bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lysophosphatidylcholine potentiates vascular contractile responses in rat aorta via activation of tyrosine kinase
Authors: Suenaga Hiroshi , Kamata Katsuo 
Published: January 2005

We previously reported that while lysophosphatidylcholine (LPC) does not itself produce contraction, it significantly potentiates the contractile responses induced by high‐K+, UK14,304 (a selective α2‐adrenoceptor agonist) and phorbol ester in the endothelium‐denuded rat aorta. To further investigate this phenomenon, we examined the effects of genistein and tyrphostin B42 (both tyrosine kinase inhibitors) on the LPC‐induced potentiation of the contractile responses to high‐K+ and UK14,304 in the endothelium‐denuded rat aorta.
Although genistein (3×10−6 M, 10−5 M) did not affect the high‐K+‐induced contractile response, it selectively inhibited the potentiating effect of LPC on the contraction and it strongly inhibited the LPC‐induced augmentation of the associated increases in [Ca2+]i. Genistein also attenuated the LPC‐induced augmentation effects on both the increase in [Ca2+]i and contractile response induced by the UK14,304. In contrast, daidzein (10−5 M) did not inhibit the potentiating effect of LPC. Tyrphostin B42 (3×10−5 M) attenuated the potentiating effect of LPC on high K+‐induced contractions.
Western blot analysis showed that LPC increased the tyrosine phosphorylation of a number of proteins, including 42 and 44 kDa proteins and 53 – 64 kDa proteins. These protein phosphorylations were inhibited by genistein.
Sodium orthovanadate (10−4 M), a tyrosine phosphatase inhibitor, also markedly enhanced the high‐K+‐induced contractile responses. This enhancing effect was attenuated by genistein.
These results suggest that the LPC‐induced augmentation of contractile responses in the rat aorta is due to activation of tyrosine kinase, which in turn regulates Ca2+ influx.

British Journal of Pharmacology (2002) 135, 789–799; doi:10.1038/sj.bjp.0704525
Role of endothelin ETA‐ and ETB‐receptors in haemodynamic compensation following haemorrhage in anaesthetized rats
Authors: Palacios Beatriz , Lim Su Lin , Pang Catherine C Y 
Published: January 2005

This study examined the role of endothelin ETA and ETB receptors on haemodynamic compensation following haemorrhage (−17.5 ml kg−1) in thiobutabarbitone‐anaesthetized rats. Rats were divided into four groups (n=6 each): time‐control, haemorrhage‐control, haemorrhage after treatment with FR 139317 (ETA‐receptor antagonist), and haemorrhage after treatment with BQ‐788 (ETB‐receptor antagonist).
In the time‐control rats, there were no significant changes in any haemodynamics for the duration of the experiments. Relative to the time‐control rats, rats given haemorrhage had reduced mean arterial pressure (MAP), cardiac output (CO) and mean circulatory filling pressure (MCFP), but increased systemic vascular resistance (RSV). Venous resistance (RV) was slightly (but insignificantly) reduced by haemorrhage. MAP, however, gradually returned towards baseline (−17±4 and −3±2 mmHg at 10 and 60 min after haemorrhage, respectively) as a result of a further increase in RSV.
Pre‐treatment with FR 139317 (i.v. 1 mg kg−1, followed by 1 mg kg−1 h−1) accentuated haemorrhage‐induced hypotension through abolition of the increase in RSV. FR 139317 did not modify haemorrhage‐induced changes in CO, MCFP and RV.
Pre‐treatment of BQ‐788 (3 mg kg−1) did not affect MAP or MCFP following haemorrhage; however, CO was lower, and RSV as well as RV were higher relative to the readings in the haemorrhaged‐control rats.
These results show that following compensated haemorrhage, ET maintains arterial resistance and blood pressure via the activation of ETA but not ETB receptors.

British Journal of Pharmacology (2002) 135, 876–882; doi:10.1038/sj.bjp.0704530
Lack of critical involvement of endothelial nitric oxide synthase in vascular nitrate tolerance in mice
Authors: Wang Ellen Q , Lee Woo‐In , Fung Ho‐Leung 
Published: January 2005

We examined the direct involvement of endothelial nitric oxide (eNOS) in nitrate tolerance using eNOS knockout (eNOS (−/−)) and wild‐type (eNOS (+/+)) mice. Animals were treated with either nitroglycerin (NTG, 20 mg kg−1s.c. 3×daily for 3 days) or vehicle (5% dextrose, D5W), and nitrate tolerance was assessed ex vivo in isolated aorta by vascular relaxation studies and cyclic GMP accumulation. Western blot was performed to determine NOS expression after NTG treatment. In both the eNOS (−/−) and (+/+) mice, the EC50 from NTG concentration‐response curve was increased by ∼3 fold, and vascular cyclic GMP accumulation was similarly decreased after NTG pretreatment. Vascular tolerance did not lead to changes in eNOS protein expression in eNOS (+/+) mice. These results indicate that vascular nitrate tolerance was similarly induced in eNOS (−/−) and (+/+) mice, suggesting that eNOS may not be critically involved in nitrate tolerance development in mice.British Journal of Pharmacology (2002) 135, 299–302; doi:10.1038/sj.bjp.0704532
Stimulation of β3‐adrenoceptors causes phosphorylation of p38 mitogen‐activated protein kinase via a stimulatory G protein‐dependent pathway in 3T3‐L1 adipocytes
Authors: Mizuno Katsushige , Kanda Yasunari , Kuroki Yasutomi , Nishio Masahiro , Watanabe Yasuhiro 
Published: January 2005

This study deals with phosphorylation and activation of p38 mitogen‐activated protein kinase (MAPK) via β3‐adrenoceptor (AR) and the signal transduction pathway in 3T3‐L1 adipocytes.
β3‐AR agonist BRL37344A (10 nM) caused phosphorylation and activation of p38 MAPK in 3T3‐L1 adipocytes but not in fibroblasts. BRL37344A and also the other β3‐AR agonists, CGP12177A and SR58611A, caused p38 MAPK phosphorylation in dose‐dependent manners.
The p38 MAPK phosphorylations by BRL37344A (10 nM), CGP12177A (100 nM), and SR58611A (10 nM) were not antagonized by β1‐ and β2‐ARs antagonist 1‐propranolol (100 nM) but blocked by β3‐AR antagonist SR59230A (10 μM), suggesting the phosphorylation was caused via β3‐AR.
The phosphorylations of p38 MAPK were completely abolished by treatment with cholera toxin (CTX) but not pertussis toxin (100 ng ml−1, 24 h). Activation of Gs by CTX (100 ng ml−1) and adenylyl cyclase by forskolin mimicked p38 MAPK phosphorylation.
p38 MAPK phosphorylation by BRL37344A was reduced to almost 50% by cyclic AMP‐dependent protein kinase (PKA) inhibitors such as H89 (10 μM) and PKI (10 μM). A src‐family tyrosine kinases inhibitor PP2 (1 μM) also halved the p38 MAPK phosphorylation. Combined use of H89 (10 μM) and PP2 (10 μM) did not bring about further inhibition.
These results suggest that β3‐AR caused phosphorylation of p38 MAPK via Gs protein and partly through a pathway involving PKA and src‐family kinase(s), although the contribution of the unidentified pathway remains to be clarified.

British Journal of Pharmacology (2002) 135, 951–960; doi:10.1038/sj.bjp.0704537
Involvement of caspases and calpains in cerebrocortical neuronal cell death is stimulus‐dependent
Authors: Moore Jonathan D , Rothwell Nancy J , Gibson Rosemary M 
Published: January 2005

Caspases and calpains are mediators of apoptotic cell death. The objective of this study was to determine the role of caspases and calpains in primary cerebrocortical neuronal (CCN) death in response to a range of stimuli which reportedly induce neuronal apoptosis.
Cell death of primary cultures of rat CCN was induced by staurosporine (STS), C2‐ceramide (CER), camptothecin (CMT), hydrogen peroxide (H2O2) or N‐methyl‐D‐aspartate (NMDA). Caspase and calpain activity were assessed by cleavage of α‐fodrin or fluorogenic substrates. Cell death was analysed by lactate dehydrogenase (LDH) assay in the absence or presence of the pan‐caspase inhibitor Boc‐Asp‐(OMe)‐Fluoromethylketone (Baf) and/or the calpain inhibitor calpeptin (CP).
Cell death induced by STS, CER or CMT was accompanied by chromatin condensation and activation of multiple caspases, particularly caspase‐3‐type proteases. Hydrogen peroxide (H2O2) treatment was accompanied by activation of caspases −1, −6 and −8, but not −3, whereas none of the caspases tested were activated in response to NMDA.
With the exception of H2O2, when cell death was accompanied by caspase activation, it was significantly suppressed by Baf.
All stimuli also induced calpain activation, but calpeptin only suppressed cell death induced by H2O2. Furthermore, co‐treatment with Baf and calpeptin did not alter the cell death relative to either inhibitor alone.
These findings suggest the existence of stimulus‐dependent routes for the activation of caspases and calpains during death of cortical neurones and imply that although caspases and calpains are activated, their involvement in the execution of cell death varies with the stimulus.

British Journal of Pharmacology (2002) 135, 1069–1077; doi:10.1038/sj.bjp.0704538
Glucocorticoids reverse IL‐1β‐induced impairment of β‐adrenoceptor‐mediated relaxation and up‐regulation of G‐protein‐coupled receptor kinases
Authors: Mak Judith C W , Hisada Takeshi , Salmon Michael , Barnes Peter J , Chung K Fan 
Published: January 2005

The aim of the present study was to examine the effects of glucocorticoid dexamethasone on airway responsiveness to albuterol after intratracheal instillation of saline or IL‐1β in Brown‐Norway rats in vivo and to elucidate the molecular mechanism of this effect.
IL‐1β caused a significant reduction in albuterol‐mediated relaxation to protect against MCh‐induced bronchoconstriction. Dexamethasone attenuated the IL‐1β‐induced impaired relaxation while alone had no effect when compared to rats treated identically with saline.
The density of β2‐adrenoceptors was significantly reduced in lung membranes harvested from IL‐1β‐treated rats, which was associated with impaired isoproterenol‐ and forskolin‐stimulated cyclic AMP accumulation and adenylyl cyclase (AC) activity ex vivo. Dexamethasone did not prevent IL‐1β‐induced down‐regulation of β2‐adrenoceptors but completely blocked IL‐1β‐induced impairment of cyclic AMP accumulation and AC activity stimulated by isoproterenol and forskolin.
The inhibitory G‐protein subtypes, Giα1, Giα2 and Giα3, were detected in lung membranes prepared from all groups of rats but the intensity of Giα1 and Giα2 was markedly increased in IL‐1β‐treated rats, which were not prevented by dexamethasone.
The activity of cytosolic GRK and the expression of GRK2 and GRK5 were elevated in the lung of IL‐1β‐treated rats, which were completely abolished by dexamethasone.
These results indicate that treatment of rats with IL‐1β results in desensitization of pulmonary β2‐adrenoceptors. In light of data obtained in this study, we propose that both the decrease in AC activity and the increase in GRK activity, which are reversed by dexamethasone, may underlie β2‐adrenoceptor desensitization.

British Journal of Pharmacology (2002) 135, 987–996; doi:10.1038/sj.bjp.0704545
Proarrhythmic potential of halofantrine, terfenadine and clofilium in a modified in vivo model of torsade de pointes
Authors: Batey Andrew J , Coker Susan J 
Published: January 2005

This study was designed to compare the proarrhythmic activity of the antimalarial drug, halofantrine and the antihistamine, terfenadine, with that of clofilium a K+ channel blocking drug that can induce torsade de pointes.
Experiments were performed in pentobarbitone‐anaesthetized, open‐chest rabbits. Each rabbit received intermittent, rising dose i.v. infusions of the α‐adrenoceptor agonist phenylephrine. During these infusions rabbits also received increasing i.v. doses of clofilium (20, 60 and 200 nmol kg−1 min−1), terfenadine (75, 250 and 750 nmol kg−1 min−1), halofantrine (6, 20 and 60 μmol kg−1) or vehicle.
Clofilium and halofantrine caused dose‐dependent increases in the rate‐corrected QT interval (QTc), whereas terfenadine prolonged PR and QRS intervals rather than prolonging cardiac repolarization. Progressive bradycardia occurred in all groups. After administration of the highest dose of each drug halofantrine caused a modest decrease in blood pressure, but terfenadine had profound hypotensive effects resulting in death of most rabbits.
The total number of ventricular premature beats was highest in the clofilium group. Torsade de pointes occurred in 6 out of 8 clofilium‐treated rabbits and 4 out of 6 of those which received halofantrine, but was not seen in any of the seven terfenadine‐treated rabbits.
These results show that, like clofilium, halofantrine can cause torsade de pointes in a modified anaesthetized rabbit model whereas the primary adverse effect of terfenadine was cardiac contractile failure.

British Journal of Pharmacology (2002) 135, 1003–1012; doi:10.1038/sj.bjp.0704550
Influence of antioxidant depletion on nitrergic relaxation in the pig gastric fundus
Authors: Colpaert E E , Timmermans J ‐P , Lefebvre R A 
Published: January 2005

The hypothesis that endogenous tissue antioxidants might explain the inability of the superoxide generators 6‐anilino‐5,8‐quinolinedione (LY83583) and hydroquinone (HQ) and of the NO‐scavengers hydroxocobalamin (HC) and 2‐(4‐carboxyphenyl)‐4,4,5,5‐tetramethylimidazoline‐1‐oxyl‐3‐oxide (c‐PTIO) to affect nitrergic neurotransmission in the porcine gastric fundus was tested by selective pharmacological depletion of respectively Cu/Zn superoxide dismutase (Cu/Zn SOD) and reduced glutathione (GSH) in circular smooth muscle preparations.
Diethyldithiocarbamate (DETCA; 3×10−3 M), which almost completely abolished tissue Cu/Zn SOD activity, had no effect per se on nitrergic relaxations induced by either electrical field stimulation (EFS; 4 Hz, 10 s) or exogenous nitric oxide (NO; 10−5 M). In these DETCA‐treated tissues however, electrically‐induced nitrergic relaxations became sensitive to inhibition by LY83583 (10−5 M) or HC (10−4 M), but not by HQ (10−4 M) or c‐PTIO (10−4 M); only for the combination of DETCA plus LY83583, this inhibition was partially reversed by exogenous Cu/Zn SOD (1000 u ml−1).
Immunohistochemical analysis of porcine gastric fundus revealed a 100% colocalization of Cu/Zn SOD and neuronal nitric oxide synthase (nNOS) in the intrinsic neurons of the myenteric plexus.
Buthionine sulphoximine (BSO; 10−3 M) in the absence or presence of LY83583 (10−5 M) or HC (10−4 M) did not alter nitrergic relaxations, although it reduced per se the tissue GSH content to 62% of control.
Pharmacological depletion studies, corroborated by immunohistochemical data, thus suggest a role for Cu/Zn SOD but not for GSH in nitrergic neurotransmission in the porcine gastric fundus.

British Journal of Pharmacology (2002) 135, 917–926; doi:10.1038/sj.bjp.0704553
KMUP‐1 relaxes rabbit corpus cavernosum smooth muscle in vitro and in vivo: involvement of cyclic GMP and K+ channels
Authors: Lin Rong‐Jyh , Wu Bin‐Nan , Lo Yi‐Ching , Shen Kuo‐Pyng , Lin Young‐Tso , Huang Chun‐Hsiung , Chen Ing‐Jun 
Published: January 2005

In isolated endothelium‐intact or denuded rabbit corpus cavernosum preconstricted with phenylephrine, KMUP‐1 (0.001 – 10 μM) caused a concentration‐dependent relaxation.
This relaxation of KMUP‐1 was attenuated by endothelium removed, high K+ and pretreatments with a soluble guanylyl cyclase (sGC) inhibitor ODQ (1 μM), a NOS inhibitor L‐NAME (100 μM), a K+ channel blocker TEA (10 mM), a KATP channel blocker glibenclamide (1 μM), a voltage‐dependent K+ channel blocker 4‐AP (100 μM) and Ca2+‐dependent K+ channel blockers apamin (1 μM) and charybdotoxin (ChTX, 0.1 μM).
The relaxant responses of KMUP‐1 (0.01, 0.05, 0.1 μM) together with a PDE inhibitor IBMX (0.5 μM) had additive actions on rabbit corpus cavernosum smooth muscle (CCSM).
KMUP‐1 (0.01 – 10 μM) induced increase of intracellular cyclic GMP level in the primary cell culture of rabbit CCSM. This increase in cyclic GMP content was abolished in the presence of ODQ (10 μM).
Both KMUP‐1 and sildenafil at 0.2, 0.4, 0.6 mg kg−1 caused increases of intracavernous pressure (ICP) and duration of tumescene (DT) in a dose‐dependent manner. These in vivo activities of ICP for sildenafil and KMUP‐1 are consistent with those of in vitro effects of cyclic GMP.
KMUP‐1 has the following merits: (1) inhibition of PDE or cyclic GMP breakdown, (2) stimulation of NO/sGC/cyclic GMP pathway, and (3) subsequent stimulation of K+ channels, in rabbit CCSM. We suggest that these merits play prominent roles in KMUP‐1‐induced CCSM relaxation‐associated increases of ICP and penile erection.

British Journal of Pharmacology (2002) 135, 1159–1166; doi:10.1038/sj.bjp.0704554
Permeability of porcine blood brain barrier to somatostatin analogues
Authors: Fricker Gert , Nobmann Stephanie , Miller David S 
Published: January 2005

Transport of a fluorescent somatostatin analogue (NBD‐octreotide) across freshly isolated functionally intact capillaries from porcine brain was visualized by confocal microscopy and quantitated by image analysis.
Luminal accumulation of NBD‐octreotide showed all characteristics of specific and energy‐dependent transport. Steady‐state luminal fluorescence averaged 2 – 3 times cellular fluorescence and was reduced to cellular levels when metabolism was inhibited by NaCN.
The accumulation of NBD‐octreotide in capillary lumens was inhibited in a concentration‐dependent manner by unlabelled octreotide, by verapamil, PSC‐833 and cyclosporin A, potent inhibitors of p‐glycoprotein, and by leucotriene C4, a strong modulator of Mrp2. Conversely, unlabelled octreotide reduced luminal accumulation of fluorescent BODIPY‐verapamil on p‐glycoprotein and of fluorescein‐methotrexate, on Mrp2. None of the inhibitors used significantly reduced cellular accumulation of the fluorescent substrates.
Together, the data are consistent with octreotide being transported across the luminal membrane of porcine brain capillaries by both P‐gp and Mrp2, providing further evidence that both transporters contribute substantially to the active barrier function of this endothelium.

British Journal of Pharmacology (2002) 135, 1308–1314; doi:10.1038/sj.bjp.0704557
The flavonol quercetin activates basolateral K+ channels in rat distal colon epithelium
Authors: Cermak Rainer , Kuhn Gisela , Wolffram Siegfried 
Published: January 2005

The flavonol quercetin has been shown to activate a Cl− secretion in rat colon. Unlike the secretory activity of the related isoflavone genistein, quercetin's secretory activity does not depend on cyclic AMP; instead, it depends on Ca2+. We investigated the possible involvement of Ca2+ dependent basolateral K+ channels using apically permeabilized rat distal colon epithelium mounted in Ussing chambers.
In intact epithelium, quercetin induced an increase in short‐circuit current (Isc), which was diminished by the Cl− channel blockers NPPB and DPC, but not by glibenclamide, DIDS or anthracene‐9‐carboxylic acid. The effect of the flavonol was also inhibited by several serosally applied K+ channel blockers (Ba2+, quinine, clotrimazole, tetrapentylammonium, 293B), whereas other K+ channel blockers failed to influence the quercetin‐induced increase in Isc (tetraethylammonium, charybdotoxin).
The apical membrane was permeabilized by mucosal addition of nystatin and a serosally directed K+ gradient was applied. The successful permeabilization was confirmed by experiments demonstrating the failure of bumetanide to inhibit the carbachol‐induced current.
In apically permeabilized epithelium, quercetin induced a K+ current (IK), which was neither influenced by ouabain nor by bumetanide. Whereas DPC, NPPB, charybdotoxin and 293B failed to inhibit this IK, quinine, Ba2+, clotrimazole and tetrapentylammonium were effective blockers of this current.
We conclude from these results that at least part of the quercetin‐induced Cl− secretion can be explained by an activation of basolateral K+ channels.

British Journal of Pharmacology (2002) 135, 1183–1190; doi:10.1038/sj.bjp.0704564
Modulation of contraction by α2A/D‐adrenoceptors in mouse aorta: evidence employing knockout technology
Authors: Vandeputte Catherine , Docherty James R 
Published: January 2005

We have investigated noradrenaline‐evoked contractions in endothelium‐denuded aorta from wild‐type and α2A/D‐adrenoceptor knockout mice. The maximum contraction to noradrenaline was significantly larger (1.36±0.24 mN, n=5) in aorta from knockout than from wild‐type animals (0.78±0.14 mN, n=12, P<0.05), but there was no difference in potency of noradrenaline. There was no difference between groups in the contraction to KCl (80 mM) or PGF2α (10 μM).
The contraction to noradrenaline (10 μM) was significantly larger in aorta from knockout animals, but yohimbine (1 μM) significantly increased this contraction (to 136±10% of control, n=6) in aorta from wild‐type but not from knockout (97±10%, n=6, P<0.05).
In tissues precontracted with PGF2α (10 μM), xylazine (1 μM) produced relaxations only in tissues from wild‐type mice.
The K+ channel blocker glibenclamide (1 μM) had no significant effects on contractions to noradrenaline in either group.
It is concluded that an α2A/D‐adrenoceptor exerts an inhibitory modulation of contraction in mouse aorta.

British Journal of Pharmacology (2002) 135, 1209–1212; doi:10.1038/sj.bjp.0704567
Proteinase‐activated receptor‐1 agonists attenuate nociception in response to noxious stimuli
Authors: Asfaha Samuel , Brussee Valentine , Chapman Kevin , Zochodne Douglas W , Vergnolle Nathalie 
Published: January 2005

Proteinase‐activated receptor‐1 (PAR‐1) is activated by thrombin and can be selectively activated by synthetic peptides (PAR‐1‐activating peptide: PAR‐1‐AP) corresponding to the receptor's tethered ligand. PAR‐1 being expressed by afferent neurons, we investigated the effects of PAR‐1 agonists on nociceptive responses to mechanical and thermal noxious stimuli. Intraplantar injection of selective PAR‐1‐AP increased nociceptive threshold and withdrawal latency, leading to mechanical and thermal analgesia, while control peptide had no effect. Intraplantar injection of thrombin also showed analgesic properties in response to mechanical, but not to thermal stimulus. Co‐injection of PAR‐1‐AP with carrageenan significantly reduced carrageenan‐induced mechanical and thermal hyperalgesia, while thrombin reduced carrageenan‐induced mechanical but not thermal hyperalgesia. The fact that thrombin is not a selective agonist for PAR‐1 may explain the different effects of thrombin and PAR‐1‐AP. These results identified analgesic properties for selective PAR‐1 agonists that can modulate nociceptive response to noxious stimuli in normal and inflammatory conditions.British Journal of Pharmacology (2002) 135, 1101–1106; doi:10.1038/sj.bjp.0704568