the cells with AD (adenosine deaminase), to remove extracellular adenosine from the medium. On the other hand, acute stimulation of adenylyl cyclase by secretin, iloprost, NaF and forskolin was the same in GRK2 overexpressing cells and plasmid‐transfected control cells.
Cells overexpressing GRK2 were more sensitive to adenosine receptor agonist‐induced desensitization than plasmid‐transfected control cells. This effect was selective since the agonist sensitivity of desensitization for secretin and IP‐prostanoid receptor‐stimulated adenylyl cyclase activity was not affected by GRK2 overexpression.
These results further implicate GRK2 as the likely mechanism by which A2 adenosine receptors undergo short‐term desensitization in NG108‐15 cells, and indicate that even when overexpressed, GRK2 retains its substrate specificity for native receptors in intact cells. Furthermore, the susceptibility of GPCRs to desensitization appears to depend on the level of GRK expression, such that in cells that express high levels of GRK2, low agonist concentrations may be sufficient to trigger GRK‐mediated desensitization.

British Journal of Pharmacology (1998) 125, 347–356; doi:10.1038/sj.bjp.0702081