bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevention by α‐tocopherol and rutin of glutathione and ATP depletion induced by oxidized LDL in cultured endothelial cells
Authors: Schmitt Anne , Salvayre Robert , Delchambre Jean , Négre‐Salvayre Anne 
Published: July 2012

Oxidized low density lipoproteins (LDL) are thought to play an important role in atherogenesis. Mildly oxidized LDL are cytotoxic to cultured endothelial cells. Toxic doses of oxidized LDL promote the peroxidation of cellular lipids (beginning at 6 h and being maximal after 12 h of pulse with oxidized LDL) and glutathione and ATP depletion (beginning after 15 h of pulse and evolving concurrently with the cytotoxicity).
Antioxidants from 3 different classes (rutin, ascorbic acid and α‐tocopherol) were compared as to their ability to inhibit the cytotoxic effect of oxidized LDL to endothelial cells.
Effective concentrations of α‐tocopherol inhibited cellular lipid peroxidation, glutathione and ATP depletion and the cytotoxic effect.
Ascorbic acid was less effective than α‐tocopherol and rutin, and exhibited a dose‐dependent biphasic effect in the presence of oxidized LDL.
Effective concentrations of rutin inhibited glutathione and ATP depletion as well as cytotoxicity, but did not block cellular lipid peroxidation. This suggests that the glutathione and ATP depletion is directly correlated to the cytotoxicity of oxidized LDL, whereas cellular lipid peroxidation is probably not directly the cause of cellular damage leading to cell death.
The association of antioxidants of 3 different classes allowed the suppression of the biphasic effect of ascorbic acid and increased the efficacy of the protective effect. The potential consequences for prevention of the pathogenic role of oxidized LDL in endothelial injury are discussed.
The formation of nitric oxide donors from peroxynitrite
Authors: Moro María Ángeles , Darley‐Usmar Victor M. , Lizasoain Ignacio , Su Yunchao , Knowles Richard G. , Moncada Salvador , Radomski Marek W. 
Published: July 2012

Administration of peroxynitrite (ONOO−, 30–300 μM) caused relaxation of rabbit aortic strips superfused in series in a cascade. The compound responsible for this effect had a half‐life greater than 20 s and could not therefore be either nitric oxide (NO) or ONOO− which have half‐lives in the order of 1–2 s under these conditions. However the relaxation was inhibited by oxyhemoglobin, suggesting that the compound could be converted to NO in the vascular tissues or in the superfusate.
The products of the reaction between ONOO− and Krebs buffer containing 11 mM glucose, but not glucose‐free Krebs buffer, caused relaxation of the bioassay tissues. These data suggest that stable NO donor(s) were formed from the reaction of ONOO− with glucose. We therefore prepared these NO donor(s) by the reaction of glucose solutions with ONOO− in order to characterize their pharmacological actions both in the cascade bioassay and on platelets and to study their ability to release NO.
These reaction product(s) caused relaxation in the cascade and inhibition of platelet aggregation. Both effects were dependent on the concentration of D‐glucose, were equally effective if L‐glucose was used as a reactant and were reversed by oxyhaemoglobin.
The products of the reaction between ONOO− and glucose or other biological molecules containing an alcohol functional group, such as fructose, glycerol, or glyceraldehyde, released NO in the presence of Cu2+ and L‐cysteine.
These results indicate that ONOO− reacts with sugars or other compounds containing an alcohol functional group(s) to form NO donor(s) with the characteristics of organic nitrate/nitrites. This may represent a further detoxification pathway for ONOO− in vivo.
Action of adenosine receptor antagonists on hypoxia‐induced effects in the rat hippocampus in vitro
Authors: Croning M.D.R. , Zetterstróm T.S.C. , Grahame‐Smith D.G. , Newberry N.R. 
Published: July 2012

We have studied three hypoxia‐induced phenomena in the CA1 stratum pyramidale of the rat hippocampal slice: (a) the increase in extracellular potassium ion concentration ([K+]e) measured with ion‐sensitive microelectrodes, (b) the intracellularly‐recorded pyramidal cell hyperpolarization and (c) the extracellularly‐recorded depression of the synaptically‐evoked field potential recorded in stratum pyramidale.
The extracellular potassium ion concentration ([K+]e) rose from 3 mM to 4.1–4.4 mM at a time when the pyramidal cells hyperpolarized by about 6 mV and neurotransmission was virtually abolished.
Presumed glial cells depolarized in response to hypoxia. The shape and time course of this response was remarkably similar to the rise in [K+]e so induced. This is consistent with findings that glial cell membrane potential is dependent on transmembrane K+ gradient.
We investigated the effects of theophylline (100 μm) and 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX, 0.1 μm) on these effects. We have found that these compounds attenuated by about half the hypoxia‐induced increase in [K+]e; however, they did not reduce the hypoxia‐induced hyperpolarization. We have confirmed that they dramatically reduced the suppression of excitatory transmission caused by the hypoxia. We conclude that adenosine A1 receptors may be involved in the alteration of K+ homeostasis in the hippocampal shoe during hypoxia.
Effects of the ETA/ETB receptor antagonist, bosentan on endothelin‐1‐induced myocardial ischaemia and oedema in the rat
Authors: Filep János G. , Fournier Alain , Földes‐Filep Éva 
Published: July 2012

The purposes of this study were to assess the role of ETB receptors in mediating endothelin‐1 (ET‐1)‐induced myocardial ischaemia and oedema in rats and to study the inhibitory action of the novel non‐pep tide ETA/ETB receptor antagonist, bosentan on these actions of ET‐1
Intravenous bolus injection of ET‐1 (1 nmol kg−1) into anaesthetized rats produced marked ST segment elevation of the electrocardiogram without causing arrhythmias. ST segment elevation developed within 30–50 s and persisted for at least 30 min following injection of the peptide
Pretreatment of the animals with bosentan (10 mg kg−1, i.v.) inhibited on average by 96% the ST segment elevation elicited by ET‐1 (1 nmol kg−1) compared to the 82% inhibition observed with the ETA receptor‐selective antagonist, FR 139317 (2.5 mg kg−1, i.v.)
Bolus injection of ET‐1 (1 nmol kg−1, i.v.) to conscious chronically catheterized rats evoked a transient depressor response followed by a prolonged pressor effect. Corresponding to changes in blood pressure, a transient tachycardia and a sustained bradycardia were observed. ET‐1 (1 nmol kg−1) enhanced albumin extravasation by 119 and 93% in the left ventricle and right atrium, respectively, as measured by the local extravascular accumulation of Evans blue dye
Pretreatment of the animals with bosentan (10 mg kg−1) inhibited by 71 and 90% the depressor and pressor actions of ET‐1 (1 nmol kg−1) and the accompanying tachycardia and bradycardia, respectively. FR 139317 (2.5 mg kg−1) attenuated the pressor response to ET‐1 and accompanying bradycardia by 75%, without affecting the depressor action and accompanying tachycardia. ET‐1‐induced albumin extravasation was completely inhibited by bosentan (10 mg kg−1) both in the left ventricle and right atrium, compared to the 86% inhibition observed with FR 139317 (2.5 mg kg−1)
Like ET‐1, the ETB receptor‐selective agonist, IRL 1620 (0.3 and 1 nmol kg−1, i.v.) also produced dose‐dependent ST segment elevation in anaesthetized rats and enhanced albumin extravasation (up to 141% of control) in the left ventricle and right atrium, respectively, in conscious rats. These effects of IRL 1620 were completely prevented by bosentan (10 mg kg−1)
These results indicate that ETB receptors, albeit to a lesser extent than ETA receptors, are also involved in mediating ET‐1‐induced myocardial ischaemia and oedema in the rat, and suggest the therapeutic potential for bosentan in the treatment of ischaemic myocardial diseases.
Effects of 5‐HT receptor agonists on depolarization‐induced [3H]‐noradrenaline release in rabbit hippocampus and human neocortex
Authors: Allgaier C. , Warnke P. , Stangl A.P. , Feuerstein T.J. 
Published: July 2012

The present study attempted to determine whether noradrenaline (NA) release in rabbit hippocampus and human neocortex is modulated by presynaptic 5‐hydroxytryptamine (5‐HT) receptors
Slices of rabbit hippocampus and human neocortex, loaded with [3H]‐noradrenaline ([3H]‐NA) were superfused and the effects of 5‐hydroxytryptamine (5‐HT) receptor ligands on electrically evoked [3H]‐NA release were investigated
In rabbit hippocampus, 5‐HT, 5‐carboxamidotryptamine (5‐CT; 32 μm) and 2‐CH3‐5‐HT (32 μm) increased [3H]‐NA release elicited with 360 pulses/3 Hz. Facilitation of transmitter release was not influenced by the 5‐HT3 receptor antagonist, tropisetron but was prevented by the α2‐adrenoceptor antagonist, rauwolscine. When autoinhibition was avoided by stimulating the tissue with 4 pulses/100 Hz (pseudo‐one pulse‐(POP) stimulation), 2‐CH3‐5‐HT decreased evoked transmitter release, whereas 5‐HT and 5‐CT had no effect. Inhibition caused by 2‐CH3‐5‐HT was not affected by tropisetron but counteracted by the α2‐adrenoceptor ligands, clonidine and rauwolscine. Inhibition caused by clonidine was diminished in the presence of 5‐CT or 2‐CH3‐5‐HT
In human neocortex, [3H]‐NA release elicited with 360 pulses/3 Hz was increased by 10 μm 5‐HT and 32 μm 5‐CT, whereas 2‐CH3‐5‐HT was ineffective. [3H]‐NA release evoked with a modified POP stimulation (2 bursts of 4 pulses/100 Hz, 3.5 min apart) was not affected by 2‐CH3‐5‐HT or 5‐CT
The present results indicate that 5‐HT, 2‐CH3‐5‐HT and 5‐CT can act on presynaptic a2‐autoreceptors as partial agonists (2‐CH3‐5‐HT; in rabbit hippocampal tissue) or antagonists (5‐HT and 5‐CT; in tissue of rabbit hippocampus and human neocortex). Furthermore the existence of autoinhibition dictates whether these drugs cause facilitation of release, inhibition or have no effect.
Involvement of superoxide and xanthine oxidase in neutrophil‐independent rat gastric damage induced by NO donors
Authors: Lamarque D. , Whittle B.J.R. 
Published: July 2012

Nitric oxide (NO) and the superoxide anion can interact to form the cytotoxic moiety, peroxynitrite. The involvement and potential source of superoxide in the gastric mucosal damage induced by local infusion of NO donors, has now been investigated in the pentobarbitone‐anaesthetized rat
Local intra‐arterial infusion of the NO donor, sodium nitroprusside (40 μg kg−1 min−1) for 10 min induced macroscopically apparent gastric mucosal injury
This mucosal damage was dose‐dependently reduced by prior administration of a systemically acting form of superoxide dismutase conjugated with polyethylene glycol (500–2000 iu kg−1, i.v.)
Likewise, the mucosal damage induced by nitroprusside was dose‐dependently reduced by prior administration of the xanthine oxidase inhibitor, allopurinol (20–100 mg kg−1, i.p. or 100 mg kg−1, p.o.)
Pretreatment with allopurinol (100 mg kg−1, i.p.) also reduced the mucosal injury induced by local intra‐arterial infusion of the nitrosothiol, S‐nitroso‐N‐acetyl‐penicillamine (40 μg kg−1 min−1), but not that induced by local infusion of endothelin‐1 (5 pmol kg−1 min−1), indicating specificity of action
Prior administration (4h) of rabbit anti‐rat neutrophil serum (0.4 ml kg−1, i.p.), which reduced circulating neutrophils by 90%, did not significantly protect against mucosal injury induced by nitroprusside
Intravenous administration of the platelet‐activating factor receptor antagonists, WEB 2086 (1 mg kg−1) or BN 52021 (10 mg kg−1), or the thromboxane synthase inhibitor, OKY 15181 (25 mg kg;−1), did not modify mucosal damage induced by nitroprusside, showing lack of involvement of these neutrophil‐derived mediators
These findings indicate the involvement of superoxide in the injurious actions of the NO donors, implicating a cytotoxic role of peroxynitrite. Xanthine oxidase, but not neutrophils, appears to be a source of the superoxide.
Differential modulation of voltage‐activated conductances by intracellular and extracellular cyclic nucleotides in leech salivary glands
Authors: Everill Brian , Berry Michael S. 
Published: July 2012

Two‐electrode voltage clamp was used to study the effects of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) and guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) on voltage‐dependent ion channels in salivary gland cells of the leech, Haementeria ghilianii
Intracellular cyclic AMP specifically blocked delayed rectifier K+ channels. This was shown by use of 3‐isobutyl‐l‐methylxanthine (IBMX, a phosphodiesterase inhibitor), forskolin (an activator of adenylyl cyclase) and intracellular injection of cyclic AMP and its dibutyryl and 8‐bromo analogues. Cyclic AMP appeared to be the second messenger for the putative neuroglandular transmitter, 5‐hydroxytryptamine
Intracellular injection of cyclic GMP specifically potentiated high‐voltage‐activated (HVA) Ca2+ current and the effect was mimicked by zaprinast, an inhibitor of cyclic GMP‐dependent phosphodiesterase
Extracellularly, cyclic GMP and cyclic AMP specifically decreased the amplitude and increased the rate of inactivation of HVA Ca2+ current. These effects of the cyclic nucleotides are identical to those known for extracellular ATP, which activates a presumed purinoceptor. The pyrimidine nucleotide, UTP, was almost equipotent to ATP (threshold dose < 10−6 M), indicative of a vertebrate‐type nucleotide receptor. However, suramin (5 × 10−5 M), a non‐specific P2‐receptor antagonist, failed to block the effects of 5 × 10−6 m ATP (higher suramin doses could not be reliably tested because of the depolarization and increase in membrane conductance produced by the drug)
Activation of the putative purinoceptor by ATP did not affect inward rectifier Na+/K+ current which is known to be potentiated by intracellular cyclic AMP and reduced by intracellular cyclic GMP
The preparation may provide a useful model for study of nucleotide actions, and interactions, in channel modulation. It has technical advantages such as large cells (1200 μm in diameter) which lack intercellular coupling and may be individually dissected for biochemical studies.
Restoration of blood pressure by choline treatment in rats made hypotensive by haemorrhage
Authors: Ulus Ismail. H. , Arslan B. Yener , Savci Vahide , Kiran Burhan K. 
Published: July 2012

Intracerebroventricular (i.c.v.) injection of choline (25–150 μg) increased blood pressure in rats made acutely hypotensive by haemorrhage. Intraperitoneal administration of choline (60 mg kg−1) also increased blood pressure, but to a lesser extent. Following i.c.v. injection of 25 μg or 50 μg of choline, heart rate did not change, while 100 μg or 150 μg i.c.v. choline produced a slight and short lasting bradycardia. Choline (150 μg) failed to alter the circulating residual volume of blood in haemorrhaged rats
The pressor response to i.c.v. choline (50 μg) in haemorrhaged rats was abolished by pretreatment with mecamylamine (50 μg, i.c.v.) but not atropine (10 μg, i.c.v.). The pressor response to choline was blocked by pretreatment with hemicholinium‐3 (20 μg, i.c.v.)
The pressor response to i.c.v. choline (150 μg) was associated with a several fold increase in plasma levels of vasopressin and adrenaline but not of noradrenaline and plasma renin
The pressor response to i.c.v. choline (150 μg) was not altered by bilateral adrenalectomy, but was attenuated by systemic administration of either phentolamine (10 mg kg−1) or the vasopressin antagonist [β‐mercapto‐β,β‐cyclopenta‐methylenepropionyl1, O‐Me‐Tyr2,Arg8‐vasopressin (10 μg kg−1)
It is concluded that the precursor of acetylcholine, choline, can increase and restore blood pressure in acutely haemorrhaged rats by increasing central cholinergic neurotransmission. Nicotinic receptor activation and an increase in plasma vasopressin and adrenaline level appear to be involved in this effect of choline.
Differential effects of acute and chronic fluoxetine administration on the spontaneous activity of dopaminergic neurones in the ventral tegmental area
Authors: Prisco Simona , Esposito Ennio 
Published: July 2012

Electrophysiological techniques were used to study the effects of fluoxetine and citalopram on the basal activity of dopaminergic neurones in the ventral tegmental area (VTA) and substantia nigra, pars compacta (SNc) of rats
Acute i.v. injection of fluoxetine (20–1280 μg kg−1) caused a dose‐dependent inhibition of the firing rate of VTA dopaminergic neurones, but did not affect the activity of dopaminergic cells in the SNc. Citalopram (20–1280 μg kg−1, i.v.) inhibited the firing rate of dopaminergic neurones in the VTA, but its effect (maximal inhibition: 14 ±7%) was less pronounced than that of fluoxetine (maximal inhibition: 34 ±7%)
Pretreatment with mesulergine (80 μg kg−1, i.v.), a 5‐hydroxytryptamine2C/2B (5‐HT2C/2B) receptor antagonist, blocked the inhibitory effect of fluoxetine on VTA dopaminergic cells. Selective lesions of 5‐hydroxytryptaminergic neurones by the neurotoxin, 5,7‐dihydroxytryptamine (5,7‐DHT), abolished the fluoxetine‐induced reduction of VTA dopaminergic activity
In a series of experiments, fluoxetine (10 mg kg−1, i.p.) was administered once daily for 21 consecutive days. Acute i.v. administration of fluoxetine (20–1280 μg kg−1, 72 h after the last i.p. injection) did not cause any change in the basal firing rate of VTA dopaminergic neurones in treated rats, whereas it induced the typical inhibitory effect in control animals. A group of rats chronically treated with fluoxetine, received i.v. w‐chlorophenylpiperazine (mCPP; 10–320 μg kg−1), a 5‐HT2C/2B receptor agonist. This drug significantly inhibited VTA dopaminergic function in control rats, but did not modify the basal activity of dopaminergic cells in animals given chronic fluoxetine
It is concluded that fluoxetine inhibits dopaminergic function in the VTA by enhancing the synaptic levels of 5‐HT, which possibly acts through the 5‐HT2C/2B receptor subtype. Repeated treatment with fluoxetine induces tolerance to its inhibitory effect on dopaminergic activity, possibly as a consequence of down‐regulation of 5‐HT2C/2B receptors. The effects of fluoxetine on VTA dopaminergic cell activity might be relevant for its therapeutic actions and may explain the origin of the reported cases of akathisia.
Vasoconstrictor responses to the P2X‐purinoceptor agonist (β, γ‐methylene‐L‐ATP in human cutaneous and renal blood vessels
Authors: von Kiigelgen Ivar , Krumme Bernd , Schaible Ulrike , Schollmeyer Peter J. , Rump Lars Christian 
Published: July 2012

Strips of human saphenous veins and of human renal arteries and veins were superfused with Krebs‐Henseleit solution at 37°C. Constrictor responses were elicited by exogenous noradrenaline and the P2X‐purinoceptor‐selective agonist, β,γ‐methylene‐L‐ATP
In human saphenous veins, β,γ‐methylene‐L‐ATP (0.3–30 μm; EC50 2.2 μm) induced marked constrictor responses. The maximal response to β,γ‐methylene‐L‐ATP was similar to the maximal response to noradrenaline. The P2‐purinoceptor antagonist suramin (30 μm) shifted the concentration‐response curve of β,γ‐methylene‐L‐ATP to the right (apparent pKB value 4.8); suramin (100 μm) markedly inhibited the responses to P,y‐methylene‐L‐ATP. The preferential P2X‐purinoceptor antagonist, pyridoxal‐phosphate‐6‐azophenyl‐2,4,‐disulphonic acid (PPADS; 3 μm) slightly reduced the response to β,γ‐methylene‐L‐ATP. At a ten times higher concentration (30 μm), PPADS almost abolished the responses to p,y‐methylene‐L‐ATP. PPADS (30 μm), in contrast, caused no significant change in the concentration‐response curve of noradrenaline
In extrarenal and intrarenal arteries, EC50 values and maximal responses to noradrenaline were similar when compared with responses to noradrenaline in saphenous veins. Noradrenaline also constricted extrarenal veins. However, in contrast to the results obtained on saphenous veins, p,y‐methylene‐L‐ATP caused almost no constrictor responses in extrarenal veins and arteries and only moderate responses in intrarenal arteries
The results demonstrate marked differences in responsiveness of human blood vessels to the selective P2X‐purinoceptor agonist, β,γ‐methylene‐L‐ATP, suggesting tissue differences in the occurrence or operation of P2X‐purinoceptors in human vascular tissues. Moreover, the results indicate that PPADS blocks P2X‐purinoceptors in human isolated blood vessels as previously demonstrated in animal blood vessels.
Participation of 5‐HT1‐like and 5‐HT2A receptors in the contraction of human temporal artery by 5‐hydroxytryptamine and related drugs
Authors: Verheggen Raphaela , Freudenthaler Stefan , Meyer‐Dulheuer Frauke , Kaumann Alberto J. 
Published: July 2012

We investigated the hypothesis that, as in some other large human arteries, 5‐HT‐induced contraction of the temporal artery is mediated through two co‐existing receptor populations, 5‐HT1‐ like‐and 5‐HT2A. Temporal arterial segments were obtained from patients undergoing brain surgery and rings prepared set up to contract with 5‐HT and related agents. Fractions of maximal 5‐HT responses mediated through 5‐HT1‐like and 5‐HT2A receptors, f1, and f2 = 1 ‐ f1, were estimated by use of the 5‐HT2A‐selective antagonist ketanserin.
In rings with intact endothelium 5‐HT evoked contractions with a ‐log EC50, m of 7.0. Ketanserin (10–1000 nM) antagonized part of the 5‐HT‐induced contractions. Ketanserin‐resistant components of 5‐HT‐induced contractions were found with ‐log EC50, m of 6.9 and f1 of 0.17 (100 nM ketanserin) and ‐ log EC50, m of 6.4 and f1 of 0.20 (1000 nM ketanserin).
In rings with endothelial function attenuated by enzymatic treatment, 5‐HT caused contractions with a ‐log EC50, m of 7.2 that were partially blocked by ketanserin. Ketanserin‐resistant components of 5‐HT‐induced contractions were found with ‐log EC50, m 7.4 and f1 of 0.16 (100 nM ketanserin) and ‐log EC50, m of 7.5 and f1 of 0.14 (1000 nM ketanserin).
The ketanserin‐resistant component of 5‐HT‐evoked contraction was blocked by methiothepin (100–1000 nM) consistent with mediation through 5‐HT1‐like receptors.
In rings with intact endothelium the 5‐HT1‐like‐selective agonist, sumatriptan, caused small contractions with a ‐log EC50, m of 6.5 and intrinsic activity of 0.21 with respect to 5‐HT that were resistant to blockade by 1000 nM ketanserin but antagonized by 100 nM methiothepin.
In rings with intact endothelium the 5‐HT2A receptor partial agonist SK&F 103829 (2,3,4,5‐ tetrahydro‐8[methyl sulphonyl]‐1H3‐benzazepin‐7‐01 methensulphonate) contracted rings with a ‐log EC50, m of 5.0 and an intrinsic activity of 0.49 with respect to 5‐HT; the effects were antagonized by ketanserin 1000 nM.
We conclude that 80–86% of the maximum 5‐HT‐evoked contraction of human temporal artery is mediated through 5‐HT2A receptors, the remainder through 5‐HT1‐like‐receptors, regardless of whether or not endothelium is functional. The 5‐HT1‐like‐receptors are more likely to be 5‐HT1Dβ receptors than 5‐HT1Dα receptors and sumatriptan is a full agonist for these receptors. As found in arteries of other species, SK&F 103829 is a partial agonist for 5‐HT2A receptors of human temporal artery.