bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclic AMP‐mediated regulation of vascular smooth muscle cell cyclic AMP phosphodiesterase activity
Authors: Rose R. J. , Liu H. , Palmer D. , Maurice D. H. 
Published: January 2005

Rat cultured aortic vascular smooth muscle cells (VSMC) express both cyclic GMP‐inhibited cyclic AMP phosphodiesterase (PDE3) and Ro 20–1724‐inhibited cyclic AMP phosphodiesterase (PDE4) activities. By utilizing either cilostamide, a PDE3‐selective inhibitor, or Ro 20–1724, a PDE4‐selective inhibitor, PDE3 and PDE4 activities were shown to account for 15% and 55% of total VSMC cyclic AMP phosphodiesterase (PDE) activity.
Treatment of VSMC with either forskolin or 8‐bromo‐cyclic AMP caused significant concentration‐ and time‐dependent increases in total cellular cyclic AMP PDE activity. Using cilostamide or Ro 20–1724, we demonstrated that both PDE3 and PDE4 activities were increased following forskolin or 8‐bromo‐cyclic AMP treatment, with a relatively larger effect observed on PDE3 activity. The increase in cyclic AMP PDE activity induced by forskolin or 8‐bromo‐cyclic AMP was inhibited by actinomycin D or cycloheximide, demonstrating that new mRNA synthesis and protein synthesis were required. An analogue of forskolin which does not activate adenylyl cyclase (1,9‐dideoxyforskolin) or an analogue of cyclic GMP (8‐bromo‐cyclic GMP) did not affect total cyclic AMP PDE activity.
Incubation of VSMC with 8‐bromo‐cyclic AMP for 16 h caused a marked rightward shift in the concentration‐response curves for both isoprenaline‐ and forskolin‐mediated activation of adenylyl cyclase. A role for up‐regulated cyclic AMP PDE activity in this reduced potency is supported by our observation that cyclic AMP PDE inhibitors (IBMX, cilostamide or Ro 20–1724) partially normalized the effects of isoprenaline or forskolin in treated cells to those in untreated cells.
We conclude that VSMC cyclic AMP PDE activity is increased following long‐term elevation of cyclic AMP and that increases in PDE3 and PDE4 activities account for more than 70% of this effect. Furthermore, we conclude that increases in cyclic AMP PDE activity contribute to the reduced potency of isoprenaline or forskolin in treated VSMC. These results have implications for long‐term use of cyclic AMP PDE inhibitors as therapeutic agents.

British Journal of Pharmacology (1997) 122, 233–240; doi:10.1038/sj.bjp.0701376
Neurokinin A‐LI release after antigen challenge in guinea‐pig bronchial tubes: influence of histamine and bradykinin
Authors: Lindström Eva G. , Andersson Rolf G. G. 
Published: January 2005

Our aim was to determine if antigen challenge stimulates sensory nerves and provokes the release of tachykinins. The involvement of histamine and bradykinin was studied by using specific receptor antagonists. Capsaicin‐induced responses were also examined. Experiments were performed in vitro on tracheal and bronchial preparations from ovalbumin‐sensitized guinea‐pigs.
Characterization of ovalbumin‐induced contraction, with regard to histamine and bradykinin, was carried out on airway ring preparations in the presence of phosphoramidon. The histamine H1 receptor antagonist pyrilamine reduced allergen‐induced bronchial contractions by about 30%, whereas the bradykinin B2 receptor antagonist icatibant (Hoe 140) did not significantly affect the response. Combined treatment with pyrilamine (1 μM) and icatibant (0.1 μM) reduced the contractions by about 80%, indicating a synergistic inhibitory action. Tracheal preparations were not significantly affected by treatments, neither were capsaicin‐induced contractions.
To study the outflow of tachykinins, we used a perfused bronchial‐tube preparation, allowing simultaneous measurement of smooth muscle tension and mediator release. Neurokinin A‐like immunoreactivity (NKA‐LI) and substance P‐like immunoreactivity (SP‐LI) were determined by radioimmunoassay.
The results of the perfusion study showed an increased outflow of NKA‐LI into the perfusate in response to ovalbumin (127% of basal) challenge. SP‐LI determined in some of the samples showed a much lower amount (40 to 70 times lower) of SP‐LI than NKA‐LI. Treatment with icatibant and pyrilamine, separately and in combination, significantly reduced the ovalbumin‐induced NKA‐LI outflow by 38%, 26% and 22%, respectively.
Capsaicin‐induced outflow (124% of basal) was not significantly affected by treatments (icatibant 121%, pyrilamine 107% and combined treatment 111% of basal). However, when pyrilamine was present the increased outflow was not statistically significant.
In conclusion, we found that allergen provocation of guinea‐pig bronchi caused an increased outflow of NKA‐LI that was reduced by treatment with both pyrilamine and icatibant. These findings demonstrate that the allergen‐induced release of histamine and bradykinin stimulate sensory nerves and thereby increase outflow of tachykinins that contribute to the allergic reaction.

British Journal of Pharmacology (1997) 122, 417–422; doi:10.1038/sj.bjp.0701382
Effects of VA‐045 on learning and memory deficits in traumatic brain injury (TBI)‐induced retrograde and anterograde amnesic mice
Authors: Tang Ya‐Ping , Noda Yukihiro , Hasegawa Takaaki , Nabeshima Toshitaka 
Published: January 2005

No specific regimen has been developed to treat post‐traumatic amnesia in man. In the present study, we examined the effects of (+)‐eburnamenine‐14‐carboxylic acid (2‐nitroxyethyl) ester (VA‐045), a novel derivative of apovincaminic acid, on learning and memory deficits associated with a mild traumatic brain injury (TBI) in mice.
Two kinds of amnesia, TBI‐induced retrograde amnesia (TRA) and anterograde amnesia (TAA), were produced by means of post‐ and pre‐acquisition head injury, respectively, by a simple weight‐drop device. A novel procedure of water‐finding task was used to assess learning and memory functions.
Both TRA and TAA mice were dramatically impaired in the task performance, with prolonged latencies for finding and drinking in either retention test or retest, indicating that retention was impaired in TRA mice while learning and retention were impaired in TAA mice.
VA‐045 administered 30 min post‐trauma in TRA mice dramatically shortened the prolonged latencies for finding and drinking in both retention test and retest, indicating that VA‐045 significantly improved the retention deficit observed in TRA mice.
VA‐045 administered 30 min post‐trauma in TAA mice dramatically attenuated the prolonged latencies for finding and drinking in both retention test and retest, indicating that VA‐045 significantly improved the learning and retention deficits observed in TAA mice.
Administration of VA‐045 30 min pre‐trauma in normal mice markedly attenuated the delay of latencies for finding and drinking after trauma in both retention test and retest, which shows that VA‐045 significantly prevented learning and retention deficits after TBI.
Motor activities were not significantly affected by either the TBI or the chemical treatment at the time of task examination in either experimental model.
It is concluded that VA‐045 may have potential effects on learning and memory deficits observed in either TBI‐induced retrograde or anterograde amnesia.

British Journal of Pharmacology (1997) 122, 257–264; doi:10.1038/sj.bjp.0701385
Anti‐inflammatory activity of cationic lipids
Authors: Filion Mario C. , Phillips Nigel C. 
Published: January 2005

The effect of liposome phospholipid composition has been assumed to be relatively unimportant because of the presumed inert nature of phospholipids.
We have previously shown that cationic liposome formulations used for gene therapy inhibit, through their cationic component, the synthesis by activated macrophages of the pro‐inflammatory mediators nitric oxide (NO) and tumour necrosis factor‐α (TNF‐α).
In this study, we have evaluated the ability of different cationic lipids to reduce footpad inflammation induced by carrageenan and by sheep red blood cell challenge.
Parenteral (i.p. or s.c) or local injection of the positively charged lipids dimethyldioctadecylammomium bromide (DDAB), dioleyoltrimethylammonium propane (DOTAP), dimyristoyltrimethylammonium propane (DMTAP) or dimethylaminoethanecarbamoyl cholesterol (DC‐Chol) significantly reduced the inflammation observed in both models in a dose‐dependent manner (maximum inhibition: 70–95%).
Cationic lipids associated with dioleyol‐ or dipalmitoyl‐phosphatidylethanolamine retained their anti‐inflammatory activity while cationic lipids associated with dipalmitoylphosphatidylcholine (DPPC) or dimyristoylphosphatidylglycerol (DMPG) showed no anti‐inflammatory activity, indicating that the release of cationic lipids into the macrophage cytoplasm is a necessary step for anti‐inflammatory activity. The anti‐inflammatory activity of cationic lipids was abrogated by the addition of dipalmitoylphosphatidylethanolamine‐poly(ethylene)glycol‐2000 (DPPE‐PEG2000) which blocks the interaction of cationic lipids with macrophages.
Because of the significant role of protein kinase C (PKC) in the inflammatory process we have determined whether the cationic lipids used in this study inhibit PKC activity. The cationic lipids significantly inhibited the activity of PKC but not the activity of a non‐related protein kinase, PKA. The synthesis of interleukin‐6 (IL‐6), which is not dependent on PKC activity for its induction in macrophages, was not modified in vitro or in situ by cationic lipids. The synthesis of NO and TNF‐α in macrophages, both of which are PKC‐dependent, was downregulated by cationic lipids.
These results demonstrate that cationic lipids can be considered as novel anti‐inflammatory agents. The downregulation of pro‐inflammatory mediators through interaction of cationic lipids with the PKC pathway may explain this anti‐inflammatory activity. Furthermore, since cationic lipids have intrinsic anti‐inflammatory activity, cationic liposomes should be used with caution to deliver nucleic acids for gene therapy in vivo.

British Journal of Pharmacology (1997) 122, 551–557; doi:10.1038/sj.bjp.0701396
Presynaptic inhibition of synaptic transmission in the rat hippocampus by activation of muscarinic receptors: involvement of presynaptic calcium influx
Authors: Qian Jing , Saggau Peter 
Published: January 2005

Modulation of presynaptic voltage‐dependent calcium channels (VDCCs) by muscarinic receptors at the CA3–CA1 synapse of rat hippocampal slices was investigated by using the calcium indicator fura‐2. Stimulation‐evoked presynaptic calcium transients ([Capre]t) and field excitatory postsynaptic potentials (fe.p.s.ps) were simultaneously recorded. The relationship between presynaptic calcium influx and synaptic transmission was studied.
Activation of muscarinic receptors inhibited [Capre]t, thereby reducing synaptic transmission. Carbachol (CCh, 10 μM) inhibited [Capre]t by 35% and reduced fe.p.s.p. by 85%. The inhibition was completely antagonized by 1 μM atropine. An approximate 4th power relationship was found between presynaptic calcium influx and postsynaptic responses.
Application of the N‐type VDCC‐blocking peptide toxin ω‐conotoxin GVIA (ω‐CTx GVIA, 1 μM) inhibited [Capre]t and fe.p.s.ps by 21% and 49%, respectively, while the P/Q‐type VDCC blocker ω‐agatoxin IVA (ω‐Aga IVA, 1 μM) reduced [Capre]t and fe.p.s.ps by 35% and 85%, respectively.
Muscarinic receptor activation differentially inhibited distinct presynaptic VDCCs. ω‐CTx GVIA‐sensitive calcium channels were inhibited by muscarinic receptors, while ω‐Aga IVA‐sensitive channels were not. The percentage inhibition of ω‐CTx GVIA‐sensitive [Capre]t was about 63%.
Muscarinic receptors inhibited presynaptic VDCCs in a way similar to adenosine (Ad) receptors. The percentage inhibition of ω‐CTx GVIA‐sensitive [Capre]t by Ad (100 μM) was about 59%. There was no significant inhibition of ω‐Aga IVA‐sensitive channels by Ad. The inhibitions of [Capre]t by CCh and Ad were mutually occlusive.
These results indicate that inhibition of synaptic transmission by muscarinic receptors is mainly the consequence of a reduction of the [Capre]t due to inhibition of presynaptic VDCCs.

British Journal of Pharmacology (1997) 122, 511–519; doi:10.1038/sj.bjp.0701400
An endogenous A2B adenosine receptor coupled to cyclic AMP generation in human embryonic kidney (HEK 293) cells
Authors: Cooper Jacqui , Hill Stephen J. , Alexander Stephen P. H. 
Published: January 2005

Cyclic AMP generation by adenosine analogues was examined in human embryonic kidney (HEK 293) cells by use of a [3H]‐adenine pre‐labelling methodology.
Adenosine analogues showed the following rank order of potency (pD2 value): 5′‐N‐ethylcarboxamidoadenosine (NECA, 5.24)>2‐chloroadenosine (4.41) adenosine (4.19)=N6‐(2‐(4‐aminophenyl)‐ethylamino)adenosine (APNEA, 4.11). The A2A‐selective agonist CGS21680 failed to elicit a significant stimulation of cyclic AMP generation at concentrations below 30 μM.
Of these agents, NECA was observed to exhibit the greatest intrinsic activity, while in comparison maximal responses to adenosine (76±8% NECA response), 2‐chloroadenosine (70±6%) and APNEA (40±3%) were significantly reduced.
Antagonists of the NECA‐evoked cyclic AMP generation showed the rank order of apparent affinity (apparent pA2 value): CGS 15943 (7.79)=XAC (7.74)>DPCPX (7.01)=PD115199 (6.93)=8FB‐PTP (6.80)>KF 17837 (5.98)>3‐propylxanthine (5.13).
Agarose gel electrophoresis of the products of the polymerase chain reaction, with cDNA generated from HEK 293 cell total RNA showed virtually identical patterns and nucleotide sizes in comparison with the vector for the full length human brain A2B adenosine receptor.
We concluded that HEK 293 cells express an endogenous adenosine receptor coupled to cyclic AMP generation which is of the A2B subtype.

British Journal of Pharmacology (1997) 122, 546–550; doi:10.1038/sj.bjp.0701401
Acute gentamicin‐induced hypercalciuria and hypermagnesiuria in the rat: dose‐response relationship and role of renal tubular injury
Authors: Parsons P. P. , Garland H. O. , Harpur E. S. , Old S. 
Published: January 2005

Standard renal clearance techniques were used to assess the dose‐response relationship between acute gentamicin infusion and the magnitude of hypercalciuria and hypermagnesiuria in the anaesthetized Sprague‐Dawley rat. Also investigated were whether these effects occurred independently of renal tubular cell injury.
Acute gentamicin infusion was associated with a significant hypercalciuria and hypermagnesiuria evident within 30 min of drug infusion. The magnitude of these responses was related to the dose of drug infused (0.14–1.12 mg kg−1 min−1). Increased urinary electrolyte losses resulted from a decreased tubular reabsorption of calcium and magnesium.
A rapid dose‐related increase in urinary N‐acetyl‐β‐D‐glucosaminidase (NAG) excretion was also observed in response to gentamicin infusion. However, there was no evidence of renal tubular cell injury and no myeloid bodies were observed within the lysosomes of the proximal tubular cells. Gentamicin may thus interfere with the mechanisms for cellular uptake and intracellular processing of NAG causing increased NAG release into the tubular lumen.
The absence of changes in renal cellular morphology indicates that the excessive renal losses of calcium and magnesium were an effect of gentamicin per se and not the result of underlying renal tubular injury. The renal effects described in this paper were apparent after administration of relatively low total drug doses, and with plasma concentrations calculated to be within the clinical range. These findings suggest that disturbances of plasma electrolyte homeostasis could occur in the absence of overt renal injury in patients receiving aminoglycoside antibiotics.

British Journal of Pharmacology (1997) 122, 570–576; doi:10.1038/sj.bjp.0701403
Characterization of action potential‐triggered [Ca2+]i transients in single smooth muscle cells of guinea‐pig ileum
Authors: Kohda M. , Komori S. , Unno T. , Ohashi H. 
Published: January 2005

To characterize increases in cytosolic free Ca2+ concentration ([Ca2+]i) associated with discharge of action potentials, membrane potential and [Ca2+]i were simultaneously recorded from single smooth muscle cells of guinea‐pig ileum by use of a combination of nystatin‐perforated patch clamp and fura‐2 fluorimetry techniques.
A single action potential in response to a depolarizing current pulse elicited a transient rise in [Ca2+]i. When the duration of the current pulse was prolonged, action potentials were repeatedly discharged during the early period of the pulse duration with a progressive decrease in overshoot potential, upstroke rate and repolarization rate. However, such action potentials could each trigger [Ca2+]i transients with an almost constant amplitude.
Nicardipine (1 μM) and La3+ (10 μM), blockers of voltage‐dependent Ca2+ channels (VDCCs), abolished both the action potential discharge and the [Ca2+]i transient.
Charybdotoxin (ChTX, 300 nM) and tetraethylammonium (TEA, 2 mM), blockers of large conductance Ca2+‐activated K+ channels, decreased the rate of repolarization of action potentials but increased the amplitude of [Ca2+]i transients.
Thapsigargin (1 μM), an inhibitor of SR Ca2+‐ATPase, slowed the falling phase and somewhat increased the amplitude, of action potential‐triggered [Ca2+]i transients without affecting action potentials. In addition, in voltage‐clamped cells, the drug had little effect on the voltage step‐evoked Ca2+ current but exerted a similar effect on its concomitant rise in [Ca2+]i to that on the action potential‐triggered [Ca2+]i transient.
Similar action potential‐triggered [Ca2+]i transients were induced by brief exposures to high‐K+ solution. They were not decreased, but rather increased, after depletion of intracellular Ca2+ stores by a combination of ryanodine (30 μM) and caffeine (10 mM) through an open‐lock of Ca2+‐induced Ca2+ release (CICR)‐related channels.
The results show that action potentials, discharged repeatedly during the early period of a long membrane depolarization, undergo a progressive change in configuration but can each trigger a constant rise in [Ca2+]i. Intracellular Ca2+ stores have a role, especially in accelerating the falling phase of the action potential‐triggered [Ca2+]i transients by replenishing cytosolic Ca2+. No evidence was provided for the involvement of CICR in the action potential‐triggered [Ca2+]i transient.

British Journal of Pharmacology (1997) 122, 477–486; doi:10.1038/sj.bjp.0701407
FcεRI‐mediated chloride uptake by rat mast cells: modulation by chloride transport inhibitors in relation to histamine secretion
Authors: Redrup A. C. , Foreman J. C. , Hayes N. A. , Pearce F. L. 
Published: January 2005

We have examined the role of extracellular chloride in the mast cell secretion process. The immunologically‐directed ligand, antibody to IgE (anti‐IgE) required extracellular chloride ions for optimum secretion from rat peritoneal mast cells. In contrast, replacement of extracellular chloride did not alter the mast cell secretory response to compound 48/80, calcium ionophore A23187 or substance P.
Anti‐IgE‐stimulation of mast cells evoked a significant uptake of chloride ions compared to non‐stimulated cells. The magnitude of chloride uptake correlated with the magnitude of stimulated histamine secretion.
Compound 48/80, substance P and A23187 did not alter the rate of chloride ion uptake, although these agents caused significant histamine secretion.
The Na+/K+/2Cl− cotransport inhibitor, furosemide, reduced the rate of anti‐IgE‐stimulated chloride uptake at a relatively high concentration (700 μM). However, the more potent Na+/K+/2Cl− cotransport inhibitors, bumetanide (100 μM) and piretanide (100 μM) had no effect on the stimulated chloride uptake.
Furosemide inhibited anti‐IgE‐induced histamine secretion, bumetanide potentiated the response and piretanide had no effect. This suggests that their respective action on histamine secretion are unrelated to inhibition of the Na+/K+/2Cl− carrier.
The chloride channel blocker, 5‐nitro‐2‐((3‐phenylpropyl)‐amino)‐benzoic acid (NPPB), reduced both anti‐IgE‐stimulated chloride uptake and the corresponding histamine secretion in a dose‐dependent manner. The magnitude of the inhibitory action of the drug on these two cellular processes was comparable, implying that chloride channel activity is related to the mechanism of histamine secretion.
It is concluded that chloride uptake has a role in the control of FcεRI‐mediated histamine secretion from rodent mast cells.

British Journal of Pharmacology (1997) 122, 1188–1194; doi:10.1038/sj.bjp.0701418
Inhibition of nociceptin‐induced allodynia in conscious mice by prostaglandin D2
Authors: Minami Toshiaki , Okuda‐Ashitaka Emiko , Nishizawa Mikio , Mori Hidemaro , Ito Seiji 
Published: January 2005

We recently showed that intrathecal administration of nociceptin induced allodynia by innocuous tactile stimuli and hyperalgesia by noxious thermal stimuli in conscious mice. In the present study, we examined the effect of prostaglandins on nociceptin‐induced allodynia and hyperalgesia.
Prostaglandin D2 (PGD2) blocked the allodynia induced by nociceptin in a dose‐dependent manner with an IC50 of 26 ng kg−1, but did not affect the nociceptin‐induced hyperalgesia at doses up to 500 ng kg−1. BW 245C (an agonist for PGD (DP) receptor) blocked the allodynia with an IC50 of 83 ng kg−1.
The blockade of nociceptin‐induced allodynia by PGD2 was reversed by the potent and selective DP‐receptor antagonist BW A868C in a dose‐dependent manner with an ED50 of 42.8 ng kg−1.
Glycine (500 ng kg−1) almost completely blocked the nociceptin‐induced allodynia. A synergistic effect on the inhibition of nociceptin‐evoked allodynia was observed between glycine and PGD2 at below effective doses.
Dibutyryl cyclic AMP, but not dibutyryl cyclic GMP, blocked the nociceptin‐induced allodynia with an IC50 of 2.9 μg kg−1.
PGE2, PGF2α, butaprost (an EP2 agonist) and cicaprost (a PGI receptor agonist) did not affect the nociceptin‐induced allodynia.
These results demonstrate that PGD2 inhibits the nociceptin‐evoked allodynia through DP receptors in the spinal cord and that glycine may be involved in this inhibition.

British Journal of Pharmacology (1997) 122, 605–610; doi:10.1038/sj.bjp.0701421