bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bradykinin‐induced release of PGI2 from aortic endothelial cell lines: responses mediated selectively by Ca2+ ions or a staurosporine‐sensitive kinase
Authors: Parsaee Heydar , McEwan Jean R. , MacDermot John 
Published: July 2012

Bradykinin (100 nm) triggers release of nitric oxide and prostacyclin from both AG07680A and AG04762 bovine cultured aortic endothelial cells. The exposure of these cells to bradykinin is in each case associated with a striking rise in intracellular calcium ion concentration.
Exposure of AG07680A cells to 250 nm ionomycin was followed also by a significant release of prostacyclin, whereas 250 nm ionomycin had no capacity to stimulate release of prostacyclin from AG04762 cells.
There was a similar concentration‐dependent increase in intracellular calcium ion concentration on exposure of AG07680A and AG04762 cells to ionomycin.
Exposure of AG04762 cells for 10 min to staurosporine produced a concentration‐dependent inhibition (IC50 = 107 ± 14 nm) in bradykinin‐stimulated prostacyclin release. There was no similar inhibitory effect of staurosporine in AG07680A cells.
Bradykinin (10 nm) triggered release of nitric oxide from both AG07680A and AG04762 cells, and the effect was not inhibited by 500 nm staurosporine. There was a similar ionomycin‐dependent release of nitric oxide from both cell types.
These results identify a common pathway for bradykinin‐dependent nitric oxide release from both AG07680A and AG04762 cells, involving increases in intracellular calcium ion concentration. In contrast, the bradykinin‐dependent release of prostacyclin may involve one of two pathways (involving an increase in intracellular calcium or activation of a staurosporine‐sensitive kinase), and the two pathways are selectively exploited in AG07680A and AG04762 cells, respectively.
Specific inhibition of leukotriene B4 (LTB4)‐induced neutrophil emigration by 20‐hydroxy LTB4: implications for the regulation of inflammatory responses
Authors: Pettipher E.R. , Salter E.D. , Breslow R. , Raycroft L. , Showell H.J. 
Published: July 2012

The interaction between leukotriene B4 (LTB4) and its metabolite, 20‐hydroxy LTB4 in the control of neutrophil emigration was examined in guinea‐pig skin.
Leukotriene B4 (10–300 ng) elicited a dose‐dependent increase in neutrophil infiltration (as measured by myeloperoxidase activity) 4 h after injection into guinea‐pig skin. In contrast, 20‐hydroxy LTB4 (30–1000 ng) displayed only weak inflammatory activity in this assay.
Although 20‐hydroxy LTB4 had low agonist activity, this metabolite caused a potent dose‐dependent inhibition of responses to LTB4 (100 ng), when administered systemically (ED50= 1.3 μg kg−1, s.c.) without significantly affecting neutrophil infiltration in response to C5a (2 μg). Systemic administration of 20‐carboxy LTB4 (10 μg) did not affect neutrophil accumulation in response to LTB4 or C5a. In addition, neither 15(S)‐hydroxy 5(S)‐HPETE(10 μg) nor lipoxin A4 (10 μg) inhibited responses to LTB4.
Addition of 20‐hydroxy LTB4 (10−11–10−8 m) to human blood prior to isolation of the neutrophils led to concentration‐dependent decrease in the number of LTB4 receptors and decreased chemotactic responsiveness to LTB4 without affecting responses to C5a. Incubation of blood with 20‐carboxy LTB4 (10−8 m) did not reduce LTB4 receptor number of chemotactic responsivness to LTB4.
These data indicate that although 20‐hydroxy LTB4 is a weak agonist at LTB4 receptors, it can desensitize neutrophils to the effects of LTB4 via down‐regulation of the high affinity receptor and thus provides evidence for a mechanism whereby inflammatory responses may be regulated.
Cerebral blood flow and cerebrovascular reactivity after inhibition of nitric oxide synthesis in conscious goats
Authors: Fernández N. , García J.L. , García‐Villalón A.L. , Monge L. , Gómez B. , Diéguez G. 
Published: July 2012

The role of nitric oxide in the cerebral circulation under basal conditions and after vasodilator stimulation was studied in instrumented, conscious goats, by examining the action of inhibiting endogenous nitric oxide production with NG‐nitro‐l‐arginine methyl ester (l‐NAME).
In 6 unanaesthetized goats, blood flow to one brain hemisphere (electromagnetically measured), systemic arterial blood pressure and heart rate were continuously recorded. l‐NAME (35 mg kg−1 by i.v. bolus) decreased resting cerebral blood flow by 43 ± 3%, increased mean arterial pressure by 21 ± 2%, and decreased heart rate by 41 ± 2%; cerebrovascular resistance increased by 114 ± 13% (P < 0.01); the immediate addition of i.v. infusion of l‐NAME (0.15–0.20 mg kg−1 during 60–80 min) did not significantly modify these effects. Cerebral blood flow recovered at 72 h, arterial pressure and cerebrovascular resistance at 48 h, and heart rate at 6 days after l‐NAME treatment.
A second treatment with l‐NAME scheduled as above reproduced the immediate haemodynamic effects of the first treatment, which (except bradycardia) reversed with l‐arginine (200–300 mg kg−1 by i.v. bolus).
Acetylcholine (0.01–0.3 μg), sodium nitroprusside (3–100 μg) and diazoxide (0.3–9 mg), injected into the cerebral circulation of 5 conscious goats, produced dose‐dependent increases in cerebral blood flow, and decreases in cerebrovascular resistance; sodium nitroprusside (30 and 100 μg) also caused hypotension and tachycardia.
The reduction in cerebrovascular resistance from resting levels (in absolute values) to lower doses, but not to the highest dose, of acetylcholine was diminished, to sodium nitroprusside was increased, and to diazoxide was unaffected after l‐NAME, compared to control conditions. The effects on cerebrovascular resistance to acetycholine normalized within 24 h and to sodium nitroprusside within 48 h after l‐NAME treatment.
This study provides information about the evolution of the changes in cerebral blood flow and cerebrovascular reactivity after inhibition of endogenous nitric oxide in conscious animals. The results suggest: (a) endogenous nitric oxide is involved in regulation of the cerebral circulation by producing a resting vasodilator tone, (b) the cerebral vasodilatation to acetylcholine is mediated, at least in part, by nitric oxide release, and (c) inhibition of nitric oxide production induces supersensitivity of cerebral vasculature to nitrovasodilators.
Suppression of inflammatory responses to 12‐O‐tetradecanoylphorbol‐13‐acetate and carrageenin by YM‐26734, a selective inhibitor of extracellular group II phospholipase A2
Authors: Miyake Akira , Yamamoto Hirokazu , Kubota Emi , Hamaguchi Katsuhiko , Kouda Akio , Honda Kazuo , Kawashima Hiroyuki 
Published: July 2012

YM‐26734 [4‐(3,5‐didodecanoyl‐2,4,6‐trihydroxyphenyl)‐7‐hydroxy‐2‐(4‐hydroxyphenyl)chroman] dose‐dependently inhibited the activities of extracellular phospholipase A2 (PLA2): rabbit platelet‐derived group II and porcine pancreas‐derived group I PLA2, with IC50 values of 0.085 (0.056–0.129, n = 5) and 6.8 (5.0–9.6, n = 5) μm, respectively.
In contrast, YM‐26734 did not reduce the activity of intracellular PLA2 prepared from mouse macrophages, which preferentially hydrolyzed arachidonoyl phospholipids at concentrations up to 50 μm. YM‐26734 also showed no effect against either sheep seminal vesicle cyclo‐oxygenase or rat leukocyte 5‐lipoxygenase.
Lineweaver‐Burk analysis showed that YM‐26567‐1 behaved as a competitive inhibitor of group II PLA2 derived from rabbit platelets, with a Ki value of 48 nm.
In mice, YM‐26734 inhibited 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA, 1 μg/ear)‐induced ear oedema in a dose‐dependent manner, with ED50 values of 45 (30–67) μg/ear (n = 5) and 11 (4–32) mg kg−1, i.v. (n = 5), but did not decrease arachidonic acid (4 mg/ear)‐induced ear oedema at 1 mg/ear and 30 mg kg−1, i.v.
In rats, the accumulation of exudate fluids and leukocytes in the pleural cavity in response to carrageenin injection (2 mg) was significantly less in a group treated with YM‐26734 (20 mg kg−1, i.v.) than in the control group (0.43 ± 0.02 vs 0.59 ± 0.03 g per cavity and 3.8 ± 0.2 vs 4.9 ± 0.3 × 107 cells per cavity, respectively; n = 5).
These results suggest that YM‐26734 is a potent and competitive inhibitor of extracellular PLA2 with selectivity for group II PLA2, and that the inhibition of group II enzymes activity may cause the suppression of inflammatory responses to TPA and carrageenin.
Vascular actions of purines in the foetal circulation of the human placenta
Authors: Read M.A. , Boura A.L.A. , Walters W.A.W. 
Published: July 2012

The vasoactive effects of adenosine triphosphate (ATP), adenosine and other purines in the foetal circulation of the human placenta were examined. Single lobules of the placenta were bilaterally perfused in vitro with Krebs buffer (maternal and foetal sides 5 ml min−1 each, 95% O2:5% CO2, 37°C). Changes in foetal vascular tone were assessed by recording perfusion pressure during constant infusion of each purine. To allow recording of the vasodilator effects, submaximal vasoconstriction was induced by concomitant infusion of prostaglandin F2α (0.7–2.0 μmol 1−1).
ATP (1.0–100 μmol 1−1) usually caused concentration‐dependent reductions in perfusion pressure. However, biphasic with initial transient increases, or only increases in pressure were sometimes observed. Falls in pressure caused by ATP were significantly reduced by addition to the perfusate of NG‐nitro‐l‐arginine (l‐NOARG) (100 μmol 1−1) but not NG‐nitro‐d‐arginine (d‐NOARG) (100 μmol 1−1). They were not influenced by addition of indomethacin (10 μmol 1−1) or l‐arginine (100 μmol 1−1).
Adenosine (0.01–1.0 mmol 1−1) consistently caused concentration‐dependent reductions in perfusion pressure, this effect not being influenced by indomethacin. l‐NOARG, but not d‐NOARG, reduced the potency of adenosine approximately three fold. l‐Arginine, but not d‐arginine enhanced its potency by a similar amount.
2‐Methylthio‐ATP, a selective P2y agonist was approximately 50 times more potent than ATP as a vasodilator agent, always causing decreases in perfusion pressure.
β‐γ‐Methylene ATP, a selective P2x agonist, was approximately 100 times more potent than ATP as a vasoconstrictor, but only caused transient increases in perfusion pressure.
The rank order of vasodilator potencies of a selection of adenosine receptor agonists was, 2‐chloroadenosine >> 5‐(N‐cyclopropyl)‐carboxamidoadenosine, >5‐N‐ethylcarboxamidoadenosine, >2‐chloro‐N6‐cyclopentyladenosine, >CGS‐21680 > N6‐cyclohexyladenosine = adenosine. Vasodilatation due to adenosine was inhibited by the P1‐A2 receptor antagonist 3,7‐dimethyl‐1‐propargylxanthine (DMPX).
These results suggest that ATP may cause an endothelium‐dependent vasodilatation in the foetal vessels of the human placenta via activation of a P2y receptor linked to the formation of nitric oxide (NO). Vasodilatation caused by ATP may mask an accompanying vasoconstrictor effect mediated, via a P2x receptor, in the villous vascular smooth muscle. Adenosine acting on P1‐A2 receptors, which are also present in the foetal vasculature, may require synergistic interaction with NO to achieve a maximal vasodilator response.
Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics
Authors: Hermans J.J.R. , Thijssen H.H.W. 
Published: July 2012

To explain the large differences in (the stereoselectivity of) the clearances of the enantiomers of warfarin and acenocoumarol (4′‐nitrowarfarin) their human liver microsomal metabolism has been studied and enzyme kinetic parameters determined. The effects of cimetidine, propafenone, sulphaphenazole, and omeprazole on their metabolism has been investigated.
The 4‐hydroxycoumarins follow similar metabolic routes and are mainly hydroxylated at the 6‐ and 7‐position (accounting for 63 to 99% of the metabolic clearances).
Due to the lower Km values of R‐ and S‐acenocoumarol and higher Vmax values of S‐acenocoumarol, the overall metabolic clearances of R/S acenocoumarol exceed those of R/S warfarin 6 and 66 times respectively.
The metabolism of both compounds is stereoselective for the S‐enantiomers, which is 10 times more pronounced in the case of acenocoumarol.
Except for the 7‐hydroxylation of the R‐enantiomers (r = 0.90; P < 0.025), the 6‐ and 7‐hydroxylation rates of R/S warfarin do not correlate with those of R/S acenocoumarol.
Sulphaphenazole competitively inhibits the 7‐ and in some samples partly (up to 50%) the 6‐hydroxylation of S‐warfarin as well as the 7‐hydroxylation of R‐ and S‐acenocoumarol and the 6‐hydroxylation of S‐acenocoumarol (Kis ranging from 0.5– 1.3 μm).
Omeprazole partly (40–80%) inhibits the 6‐ and 7‐hydroxylation of R‐warfarin (Ki = 99 and 117 μm) and of R‐ (Ki = 219 and 7.2 μm) and S‐acenocoumarol (Ki = 6.1 and 7.7 μm) but not S‐warfarin in a competitive manner.
Differences in the partial (up to 40%) inhibition of the metabolism of the enantiomers of the 4‐hydroxycoumarins were also observed for the relatively weak inhibitors, propafenone and cimetidine.
The results suggest that the coumarin ring hydroxylations of both compounds are catalysed by different combinations of P450 isozymes. The 7‐hydroxylation of R/S acenocoumarol and the 6‐hydroxylation of S‐acenocoumarol are at least partly conducted by (a) P450 isozyme(s) of the 2C subfamily different from P450 2C9 (the main S‐warfarin 7‐ and 6‐hydroxylase).
Action of purine and pyrimidine nucleotides on the rat superior cervical ganglion
Authors: Connolly G.P. , Harrison P.J. , Stone T.W. 
Published: July 2012

Using a grease‐gap technique, we have investigated the effects of purine and pyrimidine nucleotides on the d.c. potential of the rat isolated superior cervical ganglion (SCG).
Of the purines tested, adenosine, adenosine 5′‐triphosphate (ATP), β,γ‐methylene‐adenosine 5′‐triphosphate (β,γ‐MeATP) at up to 300 μm produced concentration‐dependent hyperpolarizations, whereas 2‐methyl‐thio‐ATP (2‐Me.S.ATP) and α,β‐methylene‐ATP (α,β‐MeATP) depolarized ganglia. Of the pyrimidines tested, uridine 5′‐triphosphate (UTP) produced concentration‐dependent depolarizations and cytosine 5′‐triphosphate (CTP) at 1000 μm produced considerably smaller but significant depolarizations. In contrast uridine 5′‐monophosphate (UMP) at 1000 μm hyperpolarized ganglia. The relative order of potency of purines and pyrimidines to depolarize ganglia was:‐ UTP > α,β‐MeATP >> CTP > 2‐Me.S.ATP and to hyperpolarize ganglia was:‐ adenosine = β,γ‐MeATP > ATP > UMP.
The ability of purines and pyrimidines to alter the depolarizing response caused by muscarine and of purines to alter depolarization induced by γ‐aminobutyric acid (GABA) was determined. The relative order of potency of nucleotides in depressing submaximal depolarization caused by muscarine (100 nm) was: adenosine = ATP > β,γ‐MeATP whereas 2‐Me.S.ATP, α,β‐MeATP and UTP did not significantly alter depolarization caused by muscarine. At 100 μm β,γ‐MeATP and adenosine but not ATP potentiated GABA‐induced depolarizations.
Hyperpolarizations caused by adenosine, ATP, β,γ‐MeATP and UMP and depolarizations caused by α,β‐MeATP were enhanced in medium containing reduced concentrations of calcium (0.1 mm) and potassium (2 mm). In this medium 8‐phenyltheophylline abolished hyperpolarizations caused by adenosine and reversed hyperpolarizations caused by ATP into depolarizations. Suramin (300 μm), a P2‐purinoceptor antagonist, significantly reduced the depolarizing response caused by α,β‐MeATP and significantly increased hyperpolarizations caused by ATP and β,γ‐MeATP. Suramin (300 μm) did not significantly alter depolarizations caused by 1,1‐dimethyl‐4‐phenylpiperazinium (10 μm), potassium (3 mm) or muscarine (100 nm) and significantly potentiated depolarizations caused by UTP (100 μm).
It is concluded that the rat SCG contains P1‐purinoceptors that hyperpolarize the ganglion and diminish sensitivity to muscarine, and P2X‐purinoceptors that depolarize the SCG. There is also some evidence to suggest the presence of receptors for UTP, i.e., pyrimidinoceptors, which depolarize SCG neurones.
Modulation by nitric oxide of platelet‐activating factor‐induced albumin extravasation in the conscious rat
Authors: Filep János G. , Földes‐Filep Éva 
Published: July 2012

The objective of this study was to assess whether or not endogenous nitric oxide (NO) could mediate the hypotensive response to platelet‐activating factor (PAF) and modulate PAF‐induced microvascular albumin leakage in the conscious rat.
PAF (0.19 and 1.9 nmol kg−1, i.v.) evoked dose‐dependent hypotension and significantly enhanced albumin extravasation in the large airways, pancreas, stomach and duodenum 15 min after its administration. Inhibition of NO synthesis by NG‐nitro‐l‐arginine methyl ester (l‐NAME, 0.125–2 mg kg−1, i.v.) produced marked dose‐dependent increases in albumin accumulation (up to 290%) in large airways, liver, spleen, pancreas, kidney, stomach and duodenum as measured by the extravasation of Evans blue dye. l‐NAME (2 mg kg−1) treatment markedly potentiated PAF (1.9 nmol kg−1)‐induced albumin extravasation in these tissues, whereas it did not modify the hypotensive response to PAF.
Maintenance of mean arterial blood pressure at the level observed following 2 mg kg−1 l‐NAME by infusion of noradrenaline (620–790 ng kg−1 min−1) neither affected significantly albumin extravasation nor potentiated the permeability effect of PAF in the vascular beds studied with the exception of large airways, where noradrenaline mimicked the effects of l‐NAME.
These results indicate that inhibition of endogenous NO formation leads to an increase in albumin extravasation and to potentiation of the vascular permeability effect of PAF, whereas the hypotensive action of PAF seems to be independent of NO formation in the conscious rat. These data suggest an important role for NO in the regulation of albumin extravasation.
[Ca2+]i‐sensitive, IP3‐independent Ca2+ influx in smooth muscle of rat vas deferens revealed by procaine
Authors: Khoyi Mohammad A. , Dalziel Hugh H. , Zhang Lubo , Bjur Richard A. , Gerthoffer William T. , Buxton Iain L.O. , Westfall David P. 
Published: July 2012

The actions of procaine (10 mm) on noradrenaline‐induced effects on 45Ca‐influx, 45Ca‐efflux, 45Ca‐content, total inositol phosphates, inositol‐1,4,5‐trisphosphate, and contractile status of the rat vas deferens were examined.
Noradrenaline alone had no effect on 45Ca‐influx or 45Ca‐content, but released Ca2+ from intracellular stores as indicated by an increased 45Ca‐efflux and increased total inositol phosphates, specifically inositol‐1,4,5‐trisphosphate, leading to contraction of the rat vas deferens.
Noradrenaline, in the presence of 10 mm procaine, increased 45Ca‐influx and 45Ca‐content. Procaine blocked the noradrenaline‐induced 45Ca‐efflux, the increase in total inositol phosphates, the increase in inositol‐1,4,5‐trisphosphate, and contraction.
The noradrenaline‐induced increase in 45Ca influx which was observed in the presence of procaine was abolished by phentolamine and nifedipine but was not altered significantly by propranolol suggesting that, in the presence of procaine, noradrenaline activates dihydropyridine‐sensitive calcium channels through α‐adrenoceptors.
These findings indicate that, in the rat vas deferens, noradrenaline induces contraction by releasing intracellularly stored Ca2+. The effects of procaine appear to be due to its ability to block the release of Ca2+ from intracellular stores. Furthermore, the simultaneous increase in 45Ca influx and inhibition of inositol‐1,4,5‐trisphosphate formation in tissues treated with procaine plus noradrenaline indicates that Ca2+ influx is independent of inositol‐1,4,5‐trisphosphate formation.
Effects of sumatriptan on the cerebral intraparenchymal microcirculation in the cat
Authors: Kobari Masahiro , Fukuuchi Yasuo , Tomita Minora , Tanahashi Norio , Konno Shizuko , Takeda Hidetaka 
Published: July 2012

Sumatriptan, a 5‐hydroxytryptamine (5‐HT)1‐like receptor agonist, is effective against the headache of migraine. The effects of sumatriptan injected via the carotid artery on the cerebral microcirculation were studied in 10 anaesthetized cats.
The local cerebral blood volume (CBV), mean transit time of blood (MTT) and cerebral blood flow (CBF) in the parieto‐temporal cortex were measured by a photoelectric method. CBV represents the cumulative dimensions of the cerebral microvessels.
Sumatriptan at 5 and 50 μg kg−1 had no significant effects on the CBV, MTT, CBF, and mean arterial blood pressure (MABP); 500 μg kg−1 of sumatriptan reduced the CBV, prolonged the MTT, and decreased the CBF (approximately −20%) without affecting the MABP. Sumatriptan, 5 mg kg−1, elicited transient reductions in CBV and CBF, which were attributable to the rapid and marked falls of MABP seen with this dose.
Thus, while a high dose of sumatriptan (500 μg kg−1) exhibits direct vasoconstrictor actions on the cerebral vessels, low doses of sumatriptan, within the therapeutic range, elicit no vasoconstriction. The data do not support a vasoconstrictor action of sumatriptan playing a primary role in reversing the headache of migraine.
Regional and cardiac haemodynamic effects of NG, NG,dimethyl‐l‐arginne and their reversibility by vasodilators in conscious rats
Authors: Gardiner S.M. , Kemp P.A. , Bennett T. , Palmer R.M.J. , Moncada S. 
Published: July 2012

A series of experiments was carried out on 3 separate groups of male Long Evans rats, chronically instrumented for the measurement of regional haemodynamics, to compare the effects of NG,NG, dimethyl‐l‐arginine (ADMA) and NG‐monomethyl‐l‐arginine (l‐NMMA), and their reversibility by the nitric oxide donors, S‐nitroso‐N‐acetyl‐penicillamine (SNAP), S‐nitroso‐glutathione (SNOG), sodium nitroprusside (SNP), and the vasodilator, hydralazine.
As previously reported for l‐NMMA, ADMA (1–100 mg kg−1) caused dose‐dependent pressor and bradycardic effects, accompanied by renal, mesenteric and hindquarters vasoconstrictions. The magnitude and duration of these effects were similar for ADMA and l‐NMMA, consistent with their being equipotent inhibitors of nitric oxide synthase.
Infusion of SNAP or SNOG (300 μg kg−1 h−i) after injection of ADMA or l‐NMMA (100 mg kg−1) reversed the pressor but did not abolish the vasoconstrictor, effects of ADMA or l‐NMMA. However, a higher dose of SNAP (3 mg kg−1 h−1) caused complete reversal of the pressor and mesenteric haemodynamic effects of ADMA (100 mg kg−1), although its renal and hindquarters vasoconstrictor effects were not abolished.
Infusion of SNP (300 μg kg−1 h−1) after administration of l‐NMMA (100 mg kg−1), caused complete reversal of its pressor and mesenteric and hindquarters haemodynamic effects, and reduced substantially its renal vasoconstrictor action; hydralazine (7.5 mg kg−1 h−1) was almost as effective as SNP in reversing all these variables.
In animals chronically instrumented for the measurement of cardiac haemodynamics, ADMA (100 mg kg−1) caused a pressor effect accompanied by a rise in central venous pressure, and reductions in heart rate, cardiac index, stroke index, peak aortic flow, maximum rate of rise of aortic flow and total peripheral conductance. The reversal of the pressor effect of ADMA by SNAP (300 μg kg−1 h−1) was accompanied by a reduction of central venous pressure below resting levels and a further diminution of stroke index; all other variables showed an increase, but they still remained below resting levels (with the exception of heart rate).
Thus, following inhibition of NO synthesis, pharmacological intervention with NO donors, or other vasodilators, may cause normalisation of the mean arterial pressure without necessarily returning all associated cardiovascular variables to normal.