bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carvedilol attenuates neuroleptic‐induced orofacial dyskinesia: possible antioxidant mechanisms
Authors: Naidu Pattipati S , Singh Amanpreet , Kulkarni Shrinivas K 
Published: January 2005

Tardive dyskinesia (TD), a syndrome of potentially irreversible, involuntary hyperkinetic disorder occurring in 20–40% of the patient population undergoing chronic neuroleptic treatment is a major limitation of neuroleptic therapy.
Oxidative stress and products of lipid peroxidation are implicated in the pathophysiology of various neurological disorders including tardive dyskinesia.
Chronic treatment with neuroleptics leads to the development of abnormal oral movements in rats known as vacuous chewing movements (VCMs). Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia.
All the antipsychotics were administered i.p. once daily for 21 days, whereas carvedilol (also i.p.) was administered twice daily. Rats chronically treated with haloperidol (1.0 mg kg−1) or chlorpromazine (5 mg kg−1) but not clozapine (2 mg kg−1) significantly developed vacuous chewing movements and tongue protrusions. Carvedilol dose dependently (0.5–2 mg kg−1) reduced the haloperidol or chlorpromazine‐induced vacuous chewing movements and tongue protrusions.
Biochemical analysis revealed that chronic haloperidol or chlorpromazine but not clozapine treatment significantly induced lipid peroxidation and decreased the glutathione (GSH) levels in the forebrains of rats. Chronic haloperidol or chlorpromazine but not clozapine treated rats showed decreased forebrain levels of antioxidant defence enzymes, superoxide dismutase (SOD) and catalase.
Co‐administration of carvedilol (0.5–2 mg kg−1) significantly reduced the lipid peroxidation and restored the decreased glutathione levels by chronic haloperidol or chlorpromazine treatment. Co‐administration of carvedilol (1–2 mg kg−1) significantly reversed the haloperidol or chlorpromazine‐induced decrease in forebrain SOD and catalase levels in rats. However, lower dose of carvedilol (0.5 mg kg−1) failed to reverse chronic haloperidol or chlorpromazine‐induced decrease in forebrain SOD and catalase levels.
The major findings of the present study suggest that oxidative stress might play a significant role in neuroleptic‐induced orofacial dyskinesia. In conclusion, carvedilol could be a useful drug for the treatment of neuroleptic‐induced orofacial dyskinesia.

British Journal of Pharmacology (2002) 136, 193–200; doi:10.1038/sj.bjp.0704717
Caprylic acid and medium‐chain triglycerides inhibit IL‐8 gene transcription in Caco‐2 cells: comparison with the potent histone deacetylase inhibitor trichostatin A
Authors: Hoshimoto Aihiro , Suzuki Yasuo , Katsuno Tatsuro , Nakajima Hiroshi , Saito Yasushi 
Published: January 2005

Medium‐chain triglyceride (MCT) is often administered to patients with Crohn's disease (CD) or short‐bowel syndrome. However, little is known about the effects of medium‐chain fatty acids (MCFAs) and MCT on intestinal inflammation. In this study we examined whether caprylic acid, one of the MCFAs, and MCT suppress IL‐8 secretion by differentiated Caco‐2 cells.
We found for the first time that caprylic acid and MCT suppress IL‐8 secretion by Caco‐2 cells at the transcriptional level when precultured together for 24 h. We also tried to clarify the mechanism of IL‐8 gene inhibition by examining the activation of NF‐κB and other transcription factors by electrophoretic mobility shift assay (EMSA), and found that caprylic acid did not modulate their activation.
The result of dual‐luciferase assay using Caco‐2 cells transfected with IL‐8 promoter/luciferase reporter plasmid revealed that caprylic acid inhibited the activation of IL‐8 promoter.
Similar results were observed when cells were precultured with the well‐known potent histone deacetylase inhibitor trichostatin A (TSA).
We examined the state of H4 acetylation in IL‐8 promoter using the technique known as chromatin immunoprecipitation (Chr‐IP). TSA rapidly induced H4 acetylation in IL‐8 promoter chromatin, whereas caprylic acid did not. These results suggest that the inhibition of IL‐8 gene transcription induced by caprylic acid and TSA does not necessarily require the marked suppression of transcription factors, and the mechanism of inhibition of IL‐8 gene transcription may be different between caprylic acid and TSA.

British Journal of Pharmacology (2002) 136, 280–286; doi:10.1038/sj.bjp.0704719
Protective effect of propranolol on mitochondrial function in the ischaemic heart
Authors: Iwai Takeshi , Tanonaka Kouichi , Kasahara Sayaka , Inoue Rie , Takeo Satoshi 
Published: January 2005

The present study was aimed to determine whether propranolol improves contractile function of the ischaemic/reperfused heart through protection of the mitochondrial function during ischaemia.
Isolated perfused rat hearts were subjected to 35‐min ischaemia followed by 60‐min reperfusion. Pre‐treatment with propranolol at the concentrations of 10 to 100 μM for the final 3 min of pre‐ischaemia resulted in the improvement of ischaemia/reperfusion‐induced contractile dysfunction, release of creatine kinase (CK) into perfusate, and decrease in myocardial high‐energy phosphates. Propranolol also attenuated ischaemia‐induced accumulation in Na+, suggesting that cytosolic sodium overload during ischaemia was prevented by propranolol.
The mitochondrial oxygen consumption rate of skinned bundles from the perfused heart decreased at the end of ischaemia and it further decreased at the end of reperfusion. These decreases were cancelled by treatment with propranolol. A release of cytochrome c from the perfused heart was observed during ischaemia, and this release was suppressed by treatment with propranolol.
To elucidate the direct effect of propranolol on mitochondria, the mitochondria were isolated from normal hearts and their activities were determined in the presence of various concentrations of Na+ and propranolol. The addition of sodium lactate, which mimicked sodium overload in the ischaemic heart, reduced the state 3 respiration, whereas this reduction was not attenuated by the presence of propranolol.
These results suggest that cardioprotection of propranolol may be exerted via attenuating Na+ influx into cardiac cells followed by prevention of the mitochondrial dysfunction in the ischaemic heart, leading to improvement of energy production of the heart during reperfusion.

British Journal of Pharmacology (2002) 136, 472–480; doi:10.1038/sj.bjp.0704724
‘Entourage’ effects of N‐acyl ethanolamines at human vanilloid receptors. Comparison of effects upon anandamide‐induced vanilloid receptor activation and upon anandamide metabolism
Authors: Smart Darren , Jonsson Kent‐Olov , Vandevoorde Séverine , Lambert Didier M , Fowler Christopher J 
Published: January 2005

The abilities of a series of saturated N‐acyl ethanolamines and related compounds to affect the ability of anandamide (AEA) to produce a Ca2+ influx into human embryonic kidney cells expressing the human vanilloid receptor (hVR1‐HEK293 cells) has been investigated.
The C3:0, C4:0, C6:0 and C10:0 ethanolamides neither affected basal Ca2+‐influx, nor the influx in response to a submaximal concentration of AEA (1 μM). In contrast, the C12:0, C17:0, C18:0 ethanolamides and the monounsaturated compound oleoylethanolamide (C18:1) greatly potentiated the response to AEA. Palmitoylethanolamide (C16:0) produced both a response per se and an augmentation of the response to AEA.
Lauroylethanolamide (C12:0) produced a leftward shift in the dose‐response curve for AEA. EC50 values for AEA to produce Ca2+ influx into hVR1‐HEK293 cells were 1.8, 1.5, 1.1 and 0.22 μM in the presence of 0, 1, 3 and 10 μM lauroylethanolamide, respectively. Lauroylethanolamide did not affect the dose – response curves to capsaicin.
Palmitoylethylamide was synthesized and found to be a mixed‐type inhibitor (Ki(slope) 4.1 μM, Ki(intercept) 66 μM) of [3H]‐AEA metabolism by rat brain membranes.
The ‐amide, ‐ethylamide, ‐isopropylamide, ‐butylamide, ‐cyclohexamide and ‐trifluoromethyl ketone analogues of palmitoylethanolamide had little or no effect on the Ca2+ influx response to 1 μM AEA.
There was no obvious relation between the abilities of the compounds to enhance the Ca2+ influx response to 1 μM AEA into hVR1‐HEK293 cells and to prevent the hydrolysis of AEA by rat brain membranes.
It is concluded that although palmitoylethanolamide has entourage‐like effects at VR1 receptors expressed on hVR1‐HEK293 cells, other N‐acyl ethanolamines have even more dramatic potentiating effects. It is possible that they may play an important role under conditions where their synthesis is increased, such as in severe inflammation.

British Journal of Pharmacology (2002) 136, 452–458; doi:10.1038/sj.bjp.0704732
Pharmacologically activated migration of aortic endothelial cells is mediated through p38 SAPK
Authors: Dénes László , Jednákovits Andrea , Hargitai Judit , Pénzes Zoltán , Balla András , Tálosi László , Krajcsi Péter , Csermely Péter 
Published: January 2005

Impairment in endothelial cell (EC) function plays a central role in vascular diseases (e.g. atherosclerosis, restenosis, diabetic angiopathies, microvascular angina, peripheral arterial disease). BRX‐235 (a novel small molecule synthesized by Biorex, Hungary) has a potent vasculoprotective activity in different in vivo and in vitro studies. Since the importance of the p38 pathway in EC homeostasis and migration in particular is well documented, we have carried out studies to address the role of the p38 stress activated protein kinase (p38 SAPK) in the mode of action of BRX‐235. In this study, Bovine aortic endothelial cells were used in a wounding migration assay (WMA) and for Western‐blot analysis to study the effect and molecular mechanism of BRX‐235‐induced EC migration.
The bovine aortic endothelial (BAE) cells were shown to be good models for EC migration.
Both endothelial cell growth factor (ECGF)‐ and BRX‐235‐induced BAE cell migration were shown to be inhibited by SB 203580, a specific inhibitor of p38 SAPK.
It was also shown that, BRX‐235 induces phosphorylation of p38 SAPK without affecting p38 SAPK protein levels. Thus, BRX‐235 acts upstream of p38 SAPK.
In summary, we have shown that p38 SAPK is a potential pharmacological mediator for candidate drugs that target the endothelium.

British Journal of Pharmacology (2002) 136, 597–603; doi:10.1038/sj.bjp.0704738
Long PDE4 cAMP specific phosphodiesterases are activated by protein kinase A‐mediated phosphorylation of a single serine residue in Upstream Conserved Region 1 (UCR1)
Authors: MacKenzie Simon J , Baillie George S , McPhee Ian , MacKenzie Carolynn , Seamons Rachael , McSorley Theresa , Millen Jenni , Beard Matthew B , van Heeke Gino , Houslay Miles D 
Published: January 2005

Challenge of COS1 cells with the adenylyl cyclase activator forskolin led to the activation of recombinant PDE4A8, PDE4B1, PDE4C2 and PDE4D5 cAMP‐specific phosphodiesterase long isoforms.
Forskolin challenge did not activate mutant long PDE4 isoforms where the serine target residue (STR) within the protein kinase A (PKA) consensus phosphorylation site in Upstream Conserved Region 1 (UCR1) was mutated to alanine.
The PKA inhibitor, H89, ablated forskolin activation of wild‐type long PDE4 isoforms.
Activated PKA caused the in vitro phosphorylation of recombinant wild‐type long PDE4 isoforms, but not those where the STR was mutated to alanine.
An antiserum specific for the phosphorylated form of the STR detected a single immunoreactive band for recombinant long PDE4 isoforms expressed in COS1 cells challenged with forskolin. This was not evident in forskolin‐challenged cells treated with H89. Neither was it evident in forskolin‐challenged cells expressing long isoforms where the STR had been mutated to alanine.
In transfected COS cells challenged with forskolin, only the phosphorylated PDE4D3 long form showed a decrease in mobility in Western blotting analysis. This decreased mobility of PDE4D3 was ablated upon mutation of either of the two serine targets for PKA phosphorylation in this isoform, namely Ser54 in UCR1 and Ser13 in the isoform‐specific N‐terminal region.
Activation by forskolin challenge did not markedly alter the sensitivity of PDE4A8, PDE4B1, PDE4C2 and PDE4D5 to inhibition by rolipram.
Long PDE4 isoforms from all four sub‐families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.

British Journal of Pharmacology (2002) 136, 421–433; doi:10.1038/sj.bjp.0704743
Dual effect mediated by protease‐activated receptors on the mechanical activity of rat colon
Authors: Mulè Flavia , Baffi Maria Carmela , Cerra Maria Carmela 
Published: January 2005

The present study examined the mechanical effects of agonist enzymes and receptor‐activating peptides for protease‐activated receptor (PAR)‐1 and PAR‐2 on longitudinal and circular muscle of rat isolated colonic segments in the attempt to clarify the PAR functional role in intestinal motility.
The responses to PAR‐1 and PAR‐2 activation were examined in vitro by recording simultaneously the changes of endoluminal pressure (index of circular muscle activity) and of isometric tension (index of longitudinal muscle activity).
Both PAR‐1 agonists, thrombin (0.1 nM – 3 μM) and SFLLRN‐NH2 (1 nM – 3 μM), and PAR‐2 agonists, trypsin (0.1 nM – 10 μM) and SLIGRL‐NH2 (1 nM – 10 μM), induced different effects in the two muscular layers: a reduction of the spontaneous contractions in the circular muscle and a contractile effect or biphasic, relaxation followed by contraction, depending on the concentration, in the longitudinal muscle.
The inhibitory effects were greatly reduced or abolished by apamin (0.1 μM) indicating that they mainly occur via activation of Ca2+‐dependent small conductance, K+‐channels.
The responses to PAR‐1 and PAR‐2 were unaffected by tetrodotoxin (1 μM) or indomethacin (1 μM) suggesting that are independent by products of cyclooxygenase or by neural action potentials.
These findings indicate that both PAR‐1 and PAR‐2 are functionally expressed in rat colon. PARs mediate changes of the mechanical activity of longitudinal and circular muscle which might explain the alterations of colonic motility observed during inflammatory conditions.

British Journal of Pharmacology (2002) 136, 367–374; doi:10.1038/sj.bjp.0704746
Sirolimus/cyclosporine/tacrolimus interactions on bile flow and biliary excretion of immunosuppressants in a subchronic bile fistula rat model
Authors: Deters Michael , Klabunde Til , Kirchner Gabriele , Resch Klaus , Kaever Volkhard 
Published: January 2005

The new immunosuppressive agent sirolimus generally is combined in transplant patients with cyclosporine and tacrolimus which both exhibit cholestatic effects. Nothing is known about possible cholestatic effects of these combinations which might be important for biliary excretion of endogenous compounds as well as of immunosuppressants.
Rats were daily treated with sirolimus (1 mg kg−1 p.o.), cyclosporine (10 mg kg−1 i.p.), tacrolimus (1 mg kg−1 i.p.), or a combination of sirolimus with cyclosporine or tacrolimus. After 14 days a bile fistula was installed to investigate the effects of the immunosuppressants and their combinations on bile flow and on biliary excretion of bile salts, cholesterol, and immunosuppressants.
Cyclosporine as well as tacrolimus reduced bile flow (−22%; −18%), biliary excretion of bile salts (−15%;−36%) and cholesterol (−15%; −47%). Sirolimus decreased bile flow by 10%, but had no effect on cholesterol or bile salt excretion.
Combination of sirolimus/cyclosporine decreased bile flow and biliary bile salt excretion to the same extent as cyclosporine alone, but led to a 2 fold increase of biliary cholesterol excretion. Combination of sirolimus/tacrolimus reduced bile flow only by 7.5% and did not change biliary bile salt and cholesterol excretion.
Sirolimus enhanced blood concentrations of cyclosporine (+40%) and tacrolimus (+57%). Sirolimus blood concentration was increased by cyclosporine (+400%), but was not affected by tacrolimus.
We conclude that a combination of sirolimus/tacrolimus could be the better alternative to the cotreatment of sirolimus/cyclosporine in cholestatic patients and in those facing difficulties in reaching therapeutic ranges of sirolimus blood concentration.

British Journal of Pharmacology (2002) 136, 604–612; doi:10.1038/sj.bjp.0704756
Airway function, oedema, cell infiltration and nitric oxide generation in conscious ozone‐exposed guinea‐pigs: effects of dexamethasone and rolipram
Authors: Toward Toby J , Broadley Kenneth J 
Published: January 2005

The effects of ozone inhalation (90 min, 2.15±0.05 p.p.m.) and their modification by dexamethasone (20 mg kg−1) or the phosphodiesterase‐4 inhibitor, rolipram (1 mg kg−1), administered (i.p.) 24 and 0.5 h before and 24 h after ozone exposure were examined in conscious guinea‐pigs.
Ozone caused an early‐phase bronchoconstriction (EPB) as a fall in specific airways conductance (sGaw) measured by whole body plethysmography, followed at 5 h by a late‐phase bronchoconstriction (LPB) and increased respiratory rate. Rolipram did not alter this profile but dexamethasone inhibited the EPB.
Airway hyperreactivity to inhaled histamine (1 mM, 20 s) occurred at 0.5, 2, 12, 24 and 48 h after ozone inhalation, the 2 h change being abolished by rolipram and dexamethasone.
Bronchoalveolar lavage fluid (BALF) macrophages, eosinophils and neutrophils were significantly (P<0.05) elevated at 12, 24 and 48 h after ozone exposure, the 48 h influx being significantly attenuated (P<0.05) by rolipram and dexamethasone.
BALF nitric oxide (NO) metabolites decreased 0.5 h after ozone exposure by 52%, recovered at 2 h and significantly increased at 12 (101%) and 24 h (127%). The elevated NO was unaffected by rolipram or dexamethasone.
Lung oedema, measured from wet/dry weight differences, was significant 12, 24 and 48 h after ozone exposure, the latter being significantly attenuated (P<0.05) by rolipram and dexamethasone.
Ozone exposure of guinea‐pigs produced features common to COPD. Although rolipram and dexamethasone did not affect the airway function changes, they inhibited the inflammation, airway hyperreactivity and oedema.

British Journal of Pharmacology (2002) 136, 735–745; doi:10.1038/sj.bjp.0704764
Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2‐arachidonoyl glycerol
Authors: Kirkham Tim C , Williams Claire M , Fezza Filomena , Marzo Vincenzo Di 
Published: January 2005

Endocannabinoids are implicated in appetite and body weight regulation. In rodents, anandamide stimulates eating by actions at central CB1 receptors, and hypothalamic endocannabinoids may be under the negative control of leptin. However, changes to brain endocannabinoid levels in direct relation to feeding or changing nutritional status have not been investigated.
We measured anandamide and 2‐arachidonoyl glycerol (2‐AG) levels in feeding‐associated brain regions of rats, during fasting, feeding of a palatable food, or after satiation. Endocannabinoid levels were compared to those in rats fed ad libitum, at a point in their daily cycle when motivation to eat was absent. Fasting increased levels of anandamide and 2‐AG in the limbic forebrain and, to a lesser extent, of 2‐AG in the hypothalamus. By contrast, hypothalamic 2‐AG declined as animals ate. No changes were detected in satiated rats. Endocannabinoid levels in the cerebellum, a control region not directly involved in the control of food intake, were unaffected by any manipulation.
As 2‐AG was most sensitive to variation during feeding, and to leptin regulation in a previous study, we examined the behavioural effects of 2‐AG when injected into the nucleus accumbens shell, a limbic forebrain area strongly linked to eating motivation. 2‐AG potently, and dose‐dependently, stimulated feeding. This effect was attenuated by the CB1 receptor antagonist SR141716.
These findings provide the first direct evidence of altered brain levels of endocannabinoids, and of 2‐AG in particular, during fasting and feeding. The nature of these effects supports a role for endocannabinoids in the control of appetitive motivation.

British Journal of Pharmacology (2002) 136, 550–557; doi:10.1038/sj.bjp.0704767
Effects of sildenafil on erectile activity in mice lacking neuronal or endothelial nitric oxide synthase
Authors: Cashen Doreen E , MacIntyre D Euan , Martin William J 
Published: January 2005

Using an in vivo model of erectile activity, the effects of sildenafil were studied in mice lacking neuronal or endothelial nitric oxide synthase (nNOS and eNOS, respectively).
Under pentobarbitone anaesthesia, intracavernous pressure (ICP) and mean arterial pressure (MAP) were monitored continuously in wild‐type, nNOS−/− and eNOS−/− mice. The magnitude of erectile activity was quantified as the ratio of ICP to MAP.
No differences in basal ICP or MAP were observed amongst wild‐type, eNOS−/− and nNOS−/− mice. Electrical stimulation of the cavernous nerve (ESCN; 4.0 V, 16 Hz, 1 ms, 30 s) evoked increases in ICP and ICP/MAP as well as penile tumescence. Responses to ESCN were reduced in nNOS−/−, but not in eNOS−/− mice.
L‐NAME (50 mg kg−1, i.v.) significantly increased MAP and attenuated erectile responses in both wild‐type and eNOS−/− mice.
Sildenafil (1 mg kg−1, i.v.) augmented electrically‐evoked erectile activity in a voltage‐dependent manner in wild‐type mice and facilitated erectile responses in eNOS−/− mice. By contrast, sildenafil failed to augment the diminished erectile responses in mice lacking the nNOS isoform.
These data reveal the relative importance of nNOS, compared to eNOS, as the critical NOS isoform in the control of erectile function and illustrate that the nNOS isoform is required for sildenafil‐induced facilitation of erectile responses in vivo in mice.

British Journal of Pharmacology (2002) 136, 693–700; doi:10.1038/sj.bjp.0704772
Enhancement of apomorphine‐induced penile erection in the rat by a selective α1D‐adrenoceptor antagonist
Authors: Mizusawa Hiroya , Hedlund Petter , Sjunnesson Johan , Brioni Jorge D , Sullivan James P , Andersson Karl‐Erik 
Published: January 2005

Effects of A‐322312 (α1B‐adrenoceptor (AR) antagonist), A‐119637 (α1D‐AR antagonist), prazosin (non‐selective α1‐AR antagonist), and yohimbine (α2‐AR antagonist) were studied in rat corpus cavernosum (CC) and cavernous artery (Acc) preparations. Effects of intracavernous (i.c.) or intraperitoneal (i.p.) administration of α1‐AR antagonists on apomorphine‐induced erections were investigated.
A‐119637 attenuated electrically induced contractions in isolated CC (−logIC50; 8.12±0.15), and relaxed noradrenaline (NA)‐contracted preparations by more than 90% at 10−7 M. At the same concentration, the −logEC50 value for NA in Acc was altered from 6.79±0.07 to 4.86±0.13. In the CC and Acc, prazosin similarily inhibited contractile responses.
Inhibitory effects of A‐322312 (10−7 M) in electrically activated CC were 32.3±5.1%, whereas no effect on concentration‐response curves for NA was observed in the Acc. Yohimbine (10−8 M and 10−7 M), enhanced electrically‐induced contractions in isolated CC by 20 to 50%. At 10−6 M, inhibitory effects of yohimbine were obtained.
A‐119637 (0.3 μmol kg−1, i.p.) tripled the number of erections, and produced a 6 fold increase in the duration of apomorphine‐induced erectile responses. A‐322312, prazosin, or yohimbine did not enhance erections induced by apomorphine. None of the α1‐AR antagonists significantly increased ICP upon i.c. administration. Decreases in blood pressure were seen with A‐119637 and prazosin.
The present findings show that there is a functional predominance of the α1D‐AR subtype in the rat erectile tissue, and that blockade of this receptor facilitates rat penile erection induced by a suboptimal dose of apomorphine.

British Journal of Pharmacology (2002) 136, 701–708; doi:10.1038/sj.bjp.0704773