bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lysosphingolipid receptor‐mediated diuresis and natriuresis in anaesthetized rats
Authors: Bischoff Angela , Heringdorf Dagmar Meyer zu , Jakobs Karl H , Michel Martin C 
Published: January 2005

Lysosphingolipids such as sphingosine‐1‐phosphate (SPP) and sphingosylphosphorylcholine (SPPC) can act on specific G‐protein‐coupled receptors. Since SPP and SPPC cause renal vasoconstriction, we have investigated their effects on urine and electrolyte excretion in anaesthetized rats.
Infusion of SPP (1 – 30 μg kg−1 min−1) for up to 120 min dose‐dependently but transiently (peak after 15 min, disappearance after 60 min) reduced renal blood flow without altering endogenous creatinine clearance. Nevertheless, infusion of SPP increased diuresis, natriuresis and calciuresis and, to a lesser extent, kaliuresis. These tubular lysosphingolipid effects developed more slowly (maximum after 60 – 90 min) and also abated more slowly upon lysosphingolipid washout than the renovascular effects.
Infusion of SPPC, sphingosine and glucopsychosine (3 – 30 μg kg−1 min−1 each) caused little if any alterations in renal blood flow but also increased diuresis, natriuresis and calciuresis and, to a lesser extent, kaliuresis.
Pretreatment with pertussis toxin (10 μg kg−1 3 days before the acute experiment) abolished the renovascular and tubular effects of 30 μg kg−1 min−1 SPP.
These findings suggest that lysosphingolipids are a hitherto unrecognized class of endogenous modulators of renal function. SPP affects renovascular tone and tubular function via receptors coupled to Gi‐type G‐proteins. SPPC, sphingosine and glucopsychosine mimic only the tubular effects of SPP, and hence may act on distinct sites.

British Journal of Pharmacology (2001) 132, 1925–1933; doi:10.1038/sj.bjp.0703969
Docosahexaenoic acid improves long‐term potentiation attenuated by phospholipase A2 inhibitor in rat hippocampal slices
Authors: Fujita Shinichi , Ikegaya Yuji , Nishikawa Masazumi , Nishiyama Nobuyoshi , Matsuki Norio 
Published: January 2005

We investigated the possible involvement of phospholipase A2 (PLA2) and its products in long‐term potentiation (LTP) in the CA1 neurotransmission of rat hippocampal slices.
Inhibitors of Ca2+‐independent PLA2 (iPLA2) prevented the induction of LTP without affecting the maintenance phase of LTP whereas Ca2+‐dependent PLA2 inhibitors were virtually ineffective, which suggests a pivotal role of iPLA2 in the initiation of LTP.
We then investigated the effect of docosahexaenoic acid (DHA) and arachidonic acid (AA) on BEL (bromoenol lactone, an iPLA2‐inhibitor) ‐impaired LTP, and found that either DHA or AA abolished the effect of BEL. However, DHA did not restore BEL‐attenuated LTP when applied after the tetanus. DHA per se affected neither the induction nor maintenance of LTP. Linoleic acid had no effects, either.
These results suggest that DHA is crucial for the induction of LTP and that endogenously released DHA during tetanus is sufficient to trigger the formation of LTP.

British Journal of Pharmacology (2001) 132, 1417–1422; doi:10.1038/sj.bjp.0703970
Functional characterization of rat submaxillary gland muscarinic receptors using microphysiometry
Authors: Meloy Trena D , Daniels Donald V , Hegde Sharath S , Eglen Richard M , Ford Anthony P D W 
Published: January 2005

Muscarinic cholinoceptors (MChR) in freshly dispersed rat salivary gland (RSG) cells were characterized using microphysiometry to measure changes in acidification rates. Several non‐selective and selective muscarinic antagonists were used to elucidate the nature of the subtypes mediating the response to carbachol.
The effects of carbachol (pEC50=5.74±0.02 s.e.mean; n=53) were highly reproducible and most antagonists acted in a surmountable, reversible fashion. The following antagonist rank order, with apparent affinity constants in parentheses, was noted: 4‐DAMP (8.9)=atropine (8.9)>tolterodine (8.5)>oxybutynin (7.9)>S‐secoverine (7.2)>pirenzepine (6.9)>himbacine (6.8)>AQ‐RA 741 (6.6)>methoctramine (5.9).
These studies validate the use of primary isolated RSG cells in microphysiometry for pharmacological analysis. These data are consistent with, and extend, previous studies using alternative functional methods, which reported a lack of differential receptor pharmacology between bladder and salivary gland tissue.
The antagonist affinity profile significantly correlated with the profile at human recombinant muscarinic M3 and M5 receptors. Given a lack of antagonists that discriminate between M3 and M5, definitive conclusion of which subtype(s) is present within RSG cells cannot be determined.

British Journal of Pharmacology (2001) 132, 1606–1614; doi:10.1038/sj.bjp.0703971
Effect of vanilloid drugs on gastrointestinal transit in mice
Authors: Izzo Angelo A , Capasso Raffaele , Pinto Luisa , Carlo Giulia Di , Mascolo Nicola , Capasso Francesco 
Published: January 2005

We have studied the effect of capsaicin, piperine and anandamide, drugs which activate vanilloid receptors and capsazepine, a vanilloid receptor antagonist, on upper gastrointestinal motility in mice.
Piperine (0.5 – 20 mg kg−1 i.p.) and anandamide (0.5 – 20 mg kg−1 i.p.), dose‐dependently delayed gastrointestinal motility, while capsaicin (up to 3 mg kg−1 i.p.) was without effect. Capsazepine (15 mg kg−1 i.p.) neither per se affected gastrointestinal motility nor did it counteract the inhibitory effect of both piperine (10 mg kg−1) and anandamide (10 mg kg−1).
A per se non effective dose of SR141716A (0.3 mg kg−1 i.p.), a cannabinoid CB1 receptor antagonist, counteracted the inhibitory effect of anandamide (10 mg kg−1) but not of piperine (10 mg kg−1). By contrast, the inhibitory effect of piperine (10 mg kg−1) but not of anandamide (10 mg kg−1) was strongly attenuated in capsaicin (75 mg kg−1 in total, s.c.)‐treated mice.
Pretreatment of mice with NG‐nitro‐L‐arginine methyl ester (25 mg kg−1 i.p.), yohimbine (1 mg kg−1, i.p.), naloxone (2 mg kg−1 i.p.), or hexamethonium (1 mg kg−1 i.p.) did not modify the inhibitory effect of both piperine (10 mg kg−1) and anandamide (10 mg kg−1).
The present study indicates that the vanilloid ligands anandamide and piperine, but not capsaicin, can reduce upper gastrointestinal motility. The effect of piperine involves capsaicin‐sensitive neurones, but not vanilloid receptors, while the effect of anandamide involves cannabinoid CB1, but not vanilloid receptors.

British Journal of Pharmacology (2001) 132, 1411–1416; doi:10.1038/sj.bjp.0703975
Intracellular Angiotensin II and cell growth of vascular smooth muscle cells
Authors: Filipeanu Catalin M , Henning Robert H , De Zeeuw Dick , Nelemans Adriaan 
Published: January 2005

We recently demonstrated that intracellular application of Angiotensin II (Angiotensin IIintr) induces rat aorta contraction independent of plasma membrane Angiotensin II receptors. In this study we investigated the effects of Angiotensin IIintr on cell growth in A7r5 smooth muscle cells.
DNA‐synthesis was increased dose‐dependently by liposomes filled with Angiotensin II as measured by [3H]‐thymidine incorporation at high (EC50=27±6 pM) and low (EC50=14±5 nM) affinity binding sites with increases in Emax of 58±4 and 37±4% above quiescent cells, respectively. Cell growth was corroborated by an increase in cell number.
Extracellular Angiotensin II (10 pM – 10 μM) did not modify [3H]‐thymidine incorporation.
Growth effects of Angiotensin IIintr mediated via high affinity sites were inhibited by liposomes filled with 1 μM of the non‐peptidergic antagonists losartan (AT1‐receptor) or PD123319 (AT2‐receptor) or with the peptidergic agonist CGP42112A (AT2‐receptor). Emax values were decreased to 30±3, 29±4 and 4±2%, respectively, without changes in EC50. The Angiotensin IIintr effect via low affinity sites was only antagonized by CGP42112A (Emax=11±3%), while losartan and PD123319 increased Emax to 69±4%. Intracellular applications were ineffective in the absence of Angiotensin IIintr.
Neither intracellular nor extracellular Angiotensin I (1 μM) were effective.
The Angiotensin IIintr induced growth response was blocked by selective inhibition of phosphatidyl inositol 3‐kinase (PI‐3K) by wortmannin (1 μM) and of the mitogen‐activated protein kinase (MAPK/ERK) pathway by PD98059 (1 μM) to 61±14 and 4±8% of control, respectively.
These data demonstrate that Angiotensin IIintr induces cell growth through atypical AT‐receptors via a PI‐3K and MAPK/ERK ‐sensitive pathway.

British Journal of Pharmacology (2001) 132, 1590–1596; doi:10.1038/sj.bjp.0703984
Social isolation modifies nicotine's effects in animal tests of anxiety
Authors: Cheeta Survjit , Irvine Elaine , File Sandra E 
Published: January 2005

These experiments determined whether the housing conditions of rats influenced the effects of nicotine in two animal tests of anxiety, social interaction and elevated plus‐maze tests.
In animals housed singly for 7 days, (−)nicotine (0.025 mg kg−1 s.c.) was ineffective, but 0.05, 0.1 and 0.25 mg kg−1 (s.c.) significantly increased the time spent in social interaction, without changing locomotor activity, thus indicating anxiolytic actions. (−)Nicotine (0.45 mg kg−1 s.c.) significantly reduced social interaction, indicating an anxiogenic effect.
However, in group‐housed animals, (−)nicotine (0.025 mg kg−1 s.c.) had a significant anxiolytic effect in the social interaction test, but 0.01, 0.05, 0.1, 0.25 and 0.45 mg kg−1 were ineffective. (−)Nicotine (1 mg kg−1) reduced motor activity and social interaction in the group‐housed animals.
In the elevated plus‐maze, the time‐course and the dose‐response curve to nicotine were investigated. In both singly‐ and group‐housed rats, (−) nicotine (0.1 – 0.45 mg kg−1 s.c.) decreased the per cent entries into, and per cent time spent on, the open arms, indicating anxiogenic effects.
The housing condition influenced the time course, with significant effects at 5 and 30 min after injection in group‐housed rats, and significant effects at 30 and 60 min in singly‐housed rats.
In the social interaction test there was no difference in the scores of the first and last rats removed from group cages, whereas the order of removal from the cages did affect the scores in the elevated plus‐maze.
These results provide further evidence that the two animal tests model distinct states of anxiety, and show how social isolation powerfully modifies both anxiolytic and anxiogenic effects of nicotine.

British Journal of Pharmacology (2001) 132, 1389–1395; doi:10.1038/sj.bjp.0703991
Characteristics of AMPA receptor‐mediated responses of cultured cortical and spinal cord neurones and their correlation to the expression of glutamate receptor subunits, GluR1‐4
Authors: Dai Wei‐Min , Egebjerg Jan , Lambert John D C 
Published: January 2005

Electrophysiological recordings have been used to characterize responses mediated by AMPA receptors expressed by cultured rat cortical and spinal cord neurones. The EC50 values for AMPA were 17 and 11 μM, respectively.
Responses of cortical neurones to AMPA were inhibited competitively by NBQX (pKi=6.6). Lower concentrations of NBQX (1 μM) also potentiated the plateau responses of spinal cord neurones to AMPA, which could be attributed to a depression of desensitization to AMPA.
GYKI 52466 inhibited responses of spinal cord neurones to AMPA to about twice the extent of responses of cortical neurones.
Blockade of AMPA receptor desensitization by cyclothiazide (CTZ) potentiated responses of spinal cord neurones (6.8 fold) significantly more than responses of cortical neurones (4.8 fold). Responses of cortical neurones to KA were potentiated 3.5 fold by CTZ, while responses of spinal cord neurones were unaffected.
Ultra‐fast applications of AMPA to outside‐out patches showed responses of spinal cord neurones desensitized by 97.5% and exhibit marked inward rectification, whereas cortical neurones desensitized by 91% and exhibited slight outward rectification. The time constants of deactivation and desensitization were about twice as fast in spinal cord than cortical neurones.
In cortical neurones, single‐cell RT – PCR showed GluR2 and GluR1 accounted for 91% of all subunits and were expressed together in 67% of neurones, predominantly as the flip variants (78%). GluR2 was detected alone in 24% of neurones. GluR3 and GluR4 were present in only 14 and 29% of neurones, respectively. For spinal cord neurones, GluR4o was detected in 81% of neurones, whereas predominantly flop versions of GluR1, 2 and 3 were detected in 38, 13 and 13% of neurones, respectively. These expression patterns are related to the respective pharmacological and mechanistic properties.

British Journal of Pharmacology (2001) 132, 1859–1875; doi:10.1038/sj.bjp.0703993
Novel histamine H3‐receptor antagonists and partial agonists with a non‐aminergic structure
Authors: Nickel Tobias , Bauer Ulrich , Schlicker Eberhard , Kathmann Markus , Göthert Manfred , Sasse Astrid , Stark Holger , Schunack Walter 
Published: January 2005

We determined the affinities of eight novel histamine H3‐receptor ligands (ethers and carbamates) for H3‐receptor binding sites and their agonistic/antagonistic effects in two functional H3‐receptor models. The compounds differ from histamine in that the ethylamine chain is replaced by a propyloxy chain; in the three ethers mentioned below (FUB 335, 373 and 407), R is n‐pentyl, 3‐methylbutyl and 3,3‐dimethylbutyl, respectively.
The compounds monophasically inhibited [3H]‐Nα‐methylhistamine binding to mouse cerebral cortex membranes (pKi 7.51 – 9.53).
The concentration‐response curve of histamine for its inhibitory effect on the electrically evoked [3H]‐noradrenaline overflow from mouse cortex slices was shifted to the right by these compounds (apparent pA2 6.61 – 8.00). Only FUB 373 and 407 inhibited the evoked overflow by themselves (intrinsic activities 0.3 and 0.4); these effects were counteracted by the H3‐receptor antagonist clobenpropit.
[35S]‐GTPγS binding to mouse cortex membranes was stimulated by the H3‐receptor agonist (R)‐α‐methylhistamine in a manner sensitive to clobenpropit. Among the novel compounds only FUB 373 and 407 stimulated [35S]‐GTPγS binding (intrinsic activities 0.6 and 0.4).
In conclusion, the novel compounds are partial H3‐receptor agonists (FUB 373 and 407) or H3‐receptor antagonists; comparison with FUB 335 shows that the transition from antagonist to agonist is caused by a slight structural change. A protonated N atom in the side chain is not necessary for agonism at H3 receptors, proposing a receptor‐ligand interaction different from that of classical agonists.

British Journal of Pharmacology (2001) 132, 1665–1672; doi:10.1038/sj.bjp.0704013
The nitric oxide donor pentaerythritol tetranitrate can preserve endothelial function in established atherosclerosis
Authors: Hacker Andreas , Müller Senta , Meyer Wilfried , Kojda Georg 
Published: January 2005

Recent results suggested that long‐term treatment with a low dose of the organic nitrate pentaerythritol tetranitrate (PETN, 6 mg kg−1 per day) for 16 weeks slightly decreases aortic superoxide production in normal rabbits. We sought to determine if PETN can preserve endothelium dependent relaxation (EDR) in atherosclerotic rabbits.
Three groups of 9 – 10 New Zealand White rabbits received a cholesterol chow (0.75%) for 16 weeks. One group (CHOL16) served as control and two groups were fed for another 16 weeks a cholesterol‐chow without (CHOL32) or with 6 mg PETN kg−1 per day (PETN32).
Isolated aortic rings of CHOL16 showed a typical impairment of EDR with a maximal relaxation at 1 μM acetylcholine of 28±16%. In CHOL32‐rings EDR was completely impaired. In striking contrast, EDR in PETN32 (24±15%) was similar to that of CHOL16 indicating a protective effect of PETN on endothelial function. Vascular superoxide production measured with the lucigenin method was not different between the groups.
Aortic lesion formation in PETN32 was smaller than in CHOL32 (P<0.008). The onset of copper‐induced LDL‐oxidation (lag‐time) after 16 weeks of cholesterol feeding (214±9 min) was reduced in CHOL32 (168±24 min, P=0.035) but not in PETN32 (220±21 min). This indicates prevention of increased LDL oxidation by PETN.
The halfmaximal effective vasodilator concentrations of PETN (in −logM) were identical in CHOL16 (7.9±0.1), CHOL32 (7.6±0.2) and PETN32 (7.7±0.2). Similar results were obtained with S‐nitroso‐N‐acetyl‐D,L‐penicillamine.
These data suggest that PETN can reduce the progression of lesion formation, endothelial dysfunction and of LDL‐oxidation in established atherosclerosis.

British Journal of Pharmacology (2001) 132, 1707–1714; doi:10.1038/sj.bjp.0704021
Structural requirements for voltage‐dependent block of muscle sodium channels by phenol derivatives
Authors: Haeseler G , Piepenbrink A , Bufler J , Dengler R , Aronson J K , Piepenbrock S , Leuwer M 
Published: January 2005

We have studied the effects of four different phenol derivatives, with methyl and halogen substituents, on heterologously expressed human skeletal muscle sodium channels, in order to find structural determinants of blocking potency.
All compounds blocked skeletal muscle sodium channels in a concentration‐dependent manner. The methylated phenol 3‐methylphenol and the halogenated phenol 4‐chlorophenol blocked sodium currents on depolarization from −100 mV to 0 mV with IC50 values of 2161 and 666 μM respectively. Methylation of the halogenated compound further increased potency, reducing the IC50 to 268 μM in 2‐methyl‐4‐chlorophenol and to 150 μM in 3,5‐dimethyl‐4‐chlorophenol.
Membrane depolarization before the test depolarization increased sodium channel blockade. When depolarizations were started from −70 mV or when a 2.5 s prepulse was introduced before the test pulse inducing slow inactivation, the IC50 was reduced more than 3 fold in all compounds. The values of KD for the fast‐inactivated state derived from drug‐induced shifts in steady‐state availability curves were 14 μM for 3,5‐dimethyl‐4‐chlorophenol, 19 μM for 2‐methyl‐4‐chlorophenol, 26 μM for 4‐chlorophenol and 115 μM for 3‐methylphenol.
All compounds accelerated the current decay during depolarization and slowed recovery from fast inactivation. No relevant frequency‐dependent block after depolarizing pulses applied at 10, 50 and 100 Hz was detected for any of the compounds.
All the phenol derivatives that we examined are effective blockers of skeletal muscle sodium channels, especially in conditions that are associated with membrane depolarization. Blocking potency is increased by halogenation and by methylation with increasing numbers of methyl groups.

British Journal of Pharmacology (2001) 132, 1916–1924; doi:10.1038/sj.bjp.0704024
Signal transduction pathways involved in kinin B2 receptor‐mediated vasodilation in the rat isolated perfused kidney
Authors: Bagaté Karim , Grima Michèle , Imbs Jean‐Louis , Jong Wybren De , Helwig Jean‐Jacques , Barthelmebs Mariette 
Published: January 2005

The signal transduction pathways involved in kinin B2 receptor‐related vasodilation were investigated in rat isolated perfused kidneys. During prostaglandin F2α or KCl‐induced constriction, the vasodilator response to a selective B2 receptor agonist, Tyr(Me)8bradykinin (Tyr(Me)8BK), was assessed.
Tyr(Me)8BK produced a concentration‐ and endothelium‐dependent relaxation that was decreased by about 30 – 40% after inhibition of nitric oxide (NO) synthase by NG‐nitro‐L‐arginine (L‐NOARG) or of cyclo‐oxygenase by indomethacin; a greater decrease (about 40 – 50%) was observed after concomitant inhibition of the two pathways.
High extracellular K+ diminished Tyr(Me)8BK‐induced relaxation by about 75% suggesting a major contribution of endothelium‐derived hyperpolarization. The residual response was almost completely suppressed by NO synthase and cyclo‐oxygenase inhibition. The K+ channel inhibitors, tetrabutylammonium (non‐specific) and charybdotoxin (specific for Ca2+‐activated K+ channel), suppressed Tyr(Me)8BK‐induced relaxation resistant to L‐NOARG and indomethacin.
Inhibition of cytochrome P450 (clotrimazole or 7‐ethoxyresorufin) decreased the NO/prostanoids‐independent relaxation to Tyr(Me)8BK by more than 60%, while inhibition of the cannabinoid CB1 receptor (SR 141716A) had only a moderate effect.
Acetylcholine induced a concentration‐dependent relaxation with characteristics nearly similar to the response to Tyr(Me)8BK. In contrast, the relaxation elicited by sodium nitroprusside was potentiated in the absence of NO (L‐NOARG or removal of endothelium) but remained unchanged otherwise.
These results indicate that the activation of kinin B2 receptors in the rat isolated kidney elicits an endothelium‐dependent vasorelaxation, mainly dependent on the activation of charybdotoxin‐sensitive Ca2+‐activated K+ channels. In addition, cytochrome P450 derivatives appear to be involved.

British Journal of Pharmacology (2001) 132, 1735–1742; doi:10.1038/sj.bjp.0704027
Characterization of palmitoylethanolamide transport in mouse Neuro‐2a neuroblastoma and rat RBL‐2H3 basophilic leukaemia cells: comparison with anandamide
Authors: Jacobsson Stig O P , Fowler Christopher J 
Published: January 2005

The endogenous cannabinoid receptor agonist anandamide (AEA) and the related compound palmitoylethanolamide (PEA) are inactivated by transport into cells followed by metabolism by fatty acid amide hydrolase (FAAH). The cellular uptake of AEA has been characterized in detail, whereas less is known about the properties of the PEA uptake, in particular in neuronal cells. In the present study, the pharmacological and functional properties of PEA and AEA uptake have been investigated in mouse Neuro‐2a neuroblastoma and, for comparison, in rat RBL‐2H3 basophilic leukaemia cells.
Saturable uptake of PEA and AEA into both cell lines were demonstrated with apparent KM values of 28 μM (PEA) and 10 μM (AEA) in Neuro‐2a cells, and 30 μM (PEA) and 9.3 μM (AEA) in RBL‐2H3 cells. Both PEA and AEA uptake showed temperature‐dependence but only the AEA uptake was sensitive to treatment with Pronase and phenylmethylsulfonyl fluoride.
The AEA uptake was inhibited by AM404, 2‐arachidonoylglycerol (2‐AG), R1‐ and S1‐methanandamide, arachidonic acid and olvanil with similar potencies for the two cell types. PEA, up to a concentration of 100 μM, did not affect AEA uptake in either cell line. AEA, 2‐AG, arachidonic acid, R1‐methanandamide, Δ9‐THC, and cannabidiol inhibited PEA transport in both cell lines. The non‐steroidal anti‐inflammatory drug indomethacin inhibited the AEA uptake but had very weak effects on the uptake of PEA.
From these data, it can be concluded that PEA is transported in to cells both by passive diffusion and by a facilitated transport that is pharmacologically distinguishable from AEA uptake.

British Journal of Pharmacology (2001) 132, 1743–1754; doi:10.1038/sj.bjp.0704029