bluuebunny/crossref_metadata_2025_split huggingface dataset:
Saint John's wort: An in vitro analysis of P‐glycoprotein induction due to extended exposure
Authors: Perloff Michael D , Von Moltke Lisa L , Störmer Elke , Shader Richard I , Greenblatt David J 
Published: January 2005

Chronic use of Saint John's wort (SJW) has been shown to lower the bioavailability for a variety of co‐administered drugs including indinavir, cyclosporin, and digoxin. Decreases in intestinal absorption through induction of the multidrug resistance transporter, P‐glycoprotein (P‐gp), may explain decreased bioavailability.
The present study characterized the response of P‐gp to chronic and acute exposure of SJW and hypericin (HYP, a presumed active moiety within SJW) in an in vitro system. Experiments were performed with 3 to 300 μg ml−1 of methanol‐extracted SJW and 0.03 to 3 μM HYP, representing low to high estimates of intestinal concentrations.
In induction experiments, LS‐180 intestinal carcinoma cells were exposed for 3 days to SJW, HYP, vehicle or a positive control (ritonavir). P‐gp was quantified using Western blot analysis. P‐gp expression was strongly induced by SJW (400% increase at 300 μg ml−1) and by HYP (700% at 3 μM) in a dose‐dependent fashion. Cells chronically treated with SJW had decreased accumulation of rhodamine 123, a P‐gp substrate, that was reversed with acute verapamil, a P‐gp inhibitor. Fluorescence microscopy of intact cells validated these findings. In Caco‐2 cell monolayers, SJW and HYP caused moderate inhibition of P‐gp‐attributed transport at the maximum concentrations tested.
SJW and HYP significantly induced P‐gp expression at low, clinically relevant concentrations. Similar effects occurring in vivo may explain the decreased bioavailability of P‐gp substrate drugs when co‐administered with SJW.

British Journal of Pharmacology (2001) 134, 1601–1608; doi:10.1038/sj.bjp.0704399
Blood‐brain barrier transport and brain distribution of morphine‐6‐glucuronide in relation to the antinociceptive effect in rats – pharmacokinetic/pharmacodynamic modelling
Authors: Bouw M René , Xie Rujia , Tunblad Karin , Hammarlund‐Udenaes Margareta 
Published: January 2005

The objective of this study was to investigate the contribution of the blood‐brain barrier (BBB) transport to the delay in antinociceptive effect of morphine‐6‐glucuronide (M6G), and to study the equilibration of M6G in vivo across the BBB with microdialysis measuring unbound concentrations.
On two consecutive days, rats received an exponential infusion of M6G for 4 h aiming at a target concentration of 3000 ng ml−1 (6.5 μM) in blood. Concentrations of unbound M6G were determined in brain extracellular fluid (ECF) and venous blood using microdialysis and in arterial blood by regular sampling. MD probes were calibrated in vivo using retrodialysis by drug prior to drug administration.
The half‐life of M6G was 23±5 min in arterial blood, 26±10 min in venous blood and 58±17 min in brain ECF (P<0.05; brain vs blood). The BBB equilibration, expressed as the unbound steady‐state concentration ratio, was 0.22±0.09, indicating active efflux in the BBB transport of M6G. A two‐compartment model best described the brain distribution of M6G. The unbound volume of distribution was 0.20±0.02 ml g brain−1. The concentration‐antinociceptive effect relationships exhibited a clear hysteresis, resulting in an effect delay half‐life of 103 min in relation to blood concentrations and a remaining effect delay half‐life of 53 min in relation to brain ECF concentrations.
Half the effect delay of M6G can be explained by transport across the BBB, suggesting that the remaining effect delay of 53 min is a result of drug distribution within the brain tissue or rate‐limiting mechanisms at the receptor level.

British Journal of Pharmacology (2001) 134, 1796–1804; doi:10.1038/sj.bjp.0704406
The involvement of L‐type Ca2+ channels in the relaxant effects of the ATP‐sensitive K+ channel opener ZD6169 on pig urethral smooth muscle
Authors: Teramoto Noriyoshi , Yunoki Takakazu , Ikawa Shigeoki , Takano Naruaki , Tanaka Kiyoshi , Seki Narihito , Naito Seiji , Ito Yushi 
Published: January 2005

The effects of ZD6169, a novel ATP‐sensitive K+ channel (KATP channel) opener, were investigated on membrane currents in isolated myocytes using patch‐clamp techniques. Tension measurement was also performed to study the effects of ZD6169 on the resting tone of pig urethral smooth muscle.
Levcromakalim was more potent than ZD6169 in lowering the resting urethral tone. Relaxation induced by low concentrations of ZD6169 (3 μM) was completely suppressed by additional application of glibenclamide (1 μM). In contrast, glibenclamide (1 – 10 μM) only partially inhibited the relaxation induced by higher concentrations of ZD6169 (10 μM).
Bay K8644 (1 μM) reduced the maximum relaxation produced by ZD6169 (10 μM).
In whole‐cell configuration, ZD6169 suppressed the peak amplitude of voltage‐dependent Ba2+ currents in a concentration‐ and voltage‐dependent manner, and at 100 μM, shifted the steady‐state inactivation curve of the voltage‐dependent Ba2+ currents to the left at a holding potential of −90 mV.
In cell‐attached configuration, open probability of unitary voltage‐dependent Ba2+ channels (27 pS, 90 mM Ba2+) was inhibited by 100 μM ZD6169 and by 10 μM nifedipine.
Reverse transcriptase‐polymerase chain reaction (RT – PCR) analysis revealed the presence of the transcript of the α1C subunit of L‐type Ca2+ channels in pig urethra.
These results demonstrate that ZD6169 causes urethral relaxation through two distinct mechanisms, activation of KATP channels at lower concentrations and inhibition of voltage‐dependent Ca2+ channels at higher concentrations (about 10 μM).

British Journal of Pharmacology (2001) 134, 1505–1515; doi:10.1038/sj.bjp.0704408
Orexin A and B evoke noradrenaline release from rat cerebrocortical slices
Authors: Hirota Kazuyoshi , Kushikata Tetsuya , Kudo Mihoko , Kudo Tsuyoshi , Lambert David G , Matsuki Akitomo 
Published: January 2005

Orexin A and B, recently identified in the rat hypothalamus are endogenous neuropeptide agonists for the G‐protein coupled orexin‐1 (OX1) and orexin‐2 (OX2) receptors.
In the present study, we have examined the effects of orexin A, B and raised extracellular K+ on noradrenaline release from the rat cerebrocortical slice. We have compared this with other sleep – wake‐related (excitatory) neurotransmitters; dopamine, glutamate, serotonin and histamine.
Neurotransmitter release studies were performed in rat cerebrocortical slices incubated in modified Krebs buffer (with and without Ca2++EGTA 1 mM) with various concentrations of orexin A, B and K+ for various times.
Orexin A and B‐evoked (10−7 M) noradrenaline release was time‐dependent reaching a maximum some 10 min after stimulation. K+ (40 mM) evoked release was also time dependent but reached a maximum after 6 min. Orexin A, B and K+ stimulation of release was concentration dependent with pEC50 and Emax (% of basal) values of 8.74±0.32 (1.8 nM) and 263±14% and 8.61±0.38 (2.4 nM) and 173±7% and 1.43±0.02 (37 mM) and 1430±70%, respectively. Orexin‐evoked release was partially extracellular Ca2+ dependent.
Of the other transmitters studied there was a weak orexin A and B stimulation of glutamate release. In contrast K+ evoked dopamine, glutamate, histamine and serotonin release with pEC50 and Emax (% of basal) values of 1.47±0.05 (34 mM) and 3430±410%, 1.38±0.04 (42 mM) and 1240±50%, 1.47±0.02 (34 mM) and 480±10% and 1.40±0.05 (40 mM) and 560±60% respectively.
We conclude that the neuropeptides orexin A and B evoke noradrenaline release from rat cerebrocortical slices.

British Journal of Pharmacology (2001) 134, 1461–1466; doi:10.1038/sj.bjp.0704409
Disruption of antigen‐induced airway inflammation and airway hyper‐responsiveness in low affinity neurotrophin receptor p75 gene deficient mice
Authors: Tokuoka Shota , Takahashi Yoshimasa , Masuda Taisei , Tanaka Hiroyuki , Furukawa Shoei , Nagai Hiroichi 
Published: January 2005

Recently, much attention has been paid to the relationship between the nervous and immune systems. The present study was conducted to clarify the role of neurotrophin low affinity receptor (p75N) in allergic airway inflammation and hyper‐responsiveness (AHR) in mice by employing p75N gene deficient mice.
Mice were immunized twice by intraperitoneal injections of ovalbumin (OA) at intervals of 12 days. OA was inhaled 10 days after the secondary immunization and repeated three times at 4 days interval. Twenty‐four hours after the last inhalation, airway responsiveness to acetylcholine was measured and bronchoalveolar lavage fluid (BALF) was obtained for examining the number of inflammatory cells and the level of cytokines. Serum immunoglobulin was measured as a marker of systemic immune response before the final inhalation.
In wild‐type mice, repeated antigen provocation resulted in airway eosinophilia, AHR and elevations in serum IgE and interleukin (IL)‐4 and −5 in BALF. In p75N gene deficient mice, none of the above parameters was observed after antigen provocation. The antigen‐induced production of interferon (IFN)‐γ and nerve growth factor (NGF) were not altered by depletion of p75N gene.
The present findings suggest that p75 gene deficiency disrupt an allergic airway inflammation and AHR in mice by interfering type 2 helper T (Th2) cell responses.

British Journal of Pharmacology (2001) 134, 1580–1586; doi:10.1038/sj.bjp.0704411
Effects of sepsis on mast cells in rat dura mater: influence of L‐NAME and VIP
Authors: Tore F , Reynier‐Rebuffel A M , Tuncel N , Callebert J , Aubineau P 
Published: January 2005

The influence of lipopolysaccharide (LPS)‐induced sepsis on the various mast cell phenotypes of rat dura mater were examined both by immunohistochemical and biochemical methods.
Three different populations of mast cells were identified in control rats: connective tissue type mast cells (CTMC) which contain rat mast cell protease1 (RMCP1), histamine, serotonin and heparin, mucosal type mast cells (MMC) which contain RMCP2, histamine and serotonin, and intermediate type which contains both RMCP1 and RMCP2 and probably various proportions of amines and heparin.
LPS (25 mg kg−1 i.p.) caused changes in the proportions of the various types of mast cells. The number of MMC and intermediate type mast cells significantly increased and the number of mast cells immunopositive for both heparin and serotonin significantly decreased. Biochemical analysis showed that the histamine concentration of dura increased while its serotonin concentration decreased.
While vasoactive intestinal peptide (VIP) (25 ng kg−1 i.p.) appears to potentiate LPS effects on dura mater mast cells, non‐selective inhibition of nitric oxide (NO) synthase by Ng‐nitro‐L‐arginine methyl ester (L‐NAME) (30 mg kg−1 i.p.) did not influence sepsis‐induced mast cell changes.
These findings suggest that mast cells of dura mater may play a role in brain protection during sepsis.

British Journal of Pharmacology (2001) 134, 1367–1374; doi:10.1038/sj.bjp.0704412
Activation of endothelial cell IKCa with 1‐ethyl‐2‐benzimidazolinone evokes smooth muscle hyperpolarization in rat isolated mesenteric artery
Authors: Walker S D , Dora K A , Ings N T , Crane G J , Garland C J 
Published: January 2005

In rat small mesenteric arteries contracted with phenylephrine, 1‐ethyl‐2‐benzimidazolinone (1‐EBIO; 3 – 300 μM) evoked concentration‐dependent relaxation that, above 100 μM, was associated with smooth muscle hyperpolarization.
1‐EBIO‐evoked hyperpolarization (maximum 22.1±3.6 mV with 300 μM, n=4) was endothelium‐dependent and inhibited by charybdotoxin (ChTX 100 nM; n=4) but not iberiotoxin (IbTX 100 nM; n=4).
In endothelium‐intact arteries, smooth muscle relaxation to 1‐EBIO was not altered by either of the potassium channel blockers ChTX (100 nM; n=7), or IbTX (100 nM; n=4), or raised extracellular K+ (25 mM). Removal of the endothelium shifted the relaxation curve to the right but did not reduce the maximum relaxation.
In freshly isolated mesenteric endothelial cells, 1‐EBIO (600 μM) evoked a ChTX‐sensitive outward K‐current. In contrast, 1‐EBIO had no effect on smooth muscle cell conductance whereas NS 1619 (33 μM) stimulated an outward current while having no effect on the endothelial cells.
These data show that with concentrations greater than 100 μM, 1‐EBIO selectively activates outward current in endothelial cells, which presumably underlies the smooth muscle hyperpolarization and a component of the relaxation. Sensitivity to block with charybdotoxin but not iberiotoxin indicates this current is due to activation of IKCa. However, 1‐EBIO can also relax the smooth muscle by an undefined mechanism, independent of any change in membrane potential.

British Journal of Pharmacology (2001) 134, 1548–1554; doi:10.1038/sj.bjp.0704415
Thromboxane receptor density is increased in human cardiovascular disease with evidence for inhibition at therapeutic concentrations by the AT1 receptor antagonist losartan
Authors: Katugampola Sidath D , Davenport Anthony P 
Published: January 2005

The aim of this study was to establish how thromboxane receptors (TP) respond to the increase in levels of plasma thromboxane observed in both cardiac (cardiomyopathy, ischaemic heart disease and pulmonary hypertension) and vascular disease (atherosclerosis of coronary artery disease and accelerated atherosclerosis of saphenous vein grafts).
The agonist radioligand [125I]‐BOP, bound rapidly to TP receptors in normal human cardiovascular tissue, displaying high affinity in left ventricle (KD 0.23±0.06 nM, Bmax 28.4±5.7 fmol mg−1 protein) and reversibility with a t1/2 of 10 min (n=five individuals±s.e.mean).
In the heart, TP receptor density in the right ventricle of primary pulmonary hypertensive patients were significantly increased (66.6±6 fmol mg−1 protein) compared to non‐diseased right ventricle (37.9±4.1 fmol mg−1 protein, n=six individuals±s.e.mean, P<0.05).
In diseased vessels, TP receptor densities were significantly increased (3 fold in the intimal layer) in atherosclerotic coronary arteries, saphenous vein grafts with severe intimal thickening (n=8 – 12 individuals, P<0.05) and aortic tissue (n=5 – 6 individuals, P<0.05), compared with normal vessels.
Losartan, tested at therapeutic doses, competed for [125I]‐BOP binding to human vascular tissue, suggesting that some of the anti‐hypertensive effects of this AT1 receptor antagonist could also be mediated by blocking human TP receptors.
The differential distribution of TP receptors in the human cardiovascular system and the alteration of receptor density, accompanying the increase in endogenous thromboxane levels in cardiovascular disease, suggest that TP receptors represent a significant target for therapeutic interventions and highlights the importance for the development of novel selective antagonist for use in humans.

British Journal of Pharmacology (2001) 134, 1385–1392; doi:10.1038/sj.bjp.0704416
Inhibition of immune‐complex mediated dermal inflammation in rats following either oral or topical administration of a small molecule C5a receptor antagonist
Authors: Strachan Anna J , Shiels Ian A , Reid Robert C , Fairlie David P , Taylor Stephen M 
Published: January 2005

Initiation of a peritoneal Arthus reaction by deposition of immune‐complexes results in vascular leakage, polymorphonuclear leukocyte (PMN) infiltration, and tumour necrosis factor α (TNFα) and interleukin‐6 (IL‐6) production. We now demonstrate in rats that oral administration of the C5a receptor antagonist AcPhe[Orn‐Pro‐D‐Cyclohexylalanine‐Trp‐Arg] (AcF‐[OPdChaWR]; 1 – 10 mg kg−1 30 min prior to immune‐complex deposition) inhibits these inflammatory markers in the peritoneal Arthus reaction.
Initiation of a dermal Arthus reaction resulted in a significant increase in vascular leakage, PMN infiltration, systemic production of TNFα and pathological changes in the dermis.
Pretreatment of rats with AcF‐[OPdChaWR] either intravenously (1 mg kg−1 10 min prior to immune‐complex deposition) or orally (1 – 10 mg kg−1 30 min prior to immune‐complex deposition) significantly inhibited immune‐complex mediated dermal vascular leakage and systemic cytokine production. Topical pretreatment with AcF‐[OPdChaWR] (400 μg site−1 in 10% dimethyl sulphoxide 10 min prior to immune‐complex deposition) also inhibited vascular leakage, as well as histopathological changes associated with a dermal Arthus reaction.
Oral administration of 3 mg kg−1 AcF‐[OPdChaWR] resulted in the appearance of the drug in plasma within 5 min, with peak blood levels ∼0.3 μM reached within 20 min. The plasma elimination half‐life was ∼70 min. The oral activity and bioavailability of AcF‐[OPdChaWR], its activity when applied topically to the skin, suggest that small molecule C5a receptor antagonists may have therapeutic utility in dermal inflammatory disorders involving complement activation.
This is the first demonstration for either an orally or topically active C5a receptor antagonist, and suggests that small molecule C5a antagonists may have therapeutic utility when given by multiple routes of application.

British Journal of Pharmacology (2001) 134, 1778–1786; doi:10.1038/sj.bjp.0704417
ECL‐cell histamine mobilization in conscious rats: effects of locally applied regulatory peptides, candidate neurotransmitters and inflammatory mediators
Authors: Norlén P , Bernsand M , Konagaya T , Håkanson R 
Published: January 2005

The ECL cells control gastric acid secretion by mobilizing histamine in response to circulating gastrin. In addition, the ECL cells are thought to operate under nervous control and to be influenced by local inflammatory processes.The purpose of the present study was to monitor histamine mobilization from ECL cells in conscious rats in response to locally applied regulatory peptides, candidate neurotransmitters and inflammatory mediators.Microdialysis probes were implanted in the submucosa of the acid‐producing part of the rat stomach. Three days later, the agents to be tested were administeredviathe microdialysis probe and their effects on basal (48 h fast) and stimulated (intravenous infusion of gastrin‐17, 3 nmol kg−1 h−1) mobilization of ECL‐cell histamine was monitored by continuous measurement of histamine in the perfusate (radioimmunoassay).Locally administered gastrin‐17 and sulfated cholecystokinin‐8 mobilized histamine as did pituitary adenylate cyclase‐activating peptide‐27, vasoactive intestinal peptide, peptide YY, met‐enkephalin, endothelin and noradrenaline, adrenaline and isoprenaline.While gastrin, sulfated‐cholecystokinin‐8, met‐enkephalin and isoprenaline induced a sustained elevation of the submucosal histamine concentration, endothelin, peptide YY, pituitary adenylate cyclase activating peptide, vasoactive intestinal peptide, noradrenaline and adrenaline induced a transient elevation.Calcitonin gene‐related peptide, galanin, somatostatin and the prostanoid misoprostol inhibited gastrin‐stimulated histamine mobilization.The gut hormones neurotensin and secretin and the neuropeptides gastrin‐releasing peptide, neuropeptide Y and substance P failed to affect ECL‐cell histamine mobilization, while motilin and neuromedin U‐25 had weak stimulatory effects. Also acetylcholine, carbachol, serotonin and the amino acid neurotransmitters aspartate, γ‐aminobutyric acid, glutamate and glycine were inactive or weakly active as was bradykinin.In summary, a range of circulating hormones, local hormones, catecholamines, neuropeptides and inflammatory mediators participate in controlling the activity of rat stomach ECL cellsin situ.British Journal of Pharmacology(2001)134, 1767–1777; doi:10.1038/sj.bjp.0704419
Analgesic activity of a novel use‐dependent sodium channel blocker, crobenetine, in mono‐arthritic rats
Authors: Laird J M A , Carter A J , Grauert M , Cervero F 
Published: January 2005

Although sodium channel blockers are effective analgesics in neuropathic pain, their effectiveness in inflammatory pain has been little studied. Sodium channels are substantially up‐regulated in inflamed tissue, which suggests they play a role in maintenance of chronic inflammatory pain. We have examined the effects of sodium channel blockers on mobility, joint hyperalgesia and inflammation induced by complete Freund's adjuvant injected in one ankle joint of adult rats. The clinically effective sodium channel blocker, mexiletine, was compared with crobenetine (BIII 890 CL), a new, highly use‐dependent sodium channel blocker.
Rats were treated for 5 days, starting on the day of induction of arthritis and were tested daily for joint hyperalgesia, hind limb posture and mobility. At post‐mortem, joint stiffness and oedema were assessed. Dose response curves were constructed for each test compound (3 – 30 mg kg day−1). Control groups were treated with vehicle or with the non‐steroidal anti‐inflammatory drug, meloxicam (4 mg kg day−1 i.p.).
Both sodium channel blockers produced dose dependent and significant reversal of mechanical joint hyperalgesia and impaired mobility with an ID50 of 15.5±1.1 mg kg day−1 for crobenetine and 18.1±1.2 mg kg day−1 for mexiletine. Neither compound affected the responses of the contralateral non‐inflamed joint, nor had any effect on swelling and stiffness of the inflamed joint.
We conclude that sodium channel blockers are analgesic and anti‐hyperalgesic in this model of arthritis. These data suggest that up regulation of sodium channel expression in primary afferent neurones may play an important role in the pain and hyperalgesia induced by joint inflammation.

British Journal of Pharmacology (2001) 134, 1742–1748; doi:10.1038/sj.bjp.0704428
trans‐4‐Amino‐2‐methylbut‐2‐enoic acid (2‐MeTACA) and (±)‐trans‐2‐aminomethylcyclopropanecarboxylic acid ((±)‐TAMP) can differentiate rat ρ3 from human ρ1 and ρ2 recombinant GABAC receptors
Authors: Vien Jimmy , Duke Rujee K , Mewett Kenneth N , Johnston Graham A R , Shingai Ryuzo , Chebib Mary 
Published: January 2005

This study investigated the effects of a number of GABA analogues on rat ρ3 GABAC receptors expressed in Xenopus oocytes using 2‐electrode voltage clamp methods.
The potency order of agonists was muscimol (EC50=1.9±0.1 μM) (+)‐trans‐3‐aminocyclopentanecarboxylic acids ((+)‐TACP; EC50=2.7±0.9 μM) trans‐4‐aminocrotonic acid (TACA; EC50=3.8±0.3 μM) GABA (EC50=4.0±0.3 μM) > thiomuscimol (EC50=24.8±2.6 μM) > (±)‐cis‐2‐aminomethylcyclopropane‐carboxylic acid ((±)‐CAMP; EC50=52.6±8.7 μM) > cis‐4‐aminocrotonic acid (CACA; EC50=139.4±5.2 μM).
The potency order of antagonists was (±)‐trans‐2‐aminomethylcyclopropanecarboxylic acid ((±)‐TAMP; KB=4.8±1.8 μM) (1,2,5,6‐tetrahydropyridin‐4‐yl)methylphosphinic acid (TPMPA; KB=4.8±0.8 μM) > (piperidin‐4‐yl)methylphosphinic acid (P4MPA; KB=10.2±2.3 μM) 4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol (THIP; KB=10.2±0.3  μM) imidazole‐4‐acetic acid (I4AA; KB=12.6±2.7 μM) > 3‐aminopropylphosphonic acid (3‐APA; KB=35.8±13.5 μM).
trans‐4‐Amino‐2‐methylbut‐2‐enoic acid (2‐MeTACA; 300 μM) had no effect as an agonist or an antagonist indicating that the C2 methyl substituent is sterically interacting with the ligand‐binding site of rat ρ3 GABAC receptors.
2‐MeTACA affects ρ1 and ρ2 but not ρ3 GABAC receptors. In contrast, (±)‐TAMP is a partial agonist at ρ1 and ρ2 GABAC receptors, while at rat ρ3 GABAC receptors it is an antagonist. Thus, 2‐MeTACA and (±)‐TAMP could be important pharmacological tools because they may functionally differentiate between ρ1, ρ2 and ρ3 GABAC receptors in vitro.

British Journal of Pharmacology (2002) 135, 883–890; doi:10.1038/sj.bjp.0704432