bluuebunny/crossref_metadata_2025_split huggingface dataset:
Involvement of hydroxyl radicals in neurogenic airway plasma exudation and bronchoconstriction in guinea‐pigs in vivo
Authors: Lei Yu‐Hong , Barnes Peter J. , Rogers Duncan F. 
Published: July 2012

Cigarette smoke induces plasma exudation in the airways of rodents by activation of capsaicin‐sensitive ‘sensory‐efferent’ nerves. The response is mediated predominantly by substance P (SP) and the magnitude of exudation is regulated by neutral endopeptidase (NEP). The component(s) of the smoke responsible for the activation of the nerves may be reactive oxygen radicals. We investigated the effect of the hydroxyl radical scavenger dimethylthiourea (DMTU), a regulator of superoxide anion, superoxide dismutase (SOD), and a regulator of hydrogen peroxide, catalase, on plasma exudation (measured using Evans blue dye) induced by cigarette smoke in guinea‐pig main bronchi in vivo. The effect of DMTU on plasma exudation and non‐cholinergic bronchoconstriction (measured as pulmonary insufflation pressure, PIP) induced by electrical stimulation of the vagus nerves was also assessed. Interaction between hydroxyl radicals and NEP was assessed with the NEP inhibitor phosphoramidon.
In each of the experiments, cigarette smoke increased plasma exudation by ∼200% above air‐exposed controls. Acute administration of DMTU (1.5 g kg−1, i.v. for 20 min) significantly reduced cigarette smoke‐induced plasma exudation by 69%. In contrast, neither SOD (240,000 u kg−1, i.v.) nor catalase (400,000 u kg−1, i.v.) significantly affected the exudative response.
Chronic pretreatment with DMTU (1.25 g kg−1 over 4 days) significantly reduced bronchial plasma exudation induced by cigarette smoke by 72%. Phosphoramidon (1.5 mg kg−1, i.v.) completely reversed the inhibition by DMTU of cigarette smoke‐induced plasma exudation.
Vagal stimulation increased plasma exudation by ∼200% and PIP by ∼250%. Acute treatment with DMTU had no significant inhibitory effect on these responses, whereas chronic pretreatment inhibited them by ∼80%. Phosphoramidon reversed the inhibition by chronic DMTU.
SP (1 nmol kg−1) increased plasma exudation by ∼250%, a response which was not inhibited by either acute or chronic DMTU.
We conclude that hydroxyl radicals, rather than superoxide anion or hydrogen peroxide, are involved in the induction of neurogenic plasma exudation and bronchoconstriction induced by cigarette smoke or by electrical stimulation of the vagus nerves. These radicals also affect the activity of NEP. Acute DMTU may affect directly the neural actions of hydroxyl radicals contained in the cigarette smoke. Chronic pretreatment with DMTU may inhibit the neurogenic airway responses by effects on tachykinin biosynthesis and/or axonal transport.
Effect of soluble P55 tumour‐necrosis factor binding fusion protein on the local Shwartzman and Arthus reactions
Authors: Norman Keith E. , Williams Timothy J. , Feldmann Marc , Rossi Adriano G. 
Published: July 2012

In this study, the effects of a protein synthesis inhibitor, cycloheximide, and a soluble tumour necrosis factor (TNF) binding/IgG fusion protein, p55‐sf2, on the priming and challenge stages of the local Shwartzman reaction (LSR) were assessed and compared with their effects on the acute inflammatory response induced by recombinant human tumour necrosis factor‐α (rhTNF), lipopolysaccharide (LPS) and a reversed passive Arthus (RPA) reaction in rabbit skin.
The LSR was induced in skin by giving an intradermal (i.d.) priming injection of LPS followed by two i.v. challenge injections 20 h and 22 h later. Accumulation of 51Cr‐labelled red blood cells and [125I]‐albumin were measured at 24 h as markers of haemorrhage and oedema formation, respectively.
The RPA reaction was induced in the rabbit by giving i.d. injections of Arthus anti‐serum (anti‐bovine‐δ‐globulin, BGG) followed 5 min later by an i.v. injection of the antigen (BGG). Oedema formation and the accumulation of 111In‐labelled neutrophils produced in the RPA reaction and in response to i.d. injection of rhTNF and LPS were measured over the 4 h period after inducing the responses.
A single local injection of cycloheximide (10 μ/site) did not inhibit neutrophil accumulation or oedema formation produced by 100% Arthus anti‐sera. Although LPS injected i.d. induced a marked dose‐dependent neutrophil accumulation, there was little associated plasma leakage. Cycloheximide (10 μ/site) did not significantly inhibit the neutrophil accumulation induced by LPS (0.1 μ/site). In the LSR, priming i.d. injections of LPS caused a dose‐dependent increase in haemorrhage and plasma leakage at skin sites after challenge with LPS (two injections of 100 μ, i.v.). Co‐injection of a single dose of cycloheximide (10 μ/site) with LPS (30 μ/site) caused a marked reduction in the amount of haemorrhage. Local cycloheximide (10 μ/site) administered immediately before LSR challenge did not affect the responses produced in the LSR.
Neutrophil accumulation induced by TNF (0.17 μ/site) was abolished by co‐administration of p55‐sf2 (3 μ/site) whereas neutrophil accumulation induced by i.d. LPS and produced in the RPA reaction was not affected. In the LSR, haemorrhage and oedema formation were inhibited by p55‐sf2 (3 μ/site) when it was administered i.d. with the LPS priming injection, but not when given i.d. immediately before LSR challenge.
These data suggest that the acute neutrophil accumulation produced in the RPA reaction and in response to i.d. LPS may not be dependent on local protein synthesis or TNF production. On the other hand, haemorrhage appears to be dependent on local protein synthesis during the priming phase but not during the challenge stage of the LSR. Importantly, haemorrhage and plasma leakage appear to be dependent on local TNF generation during the priming phase but not during the challenge stage of the LSR. Thus TNF appears to play a key role in the LSR in rabbit skin.
In vitro pharmacological profile of YM‐43611, a novel D2‐like receptor antagonist with high affinity and selectivity for dopamine D3 and D4 receptors
Authors: Hidaka Kazuyuki , Tada Shoko , Matsumoto Mitsuyuki , Ohmori Junya , Tasaki Yoshikazu , Nomura Tamako , Usuda Shinji , Yamaguchi Tokio 
Published: July 2012

We investigated some neurochemical properties of a novel benzamide, YM‐43611, [(S)‐S‐(1‐benzyl‐3‐pyrrolidinyl)‐5‐chloro‐4‐cyclopropylcarbonyl‐2‐methoxybenzamide] in comparison with putative D2‐like receptor antagonists using both rat and human cloned dopamine D2‐like receptors in vitro.
Receptor binding studies revealed that YM‐43611 had appropriately potent affinities for both rat and human D2‐like receptors, with moderate selectivity for D3 receptors and high selectivity for D4 receptors over D2 receptors (Ktvalues (nM) for rat receptors: D2, 165; D3, 35.5; D4, 1.85, and for human receptors: D2 42.9; D3, 11.2; D4, 2.10).
YM‐43611 displayed weak or negligible affinity for other neurotransmitter receptors, namely D1, D5, α1, α2, β, 5‐HT1A, 5‐HT2A, 5‐HT3, H1, M1 and M2 receptors.
Dopamine stimulated low‐Km GTPase activity on membranes from Chinese hamster ovary (CHO) cells expressing the human D2‐like receptor subtype. This response to dopamine of low‐Km GTPase activity was inhibited by use of putative D2‐like receptor antagonists. YM‐43611 showed a moderate selectivity for D3 receptors (Ki=45.5 nM) and a high selectivity for D4 receptors (Ki=3.28 nM) over D2 receptors (Ki=70.6 nM).
Dopamine inhibited forskolin‐stimulated adenylate cyclase in intact CHO cells expressing the human D2‐like receptor subtype. YM‐43611 shifted the inhibition curve of dopamine on respective D2‐like receptor subtype‐mediated cyclic AMP formation to the right in a parallel fashion, showing a pA2 value of 7.42 (38.1 nM) for D2 receptors, a pKB> value of 8.06 (8.68 nM) for D3 receptors, and a pA2 value of 8.42 (3.77 nM) for D4 receptors.
YM‐43611 but not the other D2‐like receptor antagonists exhibited good selectivity with respect to dual antagonism for D3 and D4 receptors in both receptor binding and functional assays.
These results indicate that YM‐43611 is a novel D2‐like receptor antagonist with high potency and selectivity for both D3 and D4 receptors. YM‐43611 is therefore expected to be valuable in exploration of the physiological role of D3 and D4 receptors.
Failure of BQ123, a more potent antagonist of sarafotoxin 6b than of endothelin‐1, to distinguish between these agonists in binding experiments
Authors: Maguire Janet J. , Kuc Rhoda E. , Rous Brian A. , Davenport Anthony P. 
Published: July 2012

In homogenates of human saphenous vein, [125I]‐ET‐1 and [125I]‐S6b each labelled a single population of high affinity binding sites with KD values of 0.64±0.11 nM and 0.55±0.08 nM respectively. Hill slopes were close to one. However, the density of receptors labelled by [125I]‐ET‐1 was significantly greater than that by [125I]‐S6b (187.6±23.0 compared to 91.7±23.6 fmol mg−1 protein, P<0.02).
BQ123, an ETA‐selective antagonist, inhibited specific [125I]‐ET‐1 and [125I]‐S6b binding with equal affinity. BQ123 competed in a biphasic manner for both [125I]‐ET‐1 (0.1 nM) and [125I]‐S6b (0.1 nM) with ETA KD values of 0.55±0.17 nM and 0.52±0.02 nM and ETB KD values of 14.4±2.60 μm and 11.2±0.31 μm respectively. S6b monophasically inhibited 0.1 nM [125I]‐ET‐1 (KD 1.16±0.9 nM) but competed for 0.25 nM [125I]‐ET‐1 in a bipahasic manner (KD high affinity site 1.99±0.84 nM, KD low affinity site 0.68±0.63 μm, ratio 67%: 33%).
BQ123 antagonized the vasoconstrictor responses of ET‐1 with a pKB value of 6.47 whereas BQ123 exhibited 50 fold higher affinity against S6b‐mediated vasoconstriction with a pKB value of 8.18. Regression slopes were 0.80±0.13 and 1.08±0.11 respectively.
In desensitization experiments, S6b (300 nM) did not contract preparations which were no longer responsive to ET‐1 whereas a small contraction to ET‐1 (300 nM) was obtained in preparations rendered unresponsive to S6b.
Medial sections of non‐diseased human aorta, which express only ETA receptors, were used to compare dissociation rates of the two agonists. The time course for the dissociation of [125I]‐ET‐1 and [125I]‐S6b was similar with 20–30% of each ligand dissociating at 4 h.
These data suggest that whilst BQ123, in common with other endothelin antagonists, is a much more potent blocker of S6b contractile responses than of ET‐1 contractile responses, this is not reflected by the equal affinity of BQ123 determined in competition binding experiments against both [125I]‐ET‐1 and [125I]‐S6b. This discrepancy in antagonist potency is probably not due to a marked difference in the rate of dissociation of [125I]‐ET‐1 and [125I]‐S6b from endothelin receptors. One possible explanation is that ET‐1 is activating an additional population of receptors which may have lower affinity for BQ123. This is suggested by the discrepancy in receptor density identified by [125I]‐ET‐1 and [125I]‐S6b.
Mechanical and electrophysiological effects of 8‐oxoberberine (JKL1073A) on atrial tissue
Authors: Chi Jo‐Feng , Chu Shu‐Hsun , Lee Chih‐Shone , Chou Nai‐Kaun , Su Ming‐Jai 
Published: July 2012

The effects of 8‐oxoberberine (JKL1073A) on contractions and electrophysiological characteristics of atrial tissues were examined.
In driven left atria of the rat JKL1073A (10–100 μm) increased twitch tension dose‐dependently. In spontaneously beating right atria, JKL1073A increased twitch tension but decreased beating rate slightly.
The positive inotropic and the negative chronotropic effect of 30 μm JKL1073A was not affected by prazosin (1 μm), propranolol (1 μm) and 3‐isobutyl‐1‐methyl‐xanthine (10 μm) but significantly suppressed by 4‐aminopyridine (2 mM 4‐AP).
Current‐clamp study revealed that JKL1073A prolonged rat atrial action potential duration (APD). This prolongation of APD by JKL1073A was decreased by pretreating the cells with 2 mM 4‐AP. Voltage‐clamp study showed that JKL1073A inhibited the integral of the transient outward current (Ito) dose‐dependently with a KD value of 3.66 ± 0.93 μm in rat atrial myocytes. The equilibrium dissociation constant (Kd) for JKL1073A bindings to open state Ito was 0.50 ± 0.08 μm. The suppression of Ito by 3 μm JKL1073A was accompanied by shortening of its inactivation time constant from 52.5 ± 0.9 ms to 16.8 ± 0.7 ms. V0.5 for the steady‐state inactivation curve of Ito was shifted from −25.7 ± 3.3 mV to −34.8 ± 3.2 mV.
In human atrial cells, similar inhibition of Ito and prolongation of APD by JKL1073A was found. The KD value of JKL1073A for inhibition of the integral of Ito in human atrial cells is 4.03 ± 0.02 μm. The Kd for bindings to open state Ito is 0.5 μm.
Currents through K1 channels of rat and human atrial myocytes were not inhibited by JKL1073A at concentrations up to 10 μm.
These results indicate that JKL1073A exerts a positive inotropic effect by inhibition of Ito. JKL1073A inhibit Ito by binding to open state channels or shifting of the steady‐state inactivation curve of Ito.
Inhibition of nitric oxide synthesis by NG‐nitro‐L‐arginine methyl ester (L‐NAME): requirement for bioactivation to the free acid, NG‐nitro‐L‐arginine
Authors: Pfeiffer Silvia , Leopold Eva , Schmidt Kurt , Brunner Friedrich , Mayer Bernd 
Published: July 2012

The L‐arginine derivatives NG‐nitro‐L‐arginine (L‐NOARG) and NG‐nitro‐L‐arginine methyl ester (L‐NAME) have been widely used to inhibit constitutive NO synthase (NOS) in different biological systems. This work was carried out to investigate whether L‐NAME is a direct inhibitor of NOS or requires preceding hydrolytic bioactivation to L‐NOARG for inhibition of the enzyme.
A bolus of L‐NAME and L‐NOARG (0.25 μmol) increased coronary perfusion pressure of rat isolated hearts to the same extent (21 ± 0.8 mmHg; n = 5), but the effect developed more rapidly following addition of L‐NOARG than L‐NAME (mean half‐time: 0.7 vs. 4.2 min). The time‐dependent onset of the inhibitory effect of L‐NAME was paralleled by the appearance of L‐NOARG in the coronary effluent.
Freshly dissolved L‐NAME was a 50 fold less potent inhibitor of purified brain NOS (mean IC50 = 70 μm) than L‐NOARG (IC50 = 1.4 μm), but the apparent inhibitory potency of L‐NAME approached that of L‐NOARG upon prolonged incubation at neutral or alkaline pH. H.p.l.c. analyses revealed that NOS inhibition by L‐NAME closely correlated with hydrolysis of the drug to L‐NOARG.
Freshly dissolved L‐NAME contained 2% of L‐NOARG and was hydrolyzed with a half‐life of 365 ± 11.2 min in buffer (pH 7.4), 207 ± 1.7 min in human plasma, and 29 ± 2.2 min in whole blood (n = 3 in each case). When L‐NAME was preincubated in plasma or buffer, inhibition of NOS was proportional to formation of L‐NOARG, but in blood the inhibition was much less than expected from the rates of L‐NAME hydrolysis. This was explained by accumulation of L‐NOARG in blood cells.
These results suggest that L‐NAME represents a prodrug lacking NOS inhibitory activity unless it is hydrolyzed to L‐NOARG. Bioactivation of L‐NAME proceeds at moderate rates in physiological buffers, but is markedly accelerated in tissues such as blood or vascular endothelium.
A pharmacological and histochemical study of hamster urethra and the role of urothelium
Authors: Pinna Christian , Ventura Sabatino , Puglisi Lina , Burnstock Geoffrey 
Published: July 2012

Electrical field stimulation (EFS) of circular strips of hamster proximal urethra caused frequency‐dependent relaxations at raised tone. Phentolamine (10−6 m), propranolol (10−6 m) and atropine (10−6 m) were present throughout the experiment. Neurogenic relaxation was attenuated by L‐NG‐nitroarginine methyl ester (L‐NAME) (10−4 m), was restored by L‐arginine (3 × 10−3 m) but not by D‐arginine (3 × 10−3 m) and completely blocked by tetrodotoxin (10−6 m). Neurogenic relaxation was also reduced by suramin (10−4 m) and totally blocked by suramin together with L‐NAME. Strips of hamster urethra devoid of urothelium showed little, if any, relaxant response to EFS.
An immunohistochemical study showed nitric oxide synthase‐immunoreactive nerves in the smooth muscle layers and in the lamina propria, just beneath the urothelium, but no nitric oxide synthase (NOS) staining in the urothelial layer.
Noradrenaline elicited a significantly greater contraction in strips without urothelium than in control strips. L‐NAME (10−4 m) did not affect noradrenaline‐induced contraction in both control and urothelium‐free strips. The contractile response to acetylcholine was not dependent on the presence or absence of urothelium. Nevertheless the response induced by exogenous acetylcholine (10−3 m) was increased by L‐NAME (10−4 m), both in intact and in urothelium‐free strips.
Prostaglandin E2 (10−8‐5 × 10−6 m) and 2‐methyl‐thio‐ATP (10−9‐10−5 m) relaxed proximal urethra. Suramin (10−4 m) significantly inhibited the relaxation induced by 2‐methyl‐thio‐ATP. The amplitude of these responses was not significantly different between intact and urothelium‐free strips and was not blocked by L‐NAME (10−4 m).
These results suggest that nitric oxide (NO) is the principal transmitter involved in the non‐adrenergic, non‐cholinergic (NANC) relaxation of hamster proximal urethra possibly together with another inhibitory transmitter released from nerves. NO can be released from nerves located in the circular smooth muscle layer and in the lamina propria rather than in the urothelium. The reduced neurogenic relaxation in urothelium‐free preparations suggests that a NO‐dependent inhibitory factor is released from the urothelium. In addition, ATP and prostaglandin E2 may be involved, together with NO, in the urethra during micturition.
Inhibition by memantine of the development of persistent oral dyskinesias induced by long‐term haloperidol treatment of rats
Authors: Andreassen Ole A. , Aamo Trond O. , Jørgensen Hugo A. 
Published: July 2012

Tardive dyskinesia (TD) is a serious side‐effect of long‐term treatment with neuroleptics. To investigate if neuroleptic‐induced excessive stimulation of striatal glutamate receptors may underlie TD development, the effect of the NMDA antagonist, memantine (1‐amino‐3,5‐dimethyladamantane), was studied in a rat model of TD.
In an acute experiment, six groups of rats were treated daily for 1 week with either vehicle or memantine 20 or 40 mg kg−1 day−1, and on the seventh day they received one injection of either haloperidol 1.0 mg kg−1 i.p. or saline i.p. In a subsequent long‐term experiment lasting 20 weeks, the same treatment was continued, except that haloperidol was injected i.m. as decanoate (38 mg kg−1 every 4 weeks) and control rats received sesame oil. The behaviour was videotaped and scored at intervals during both experiments, and for 16 weeks after cessation of the long‐term treatment.
In the acute experiment, haloperidol decreased motor activity and memantine increased moving and tended to attenuate the immobility induced by haloperidol. Memantine also enhanced the haloperidolinduced increase in the putative TD‐analogue vacuous chewing movements (VCM).
In the long‐term experiment, the most marked effect of haloperidol was a gradual increase in VCM and the increase persisted significantly for 12 weeks after cessation of treatment. Memantine dose‐dependently increased VCM and moving during long‐term treatment. However, only one week after stopping treatment, both these effects of memantine disappeared. In contrast to rats previously treated with haloperidol alone, rats co‐treated with memantine (both doses) and haloperidol had VCM at the level of controls two weeks after stopping treatment. The blood levels of drugs were within the therapeutic range achieved in human subjects.
These results suggest that long‐lasting changes induced by haloperidol are prevented by memantine, which supports the theory that excessive NMDA receptor stimulation may be a mechanism underlying the development of persistent VCM in rats and maybe also TD in human subjects.
Four‐dimensional temperature distributions in red blood cells withdrawn from storage and exposed to ambient temperature: a magnetic resonance thermometry study
Authors: Reiter Ursula , Reiter Gert , Wagner Thomas , Kozma Noemi , Roland Jörg , Schöllnast Helmut , Ebner Franz , Lanzer Gerhard 
Published: July 2012

BACKGROUND: Recommended by current guidelines, red blood cell (RBC) temperature should not exceed 10°C during transport. Since warming is a generically three‐dimensional process that is not homogeneous, it is necessary to clarify the term “temperature during warming.” The purpose of this study was therefore to investigate laws and relations between surface, mean, and core temperature and the corresponding times when they exceed 10°C during warm‐up.STUDY DESIGN AND METHODS: Time‐resolved three‐dimensional temperature distributions of 53 resuspended RBC units (mean volume, 253 ± 17 mL) were measured noninvasively by magnetic resonance thermometry. Warm‐up temperature maps were visualized and analyzed by dedicated software.RESULTS: Mean times when surface, mean, and core temperature exceeded 10°C were 16 ± 4, 24 ± 5, and 36 ± 7 minutes, respectively. Times strongly correlated with each other (r = 0.78‐0.95) and their variances mainly depended on RBC storage temperature and RBC pouch width (R2 = 0.81‐0.89). Measured mean temperature time courses were well described by a lumped capacitive model of heat transfer with a sample width‐dependent time constant τRBC = 56.3 ± 3.5 minutes (mean R2 = 0.996).CONCLUSION: Times when RBC surface, mean, and core temperature exceed 10°C can be estimated from each other. Moreover RBC mean temperature can be calculated for arbitrary storage and ambient temperatures. Findings might serve as a helpful tool in RBC temperature monitoring.
Fracture resistance of inter‐joined zirconia abutment of dental implant system with injection molding technique
Authors: Yang* Jianjun , Wang* Ke , Liu Guangyuan , Wang Dashan 
Published: July 2012

AbstractObjectivesZirconia powder in nanometers can be fabricated into inter‐joined abutment of dental implant system with the injection shaping technique. This study was to detect the resistance of inter‐joined zirconia abutment with different angle loading for clinical applications.Materials and MethodsThe inter‐joined abutments were shaped with the technique of injection of zirconia powder in nanometers. Sixty Osstem GSII 5 × 10 mm implants were used with 30 zirconia abutments and 30 Osstem GSII titanium abutments for fixation using 40 N torque force. The loading applications included 90°, 30°, and 0° formed by the long axis of abutments and pressure head of universal test machine. The fracture resistances of zirconia and titanium abutments were documented and analyzed.ResultsThe inter‐joined zirconia abutments were assembled to the Osstem GSII implants successfully. In the 90° loading mode, the fracture resistance of zirconia abutment group and titanium abutment group were 301.5 ± 15.4 N and 736.4 ± 120.1 N, respectively. And those in the 30°groups were 434.7 ± 36.1 N and 1073.1 ± 74 N, correspondingly. Significant difference in the two groups was found using t‐test and Wilcoxon test. No damage on the abutments of the two groups but S‐shaped bending on the implants was found when the 0° loading was 1300–2000N.ConclusionsThrough the assembly of Zirconia abutments and implants, all the components presented sufficient resistance acquired for the clinical application under loadings with different angle.