bluuebunny/crossref_metadata_2025_split huggingface dataset:
The signal transduction mechanism involved in kazinol B‐stimulated superoxide anion generation in rat neutrophils
Authors: Wang Jih P , Tsao Lo T , Raung Shue L , Lin Chun N 
Published: January 2005

In this study, the underlying mechanism of stimulation of respiratory burst by kazinol B, a natural isoprenylated flavan, in rat neutrophils in vitro was investigated.
Kazinol B concentration‐dependently stimulated the superoxide anion (O2[dot over 2]−) generation, with a lag but transient activation profile, in neutrophils but not in a cell‐free system. The maximum response (13.2±1.4 nmol O2[dot over 2]− 10 min−1 per 106 cells) was observed at 10 μM kazinol B.
Pretreatment of neutrophils with phorbol 12‐myristate 13‐acetate (PMA) or formylmethionyl‐leucyl‐phenylalanine (fMLP) significantly enhanced the O2[dot over 2]− generation following the subsequent stimulation of cells with kazinol B.
Cells pretreated with EGTA or a protein kinase inhibitor staurosporine effectively attenuated the kazinol B‐induced O2[dot over 2]− generation. However, a p38 mitogen‐activated protein kinase (MAPK) inhibitor SB203580 and a phosphoinositide 3‐kinase (PI3K) inhibitor wortmannin had no effect on the kazinol B‐induced response.
Kazinol B significantly stimulated [Ca2+]i elevation in neutrophils, with a lag and slow rate of rise activation profile, and this response was attenuated by a phospholipase C (PLC) inhibitor U73122. Kazinol B also stimulated the inositol bis‐ and trisphosphate (IP2 and IP3) formation with a 1 min lag time.
The membrane‐associated PKC‐α and PKC‐θ but not PKC‐ι were increased following the stimulation of neutrophils with kazinol B. It was more rapid and sensitive in the activation of PKC‐θ than PKC‐α by kazinol B. Kazinol B partially inhibited the [3H]phorbol 12,13‐dibutyrate ([3H]PDB) binding to the neutrophil cytosolic PKC.
Neither the cellular mass of phosphatidic acid (PA) and phosphatidylethanol (PEt), in the presence of ethanol, nor the protein tyrosine phosphorylation were stimulated by kazinol B. In addition, the kazinol B‐induced O2[dot over 2]− generation remained relatively unchanged in cells pretreated with ethanol or a tyrosine kinase inhibitor genistein.
Collectively, these results indicate that the stimulation of the respiratory burst by kazinol B is probably mediated by the synergism of PKC activation and [Ca2+]i elevation in rat neutrophils.

British Journal of Pharmacology (1998) 125, 517–525; doi:10.1038/sj.bjp.0702106
Phosphorylation and IGF‐1‐mediated dephosphorylation pathways control the activity and the pharmacological properties of skeletal muscle chloride channels
Authors: De Luca Annamaria , Pierno Sabata , Liantonio Antonella , Camerino Claudia , Conte Camerino Diana 
Published: January 2005

In the present study we tested the hypothesis that insulin‐like growth factor‐1 (IGF‐1) modulates resting chloride conductance (GCl) of rat skeletal muscle by activating a phosphatase and that the chloride channel, based on the activity of phosphorylating‐dephosphorylating pathways, has different sensitivity to specific ligands, such as the enantiomers of 2‐(p‐chlorophenoxy) propionic acid (CPP).
For this purpose GCl in EDL muscle isolated from adult rat was first lowered by treatment with 5 nM 4‐β‐phorbol 12,13 dibutyrate (4‐β‐PDB), presumably activating protein kinase C (PKC). The effects of IGF‐1 and of the enantiomers of CPP on GCl were then tested.
IGF‐1 (3.3 nM) had no effect of GCl on EDL muscle fibres in normal physiological solution, whereas it completely counteracted the 30% decrease of GCl induced by 4‐β‐PDB. No effects of IGF‐1 were observed on GCl lowered by the phosphatase inhibitor okadaic acid (0.25 μM).
Ceramide, reported to activate on okadaic acid‐sensitive phosphatase, mimicked the effects of IGF‐1. In fact, N‐acetyl‐sphingosine (2.5–5 μM), not very effective in control conditions, increased the GCl lowered by the phorbol ester, but not the GCl lowered by okadaic acid.
In the presence of 4‐β‐PDB, GCl was differently affected by the enantiomers of CPP. The S(−)‐CPP was remarkably less potent in producing the concentration‐dependent reduction of GCl, whereas the R(+)‐CPP caused an increase of GCl at all the concentrations tested.
In conclusion, the PKC‐induced lowering of GCl is counteracted by IGF‐1 through an okadaic acid sensitive phosphatase, and this effect can have therapeutic relevance in situations characterized by excessive channel phosphorylation. In turn the phosphorylation state of the channel can modulate the effects and the therapeutic potential of direct channel ligands.

British Journal of Pharmacology (1998) 125, 477–482; doi:10.1038/sj.bjp.0702107
Induction by interleukin‐1, tumor necrosis factor and lipopolysaccharides of histidine decarboxylase in the stomach and prolonged accumulation of gastric acid
Authors: Endo Yasuo , Kumagai Katsuo 
Published: January 2005

Injection of interleukin‐1 (IL‐1) into pylorus‐ligated rats has been shown strongly to inhibit gastric secretion. However, in the present study, we found that an intraperitoneal injection of IL‐1 into intact (non‐pylorus‐ligated) fasted mice rapidly (within 30 min) induced an accumulation of gastric acid (‘early response’). When the dose of IL‐1 was larger, the accumulation lasted for a longer period.
Injection of IL‐1 also caused a later elevation of the activity of histidine decarboxylase (HDC), the histamine‐forming enzyme, in the stomach (‘later response’).
Cimetidine, an antagonist of histamine H2‐receptors, suppressed the accumulation of gastric acid in both the early and later periods. An irreversible inhibitor of HDC, α‐fluoromethylhistidine, partially inhibited the accumulation in the later period.
IL‐1, when injected 1 h after feeding in mice fasted overnight, markedly retarded gastric emptying.
Tumour necrosis factor (TNF) and lipopolysaccharide (LPS) or endotoxin from E. coli both had IL‐1‐like effects on the stomach, and their effects are presumably mediated by IL‐1.
These results support the idea that an inhibition of gastric emptying and an elevation of HDC activity in the stomach may explain the findings that a long‐lasting accumulation of gastric acid is induced by IL‐1 despite its potent inhibition of gastric acid secretion.
On the basis of these results, and in the light of the known actions of histamine, the possible roles of IL‐1 in gastric inflammation and ulceration are discussed.

British Journal of Pharmacology (1998) 125, 842–848; doi:10.1038/sj.bjp.0702108
The actions of some cannabinoid receptor ligands in the rat isolated mesenteric artery
Authors: White Richard , Robin Hiley C 
Published: January 2005

The actions of a number of cannabinoid receptor ligands were investigated using the myograph‐mounted rat isolated mesenteric artery. Anandamide, CP 55,940, HU‐210, palmitoylethanolamide and WIN 55,212‐2 all caused concentration‐dependent relaxations of methoxamine‐precontracted vessels which were not affected by removal of the endothelium.
Precontracting vessels with 60 mM KCl instead of methoxamine greatly reduced the vasorelaxant effects of anandamide and palmitoylethanolamide. High K+ solution caused a modest decrease in the relaxant potency of CP 55,940 and HU‐210, and had no effect on relaxations induced by WIN 55,212‐2.
Relaxations of methoxamine‐induced tone by anandamide, CP 55,940 and HU‐210, but not palmitoylethanolamide and WIN 55,212‐2, were attenuated by the cannabinoid receptor antagonist, SR 141716A. Relaxation of vessels contracted with 60 mM KCl by CP 55,940 was also sensitive to SR 141716A.
Anandamide and CP 55,940 caused small but concentration‐dependent contractions in resting vessels in the absence of extracellular calcium. These were not sensitive to SR 141716A. Palmitoylethanolamide and WIN 55,212‐2 produced smaller contractions only at higher concentrations.
Anandamide and CP 55,940, but not palmitoylethanolamide and WIN 55,212‐2, caused concentration‐dependent inhibition of the phasic contractions induced by methoxamine in calcium‐free conditions, but only anandamide caused inhibition of contractions to caffeine under such conditions. These inhibitory effects were not antagonised by SR 141716A.
The present study provides the first detailed investigation of the actions of cannabinoid agonists on vascular smooth muscle. Our results show that these compounds exert both receptor‐dependent and ‐independent effects on agonist‐induced calcium mobilization in the rat isolated mesenteric artery.

British Journal of Pharmacology (1998) 125, 533–541; doi:10.1038/sj.bjp.0702111
Discovery of novel selective hypotensive vasopressin peptides that exhibit little or no functional interactions with known oxytocin/vasopressin receptors
Authors: Chan W Y , Wo N C , Stoev S , Cheng L L , Manning M 
Published: January 2005

Arginine‐vasopressin (VP) has both vasoconstricting and vasodilating action. We report here the discovery of four novel selective hypotensive VP analogues: d(CH2)5[D‐Tyr(Et)2,Arg3,Val4]AVP; d(CH2)5[D‐Tyr(Et)2,Lys3,Val4]AVP and their iodinatable Tyr‐NH29 analogues.
Bioassays in rats for activities characteristic of neurohypophysial peptides showed that the four VP peptides possessed little or no V1a, V2 or oxytocin (OT) receptor agonistic or antagonistic activities.
In anaesthetized rats, these peptides (0.05–0.10 mg kg−1 i.v.) elicited a marked fall in arterial blood pressure.
Blockade of cholinoceptors, adrenoceptors and bradykinin B2 receptors, and inhibition of prostaglandin synthesis had little effect on their vasodepressor action.
Classical V1a, V2 and OT receptor antagonists did not block the vasodepressor response.
L‐NAME, 0.2 mg kg−1 min−1, markedly suppressed the hypotensive response to ACh but not the vasodepressor response to the hypotensive VP peptides. However, the duration of the vasodepressor response was shortened. Very high doses of L‐NAME attenuated both the vasodepressor response and the duration of action.
These findings indicate that the vasodepressor action of these VP peptides is independent of the peripheral autonomic, bradykinin and PG systems and is not mediated by the known classical OT/VP receptors. NO does not appear to have an important role in their vasodepressor action.
The discovery of these novel VP peptides could lead to the development of new tools for the investigation of the complex cardiovascular actions of VP and the introduction of a new class of hypotensive agents. The two iodinatable hypotensive VP peptides could be radiolabelled as potential markers for the localization of the receptor system involved.

British Journal of Pharmacology (1998) 125, 803–811; doi:10.1038/sj.bjp.0702114
Pharmacological and molecular characterization of P2X receptors in rat pelvic ganglion neurons
Authors: Zhong Yu , Dunn Philip M , Xiang Zhenghua , Bo Xuenong , Burnstock Geoffrey 
Published: January 2005

The presence and characteristics of P2X receptors on neurons of the rat major pelvic ganglia (MPG) have been studied using whole cell voltage‐clamp, in situ hybridization and immunohistochemistry.
Rapid application of ATP (100 μM) to isolated rat MPG neurons induced moderately large inward currents (0.33–5.3 nA) in 39% of cells (108/277). The response to ATP occurred very rapidly, with an increase in membrane conductance, and desensitized slowly.
The concentration‐response curve for ATP yielded an EC50 of 58.9 μM. The agonist profile was ATP2MeSATP=ATPγS>BzATP, while α,β‐MeATP, β,γ‐MeATP, UTP and ADP were all inactive at concentrations up to 100 μM.
The response to ATP was antagonized by suramin (pA2=5.6), reactive blue‐2 (IC50=0.7 μM) and pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS).
Lowering the pH from 7.4 to 6.8 produced a marked potentiation (to 339% of control) of the responses to ATP (30 μM), while raising the pH to 8.0 attenuated the responses (to 20% of control). The EC50s for ATP were 28.8, 58.9 and 264 μM at pH 6.8, 7.4 and 8.0, respectively.
Co‐application of ATP with Zn2+ produced a marked enhancement of the responses to ATP, with an EC50 of 9.55 μM. In the presence of Zn2+ (30 μM), the EC50 for ATP was decreased to 4.57 μM.
In situ hybridization revealed that the P2X receptor transcripts levels in rat MPG neurons are P2X2>P2X4>P2X1, P2X3, P2X5 and P2X6. The immunohistochemical staining revealed a small number of neurons with strong P2X2 immunoreactivity.
In conclusion, our results indicate that there are P2X receptors present on MPG neurons. The pharmacological characteristics of these receptors, the in situ hybridization and immunohistochemical evidence are consistent with them being of the P2X2 subtype, or heteromultimers, with P2X2 being the dominant component.

British Journal of Pharmacology (1998) 125, 771–781; doi:10.1038/sj.bjp.0702118
Effects of intracerebroventricular leptin administration on food intake, body weight gain and diencephalic nitric oxide synthase activity in the mouse
Authors: Calapai Gioacchino , Corica Francesco , Allegra Alessandro , Corsonello Andrea , Sautebin Lidia , De Gregorio Tiziana , Di Rosa Massimo , Costantino Giuseppina , Buemi Michele , Caputi Achille P 
Published: January 2005

Intracranial administration of leptin reduces both food intake and body weight gain in the mouse. Inhibitors of nitric oxide (NO) synthase produce similar effects.
To investigate the role of the brain L‐arginine/NO pathway in mediating this effect of leptin, we have evaluated food intake and body weight gain after daily (5 days) intracerebroventricular (i.c.v.) administration of leptin (0.5–2 μg) alone or in association with L‐arginine (10 μg). Moreover, we measured diencephalic nitric oxide synthase (NOS) activity after a single i.c.v. leptin (0.25–2 μg) injection and after consecutive doses of leptin (0.25–2 μg) over 5 days. The time course of the effect of leptin on NOS activity was also evaluated.
I.c.v. injected leptin (1 and 2 μg) significantly and dose‐dependently reduced food intake and body weight gain with respect to vehicle (food intake: 5.97±0.16 g 24 h−1 and 4.27±0.18 g 24 h−1, respectively, vs 8.05±0.34 g 24 h−1, P<0.001, n=6 for each group; body weight gain: −10.7±0.46% and −15.2±0.65%, respectively, vs 5.14±0.38%, P<0.001, n=6 for each group). This effect was antagonized by L‐arginine (food intake: 7.90±0.37 g 24 h; body weight gain: 5.11±0.31%, n=6). Diencephalic NOS activity was significantly reduced by the highest doses of leptin with respect to vehicle (vehicle: 0.90±0.04 nmol citrulline min−1 g−1 tissue; leptin 1 μg: 0.62±0.03 nmol citrulline min−1 g−1 tissue, P<0.001; leptin 2 μg: 0.44±0.03 nmol citrulline min−1 g−1 tissue, P<0.001, n=6 for each group). Similar results were obtained in animals treated with daily consecutive doses of leptin. The inhibitory effect appeared rapidly (within 30 min) and was long lasting (up to 12 h).
Our results suggest that the brain L‐arginine/NO pathway may be involved in the central effect of leptin on feeding behaviour and body weight gain in mice.

British Journal of Pharmacology (1998) 125, 798–802; doi:10.1038/sj.bjp.0702121
Effects of lysophosphatidylcholine on the production of interstitial adenosine via protein kinase C‐mediated activation of ecto‐5′‐nucleotidase
Authors: Sato Toshiaki , Obata Toshio , Yamanaka Yasumitsu , Arita Makoto 
Published: January 2005

Adenosine plays a crucial role in the evolution of ischemic preconditioning. With the use of microdialysis techniques in in situ rat hearts, we assessed the activity of ecto‐5′‐nucleotidase (a key enzyme responsible for adenosine production), and examined the effects of lysophosphatidylcholine (LPC) on the production of interstitial adenosine.
The microdialysis probe was implanted in the left ventricular myocardium of anesthetized rat hearts and perfused with Tyrode solution containing adenosine 5′‐monophosphate (AMP, 100 μM). With this system, the dialysate adenosine originates from the dephosphorylation of AMP, catalyzed by endogenous ecto‐5′‐nucleotidase. The level of dialysate adenosine is a measure of the ecto‐5′‐nucleotidase activity in vivo.
LPC at concentrations of 25 and 50 μM significantly increased the level of dialysate adenosine to 122.7±4.3% (n=4, P<0.05) and 158.6±7.2% (n=5, P<0.05) of the control, respectively. Chelerythrine (200 μM), a protein kinase C (PKC) inhibitor, completely abolished the increase of dialysate adenosine afforded by LPC (50 μM) (n=5).
These data provide the first evidence that LPC does increase the concentration of interstitial adenosine in rat hearts in situ, through the PKC‐mediated activation of endogenous ecto‐5′‐nucleotidase.

British Journal of Pharmacology (1998) 125, 493–498; doi:10.1038/sj.bjp.0702122
The actions of the cannabinoid receptor antagonist, SR 141716A, in the rat isolated mesenteric artery
Authors: White Richard , Robin Hiley C 
Published: January 2005

The actions of the cannabinoid receptor antagonist, SR 141716A, were examined in rat isolated mesenteric arteries. At concentrations greater than 3 μM, it caused concentration‐dependent, but endothelium‐independent, relaxations of both methoxamine‐ and 60 mM KCl‐precontracted vessels.
SR 141716A (at 10 μM, but not at 1 μM) inhibited contractions to Ca2+ in methoxamine‐stimulated mesenteric arteries previously depleted of intracellular Ca2+ stores. Neither concentration affected the phasic contractions induced by methoxamine in the absence of extracellular Ca2+.
SR 141716A (10 μM) caused a 130 fold rightward shift in the concentration‐response curve to levcromakalim, a K+ channel activator, but had no effect at 1 μM.
SR 141716A (10 μM) attenuated relaxations to NS 1619 (which activates large conductance, Ca2+‐activated K+ channels; BKCa). The inhibitory effect of SR 141716A on NS 1619 was not significantly different from, and was not additive with, that caused by a selective BKCa inhibitor, iberiotoxin (100 nM). SR 141716A (1 μM) did not effect NS 1619 relaxation.
SR 141716A (10 μM) had no effect on relaxations to the nitric oxide donor S‐nitroso‐N‐acetylpenicillamine, or relaxations to carbachol in the presence of 25 mM KCl.
The results show that, at concentrations of 10 μM and above, SR 141716A causes endothelium‐independent vasorelaxation by inhibition of Ca2+ entry. It also inhibits relaxations mediated by K+ channel activation. This suggests that such concentrations of SR 141716A are not appropriate for investigation of cannabinoid receptor‐dependent processes.

British Journal of Pharmacology (1998) 125, 689–696; doi:10.1038/sj.bjp.0702127
Actions of adenosine A1 and A2 receptor antagonists on CFTR antibody‐inhibited β‐adrenergic mucin secretion response
Authors: Pereira M M C , Lloyd Mills C , Dormer R L , McPherson M A 
Published: January 2005

The cystic fibrosis gene protein, the cystic fibrosis transmembrane conductance regulator (CFTR) acts as a chloride channel and is a key regulator of mucin secretion. The mechanism by which 3‐isobutyl‐1‐methylxanthine (IBMX) corrects the defect in CFTR mediated β‐adrenergic stimulation of mucin secretion has not been determined. The present study has investigated the actions of adenosine A1 and A2 receptor antagonists to determine whether ability to stimulate mucin secretion correlates with correction of CFTR antibody inhibited β‐adrenergic response and whether excessive cyclic AMP rise is required.
CFTR antibodies were introduced into living rat submandibular acini by hypotonic swelling. Following recovery, mucin secretion in response to isoproterenol was measured.
The adenosine A1 receptor antagonist, 8 cyclopentyltheophylline (CPT) was a less potent stimulator of mucin secretion than was the A2 receptor antagonist dimethylpropargylxanthine (DMPX). A concentration of CPT close to the Ki for A1 receptor antagonism (10 nM) did not stimulate mucin secretion.
DMPX, although a potent stimulator of mucin secretion, did not correct CFTR antibody inhibited mucin secretion.
CPT corrected defective CFTR antibody inhibited mucin secretion at a high (1 mM) concentration, suggesting a mechanism other than adenosine receptor antagonism.
DMPX potentiated the isoproterenol induced cyclic AMP rise, whereas CPT did not.
Correction of the defective CFTR mucin secretion response did not correlate with ability to stimulate mucin secretion and did not require potentiation of β‐adrenergic induced increases in cyclic AMP. This affords real promise for the development of a selective drug treatment for cystic fibrosis.

British Journal of Pharmacology (1998) 125, 697–704; doi:10.1038/sj.bjp.0702128
Nicotine administration stimulates the in vivo N‐methyl‐D‐aspartate receptor/nitric oxide/cyclic GMP pathway in rat hippocampus through glutamate release
Authors: Fedele Ernesto , Varnier Giorgia , Antonia Ansaldo Maria , Raiteri Maurizio 
Published: January 2005

The in vivo effects of nicotine on the nitric oxide (NO) synthase/cyclic GMP pathway of the adult rat hippocampus have been investigated by monitoring the levels of extracellular cyclic GMP during microdialysis in conscious unrestrained animals.
Intraperitoneal (i.p.) administration of nicotine caused elevation of cyclic GMP levels which was prevented by mecamylamine. The effect of nicotine was abolished by local infusion of the NO synthase inhibitor NG‐nitro‐L‐arginine (L‐NOARG) or by the soluble guanylyl cyclase blocker 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxaline‐1‐one (ODQ).
Local administration of the NMDA receptor antagonists cis‐4‐(phosphonomethyl)‐2‐piperidinecarboxylic acid (CGS19755) and dizocilpine (MK‐801) inhibited by about 60% the nicotine‐induced elevation of cyclic GMP. Nicotine was able to stimulate cyclic GMP outflow also when administered directly into the hippocampus; the effect was sensitive to mecamylamine, L‐NOARG, ODQ or MK‐801.
Nicotine, either administered i.p. or infused locally, produced augmentation of glutamate and aspartate extracellular levels, whereas the outflows of γ‐aminobutyric acid (GABA) and glycine remained unaffected. Following local administration of high concentrations of nicotine, animals displayed symptoms of mild excitation (sniffing, increased motor and exploratory activity) during the first 20–40 min of infusion, followed by wet dog shake episodes; these behavioural effects were prevented by mecamylamine or MK‐801, but not by L‐NOARG or by ODQ.
It is concluded that (a) nicotine stimulates the production of NO and cyclic GMP in the hippocampus; (b) this occurs, at least in part, through release of glutamate/aspartate and activation of NMDA receptors. Modulation of the NMDA receptor/NO synthase/cyclic GMP pathway may be involved in the cognitive activities of nicotine.

British Journal of Pharmacology (1998) 125, 1042–1048; doi:10.1038/sj.bjp.0702130