bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of the firing activity of noradrenergic neurones in the rat locus coeruleus by the 5‐hydroxtryptamine system
Authors: Haddjeri Nasser , De Montigny Claude , Blier Pierre 
Published: August 2006

The aim of the present study was to investigate the putative modulation of locus coeruleus (LC) noradrenergic (NA) neurones by the 5‐hydroxytryptaminergic (5‐HT) system by use of in vivo extracellular unitary recordings and microiontophoresis in anaesthetized rats. To this end, the potent and selective 5‐HT1A receptor antagonist WAY 100635 (N‐{2‐[4(2‐methoxyphenyl)‐1‐piperazinyl]ethyl}‐N‐(2‐pyridinyl)cyclohexanecarboxamide trihydroxychloride) was used.
In the dorsal hippocampus, both local (by microiontophoresis, 20 nA) and systemic (100 μg kg−1, i.v.) administration of WAY 100635 antagonized the suppressant effect of microiontophorectically‐applied 5‐HT on the firing activity of CA3 pyramidal neurones, indicating its antagonistic effect on postsynaptic 5‐HT1A receptors.
WAY 100635 and 5‐HT failed to modify the spontaneous firing activity of LC NA neurones when applied by microiontophoresis. However, the intravenous injection of WAY 100635 (100 μg kg−1) readily suppressed the spontaneous firing activity of LC NA neurones.
The lesion of 5‐HT neurones with the neurotoxin 5,7‐dihydroxytryptamine increased the spontaneous firing activity of LC NA neurones and abolished the suppressant effect of WAY 100635 on the firing activity of LC NA neurones.
In order to determine the nature of the 5‐HT receptor subtypes mediating the suppressant effect of WAY 100635 on NA neurone firing activity, several 5‐HT receptor antagonists were used. The selective 5‐HT3 receptor antagonist BRL 46470A (10 and 100 μg kg−1, i.v.), the 5‐HT1D receptor antagonist GR 127935 (100 μg kg−1, i.v.) and the 5‐HT1A/1B receptor antagonist (−)‐pindolol (15 mg kg−1, i.p.) did not prevent the suppressant effect of WAY 100635 on the firing activity of LC NA neurones. However, the suppressant effect of WAY 100635 was prevented by the non‐selective 5‐HT receptor antagonists spiperone (1 mg kg−1, i.v.) and metergoline (1 mg kg−1, i.v.), by the 5‐HT2 receptor antagonist ritanserin (500 μg kg−1, i.v.). It was also prevented by the 5‐HT1A receptor/α1D‐adrenoceptor antagonist BMY 7378 (1 mg kg−1, i.v.) and by the α1‐adrenoceptor antagonist prazosin (100 μg kg−1, i.v.).
These data support the notion that the 5‐HT system tonically modulates NA neurotransmission since the lesion of 5‐HT neurones enhanced the LC NA neurones firing activity and the suppressant effect of WAY 100635 on the firing activity of NA neurones was abolished by this lesion. However, the location of the 5‐HT1A receptors involved in this complex circuitry remains to be elucidated. It is concluded that the suppressant effect of WAY 100635 on the firing activity of LC NA neurones is due to an enhancement of the function of 5‐HT neurones via a presynaptic 5‐HT1A receptor. In contrast, the postsynaptic 5‐HT receptor mediating this effect of WAY 100635 on NA neurones appears to be of the 5‐HT2A subtype.

British Journal of Pharmacology (1997) 120, 865–875; doi:10.1038/sj.bjp.0700968
The involvement of a novel mechanism distinct from the thrombin receptor in the vasocontraction induced by trypsin
Authors: Komuro Taro , Miwa Soichi , Minowa Tetsuya , Okamoto Yasuo , Enoki Taijiro , Ninomiya Haruaki , Zhang Xiao‐Feng , Uemura Yoshihiko , Kikuchi Haruhiko , Masaki Tomoh 
Published: August 2006

The vasocontracting effect of a serine protease trypsin and its mechanisms were investigated by monitoring the isometric tension in endothelium‐denuded rings of rabbit thoracic aortae and its effects on intracellular free Ca2+ concentrations ([Ca2+]i) in dispersed rabbit vascular smooth muscle cells with a Ca2+ indicator fura‐2. The actions of trypsin were compared with those of thrombin.
Both thrombin and trypsin reversibly contracted aortic rings without endothelium in a concentration‐dependent manner. The vasocontraction induced by trypsin was well correlated with the protease activity of trypsin actually added to the tissue baths containing the aortic rings and was completely blocked by soybean trypsin inhibitor and phenylmethylsulphonyl fluoride (PMSF), a serine protease inhibitor.
The trypsin‐induced contractions of the aortic rings were not the result of irreversible damage to vascular smooth muscle cells, since the contractile responses induced by noradrenaline or 30 mm KCl were unaffected by pretreatment with trypsin.
The contractions induced by either thrombin or trypsin were reduced to about 30% of control responses after removal of extracellular Ca2+, indicating that most of the contraction is dependent on extracellular Ca2+. By contrast, the contractions induced by either of the proteases were reduced by an antagonist of L‐type voltage‐operated Ca2+ channels, nifedipine, to about 70% of control responses, indicating that both nifedipine‐sensitive and ‐resistant Ca2+ channels are involved in these contractions.
In the aortic rings precontracted by a maximally effective concentration of thrombin, the second application of thrombin virtually failed to induce contractions but trypsin could still induce contractions amounting to 10% of control values by it's protease activity.
After the first application of a maximal concentration of thrombin, the second application of thrombin could not induce an increase in [Ca2+]i, but an application of trypsin could still induce an increase in [Ca2+]i in dispersed rabbit vascular smooth muscle cells.
These data suggest that in addition to activation of a thrombin receptor, trypsin can contract rabbit aortae by a proteinase‐activated receptor 2 or a novel mechanism.

British Journal of Pharmacology (1997) 120, 851–856; doi:10.1038/sj.bjp.0701003
Effect of binding protein surface charge on palmitate uptake by hepatocyte suspensions
Authors: Burczynski F. J. , Wang G. ‐Q. , Hnatowich M. 
Published: August 2006

Studies were directed at determining whether hepatocytes, isolated from female Sprague‐Dawley rats, facilitate the uptake of protein‐bound long‐chain fatty acids. We postulated one form of facilitated uptake may occur through an ionic interaction between the protein‐ligand complex and the cell surface. These interactions are expected to supply additional ligand to the cell for uptake.
The clearance rate of [3H]‐palmitate in the presence of α1‐acid‐glycoprotein (pI=2.7), albumin (pI=4.9) and lysozyme (pI=11.0) was investigated. Palmitate uptake was determined in the presence of protein concentrations that resulted in similar unbound ligand fractions (=0.03). The experimental clearance rates were compared to the theoretical predictions based upon the diffusion‐reaction model.
By use of our experimentally determined equilibrium binding and dissociation rate constants for the various protein‐palmitate complexes, the diffusion‐reaction model predicted clearance rates were 4.9 μl s−1/106 cells, 4.8 μl s−1/106 cells and 5.5 μl s−1/106 cells for α1‐acid‐glycoprotein, albumin and lysozyme, respectively; whereas the measured hepatocyte palmitate clearance rates were 1.2±0.1 μl s−1/106 cells, 2.3±0.3 μl s−1/106 cells and 7.1±0.7 μl s−1/106, respectively.
Hepatocyte palmitate clearance was significantly faster (P<0.01) in the presence of lysozyme than albumin which was significantly faster than α1‐acid‐glycoprotein (P<0.01). The marked difference in clearance rates could not be explained by considering differences in solution viscosity.
Our results are consistent with the notion that ionic interactions between protein‐ligand complexes and the cell surface facilitate the ligand uptake by decreasing the diffusional distance of the unbound ligand and/or by facilitating the protein‐ligand dissociation rate.

British Journal of Pharmacology (1997) 120, 1215–1220; doi:10.1038/sj.bjp.0701030
Regulation of guanosine 3′:5′‐cyclic monophosphate in ovine tracheal epithelial cells
Authors: Range Simon P. , Holland Elaine D. , Basten Graham P. , Knox Alan J. 
Published: August 2006

Guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) is an important second messenger mediating the effects of nitric oxide (NO) and natriuretic peptides. Cyclic GMP pathways regulate several aspects of lung pathophysiology in a number of airway cells. The regulation of this system has not been extensively studied in pulmonary epithelial tissue.
We have studied the production of cyclic GMP by suspensions of ovine tracheal epithelial cells in response to activators of soluble guanylyl cyclase (sodium nitroprusside (SNP) and S‐nitroso‐N‐acetyl‐penicillamine (SNAP) and particulate guanylyl cyclase (atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C‐type natriuretic peptide (CNP) and E. coli heat stable enterotoxin (STa)).
Both 10−710−3 m and 10−710−3 m SNAP generated a concentration‐dependent marked elevation in cyclic GMP production when incubated with 10−3 m 3‐isobutyl‐1‐methylxanthine (IBMX) (both greater than 25×baseline values with highest drug concentration).
The increase in production of cyclic GMP in response to 10−6 m SNP and 10−5 m SNAP was markedly inhibited by both 5×10−5 m haemoglobin (102% and 92% inhibition) and 5×10−5 m methylene blue (82% and 84% inhibition).
The increase in cyclic GMP in response to 10−3 m SNP was measured following co‐incubation with the phosphodiesterase inhibitors 10−710−3 m IBMX, 10−710−4 m milrinone and 10−710−4 m SKF 96231. Only 10−410−3 m IBMX significantly increased cyclic GMP levels.
Cyclic GMP production was also significantly elevated from baseline by 10−5 m ANP, 10−5 m BNP, 10−5 m CNP and 200 iu ml−1 of E. coli STa toxin in the presence of 10−3 m IBMX. Increases with these natriuretic peptides and STa toxin were smaller in magnitude (24 fold) than those seen with SNP and SNAP. CNP was the most potent of the natriuretic peptides studied suggesting type B membrane bound guanylate cyclase is the predominant form expressed.
These results suggest that ovine tracheal epithelial cells contain active guanylyl cyclases. The more marked response to SNP and SNAP than to natriuretic peptides suggests that soluble guanylyl cyclase predominates.

British Journal of Pharmacology (1997) 120, 1249–1254; doi:10.1038/sj.bjp.0701040
The effects of inhibitors of GABAergic transmission and stress on brain and plasma allopregnanolone concentrations
Authors: Barbaccia M. L. , Roscetti G. , Trabucchi M. , Purdy R. H. , Mostallino M. C. , Concas A. , Biggio G. 
Published: August 2006

This study was undertaken to investigate the relationship between a reduction in brain GABAA receptor function and the cerebro‐cortical content of 3α‐hydroxy‐5α‐pregnan‐20 one (allopregnanolone, AP), a potent endogenous positive modulator of γ‐aminobutyric acid (GABA) action at GABAA receptors, with anticonflict and anticonvulsant effects in rodents.
An acute depletion of the cerebral content of GABA or an attenuation of GABAA receptor‐mediated transmission by systemic injections of isoniazid (375 mg kg−1, s.c.) or FG 7142 (15 mg kg−1, i.p.) induced a transient increase in the cerebro‐cortical and plasma concentrations of AP in handling‐habituated (not stressed) rats.
Two stress paradigms, handling in naive rats and mild foot shock in handling‐habituated rats, that reduce central GABAergic tone mimicked the effects of isoniazid and FG 7142 on cortical AP content; foot shock in handling‐habituated rats, but not handling in naive animals, also increased plasma AP. Isoniazid, FG 7142, and foot shock also each increased the concentrations of the AP precursors, pregnenolone and progesterone, in both brain and plasma of handling‐habituated rats, whereas handling in naive rats increased the concentrations of these steroids only in brain.
Pretreatment of handling‐habituated rats with the anxiolytic β‐carboline derivative abecarnil, a positive allosteric modulator of GABAA receptors, which per se failed to affect the AP concentration in brain or plasma, prevented the increase in brain and plasma AP induced by foot shock or isoniazid.
In adrenalectomized and castrated rats foot shock or isoniazid failed to increase AP both in brain cortex and plasma.
These observations indicate that inhibition of GABAergic transmission, induced by foot shock or pharmacological manipulations, results in an increase in the concentrations of AP in brain and plasma, possibly via a modulation of hypothalamic‐pituitary‐adrenal (HPA) axis.
Given that AP enhances GABAA receptor function with high efficacy and potency, an increase in brain AP concentration may be important in the fine tuning of the GABA‐mediated inhibitory transmission in the central nervous system.

British Journal of Pharmacology (1997) 120, 1582–1588; doi:10.1038/sj.bjp.0701046
Inhibitory effects of ω‐3 polyunsaturated fatty acids on receptor‐mediated non‐selective cation currents in rat A7r5 vascular smooth muscle cells
Authors: Asano Michiko , Nakajima Toshiaki , Iwasawa Kuniaki , Hazama Hisanori , Omata Masao , Soma Masaaki , Yamashita Kamejiro , Okuda Yukichi 
Published: August 2006

The effects of ω‐3 polyunsaturated fatty acids on receptor‐mediated non‐selective cation current (Icat) and K+ current were investigated in aortic smooth muscle cells from foetal rat aorta (A7r5 cells). The whole‐cell voltage clamp technique was employed.
With a K+‐containing solution, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA, 30 μm) produced an outward current at a holding potential of −40 mV. This response was inhibited by tetraethylammonium (20 mm) or Cs+ in the patch pipette solution, and the reversal potential of the EPA‐induced current followed the K+ equilibrium potential in a near Nernstian manner.
Under conditions with a Cs+‐containing pipette solution, both vasopressin and endothelin‐1 (100 nm) induced a long‐lasting inward current at a holding potential of −60 mV. The reversal potential of these agonist‐induced currents was about +0 mV, and was not significantly altered by the replacement of the extracellular or intracellular Cl− concentration, suggesting that the induced current was a cation‐selective current (Icat).
La3+ and Cd2+ (1 mm) completely abolished these agonist‐induced Icat, but nifedipine (10 μm) failed to inhibit it significantly.
ω‐3 polyunsaturated fatty acids (3100 μm), EPA, DHA and docosapentaenoic acids (DPA), inhibited the agonist‐induced Icat in a concentration‐dependent manner. The potency of the inhibitory effect was EPA>DHA>DPA, and the half maximal inhibitory concentration (IC50) of EPA was about 7 μm.
Arachidonic and linoleic acids (10, 30 μm) showed a smaller inhibitory effect compared to ω‐3 fatty acids. Also, oleic and stearic acids (30 μm) did not show a significant inhibitory effect on Icat.
A similar inhibitory action of EPA was observed when Icat was activated by intracellularly applied GTPγS in the absence of agonists, suggesting that the site of action of ω‐3 fatty acids is not located on the receptor.
These results demonstrate that ω‐3 polyunsaturated fatty acids can activate a K+ current and also effectively inhibit receptor‐mediated non‐selective cation currents in rat A7r5 vascular smooth muscle cells. Thus, the data suggest that ω‐3 fatty acids may play an important role in the regulation of vascular tone.

British Journal of Pharmacology (1997) 120, 1367–1375; doi:10.1038/sj.bjp.0701047
Effect of partially modified retro‐inverso analogues derived from C‐reactive protein on the induction of nitric oxide synthesis in peritoneal macrophages
Authors: Arcoleo F. , Milano S. , D'Agostino P. , Misiano G. , Cappelletti S. , Gromo G. , Marcucci F. , Leoni F. , Cillari E. 
Published: August 2006

The ability of three modified tetrapeptides, representing fragments of the C‐reactive protein (CRP) sequence and stabilized in the first peptide bond by retro‐inverso modification, to affect the secretion of nitric oxide (NO) was studied in macrophages of BALB/c mice.
These tetrapeptides, resembling the aminoacid sequence of tuftsin (CRP I, H‐gThr‐(R,S)mLys‐Pro‐Leu‐OH, ITF 1192; CRP II, H‐gGly‐(R, S)mLys‐Pro‐Arg‐OH, ITF 1127; CRP III, H‐gThr‐(R,S)mLys‐Pro‐Gln‐OH, ITF 1193), were able to induce NO synthesis by peritoneal macrophages in a dose‐dependent manner; the most stimulating dose was 1000 ng ml−1 for CRP II and 100 ng ml−1 for CRP I and CRP III. NO synthesis was not strictly dependent on lipopolysaccharide (LPS) activation.
The enhanced effect of retro‐inverso CRP‐related analogues on the expression of iNOS (inducible NO synthase) was confirmed by higher levels of iNOS activity in the cytosol and by the increase in iNOS protein, as evaluated by Western blot analysis, in macrophages stimulated by CPR compared with untreated ones.
The production of NO by retro‐inverso CRP‐peptide analogues was significantly inhibited by dexamethasone (20 μm), NG‐monomethyl‐l‐arginine (l‐NMMA) (500 μm) and pyrrolidine dithiocarbamate (PDTC) (100 μm).
Retro‐inverso CRP‐peptide analogues stimulated macrophages to produce high levels of interleukin‐1 (IL‐1) and tumour necrosis factor‐α (TNF‐α) in the presence of LPS.
Retro‐inverso CRP‐peptide analogues stimulated NO synthesis by the enhancement of endogenously produced IL‐1 and TNF‐α, as the treatment of peritoneal macrophages with LPS in the presence of neutralizing anti‐IL‐1 and anti‐TNF monoclonal antibodies (mAbs) reduced retro‐inverso analogue‐induced NO secretion. Data indicate a predominant role for IL‐1α in the induction of NO secretion by retro‐inverso analogues.
These results suggest that retro‐inverso CRP derived analogues act as costimulators of NO and cytokine synthesis in macrophages. The mechanisms by which they cause iNOS induction appear to be strongly dependent on the activation of nuclear factor‐κB (NF‐κB).

British Journal of Pharmacology (1997) 120, 1383–1389; doi:10.1038/sj.bjp.0701050
Prostaglandin E1 potentiation of the spontaneous phasic contraction of rat isolated portal vein by a cyclopiazonic acid‐sensitive mechanism
Authors: Miwa Takaaki , Endou Masayuki , Okumura Fukuichiro 
Published: August 2006

The effect of prostaglandin E1 (PGE1) on the spontaneous phasic contraction of the rat isolated portal vein was studied.
The isolated portal vein exhibited spontaneous phasic contractions. Removal of Ca2+ from Krebs‐Ringer solution or application of nifedipine abolished the spontaneous contraction, indicating that the contraction depends exclusively on Ca2+ influx through L‐type Ca2+ channels. On the other hand, cyclopiazonic acid (CPA), a specific inhibitor of Ca2+‐ATPase of sarcoplasmic reticulum (SR) increased the amplitude of the contractions, suggesting that the SR regulates the spontaneous contractions negatively by sequestration of Ca2+ entering through L‐type Ca2+ channels and buffering the rise in cytosolic Ca2+.
PGE1 increased the amplitude of the spontaneous contraction in a concentration‐dependent manner without affecting the resting tension. The effect was completely abolished by nifedipine. Bay K 8644 and phenylephrine (PE) also increased the amplitude of the contraction in a concentration‐dependent manner. PGE1 at a concentration of 1 μm, Bay K 8644 at 100 nm and PE at 30 nm doubled the amplitude, respectively.
Pretreatment with 1 μm CPA abolished the effect of PGE1, but the effects of Bay K 8644 and PE were not inhibited by pretreatment with CPA. In contrast, 10 μm ryanodine attenuated the effect of PE without affecting the contractile effect of PGE1.
When the SR was depleted of Ca2+ by repeated applications of caffeine in a nominally Ca2+‐free Krebs‐Ringer solution, it took about 120 s to restore the spontaneous contraction after addition of Ca2+ into the solution. In CPA‐treated veins, the time taken to restore the contraction was shortened significantly. Pretreatment with 1 μm PGE1 shortened the time to the same extent as pretreatment with CPA did.
These results suggest that PGE1 increases the amplitude of the spontaneous phasic contraction by a different mechanism from those by which PE and Bay K 8644 increase it. Inhibition of Ca2+‐ATPase of the SR might be involved in the vasoactive effect of PGE1.

British Journal of Pharmacology (1997) 120, 1419–1426; doi:10.1038/sj.bjp.0701051
Stimulation of cyclic AMP‐dependent protein kinase in rat atria by (–;)‐CGP 12177 through an atypical β‐adrenoceptor
Authors: Kaumann Alberto J. , Lynham James A. 
Published: August 2006

Mammalian hearts possess an atypical β‐adrenoceptor (non‐β1, non‐β2, non‐β3) through which (–)‐4‐(3‐t‐butylamino‐2‐hydroxypropoxy)benzimidazol‐2‐one ((–)‐CGP 12177) causes cardiostimulant effects. Here we showed that (–)‐CGP 12177 increased the activity of adenosine 3′ : 5′‐cyclic monophosphate (cyclic AMP)‐dependent protein kinase in the presence of 200 nm (–)‐propranolol in rat atria at a concentration (10 μm) that elicits maximum positive chronotropic and inotropic effects. The phosphodiesterase inhibitor 3‐isobutyl‐l‐methylxanthine (IBMX) potentiated the positive chronotropic and inotropic effects of (–)‐CGP 12177. We suggest that the atypical β‐adrenoceptor is coupled positively to the Gs protein‐adenylyl cyclase system.British Journal of Pharmacology (1997) 120, 1187–1189; doi:10.1038/sj.bjp.0701053
Comparison of the reversed passive Arthus and local Shwartzman reactions of rabbit skin: effects of the long‐acting PAF antagonist UK‐74,505
Authors: Norman Keith E. , Williams Timothy J. , Rossi Adriano G. 
Published: August 2006

By using the selective, potent and long acting platelet‐activating factor (PAF) antagonist, UK‐74,505, we investigated the role of PAF in a local Shwartzman reaction (LSR) and a reversed passive Arthus (RPA) reaction in rabbit skin. For comparison, we also studied the effect of the PAF antagonist on neutrophil aggregation in vitro and on acute inflammatory responses induced by intradermally (i.d.) injected lipopolysaccharide (LPS), PAF, bradykinin and zymosan‐activated plasma.
Neutrophil aggregation was assessed photometrically. Haemorrhage, oedema formation, platelet deposition and neutrophil accumulation were quantified in rabbit skin by measuring the accumulation of i.v. injected 51Cr‐labelled red blood cells (RBC), 125I‐labelled human serum albumin, 111In‐labelled platelets and 111In‐labelled neutrophils respectively.
UK‐74,505 inhibited in vitro neutrophil aggregation induced by PAF but not by leukotriene B4. When injected i.v. into rabbits UK‐74,505 suppressed oedema formation in response to i.d. PAF for up to 4 h but had no effect on oedema induced by bradykinin or zymosan‐activated plasma.
Oedema formation, but not neutrophil accumulation, produced during the RPA reaction was significantly inhibited by i.v. UK‐74,505. The PAF antagonist also suppressed 111In‐platelet but not 111In‐neutrophil accumulation in response to i.d. LPS. UK‐74,505 did not affect haemorrhage or oedema formation produced during the LPS‐mediated LSR.
The results demonstrate that PAF is an important mediator of oedema formation, but not neutrophil accumulation, in the immune‐complex mediated RPA reaction in rabbit skin. PAF also appears to be required for platelet, but not neutrophil, accumulation in response to locally injected LPS. Our studies do not suggest a role for PAF in the LPS‐mediated LSR.

British Journal of Pharmacology (1997) 120, 1286–1293; doi:10.1038/sj.bjp.0701057