bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced expression of haem oxygenase‐1 by nitric oxide and antiinflammatory drugs in NIH 3T3 fibroblasts
Authors: Alcaraz Maria José , Habib Aïda , Lebret Marilyne , Créminon Christophe , Lévy‐Toledano Sylviane , Maclouf Jacques 
Published: January 2005

Haem oxygenase‐1 (HO‐1) can exert protective effects against oxidative stress and inflammation. Fibroblasts participate in inflammatory responses where they produce high levels of prostaglandins (PGs) and nitric oxide (NO). However, little is known of the presence of HO‐1 in these cells and the possible interactions among these pathways. Incubation of cells with NO donors, spermine nonoate (SPNO) and S‐nitroso‐N‐acetylpenicillamine (SNAP), induced a dose‐ and time‐dependent expression of HO‐1 protein.
NO donors increased basal PGE2 release although they reduced PGE2 accumulated in the medium and cyclo‐oxygenase (COX) activity when cells were stimulated with lipopolysaccharide (LPS). COX‐2 protein was weakly induced by SPNO in basal conditions and in the presence of LPS a synergy for HO‐1 and COX‐2 protein expression was observed.
Our results indicate that reactive oxygen species participate in the inductive effect of NO donors or LPS on HO‐1 expression, whereas endogenous NO production may play a role in the mechanism of the synergy exhibited by SPNO and LPS on HO‐1 and COX‐2 expression. In this system, zinc protoporphyrin IX did not affect nitrite levels but reduced COX activity.
The selective COX‐2 inhibitors SC58125 and NS398 as well as the non‐selective COX inhibitor, indomethacin, strongly reduced PGE2 synthesis and showed a synergy with NO donors in HO‐1 and COX‐2 induction. Addition of PGE2 had no effect, suggesting a mechanism independent of PGs formation.
In inflammatory conditions a number of factors could cooperate to induce HO‐1 and COX‐2, with a positive regulation by COX inhibitors.

British Journal of Pharmacology (2000) 130, 57–64; doi:10.1038/sj.bjp.0703281
Suppression of arterial intimal hyperplasia by cilostamide, a cyclic nucleotide phosphodiesterase 3 inhibitor, in a rat balloon double‐injury model
Authors: Inoue Yoshihiro , Toga Kazuyuki , Sudo Toshiki , Tachibana Kazue , Tochizawa Shirou , Kimura Yukio , Yoshida Yoji , Hidaka Hiroyoshi 
Published: January 2005

The effects of cilostamide, a cyclic nucleotide phosphodiesterase 3 (PDE3) selective inhibitor, on vascular intimal hyperplasia were evaluated using a single‐balloon injury model and a double‐injury model in which the rat common carotid artery was subjected to a second injury at a site injured 14 days previously.
In the double‐injury model, the second balloon injury caused more severe intimal hyperplasia (intima/media (IM) ratio, 1.88±0.10) than in the single‐injury model (1.09±0.08). Histopathological study revealed that vascular smooth muscle cells (VSMC) were the predominant cell‐type in the affected neointimal area.
Oral administration of cilostamide for 2 weeks after the second injury suppressed intimal hyperplasia in the double‐injury model (30 mg kg−1 bid, 83% inhibition in terms of the IM ratio, P<0.05; 100 mg kg−1 bid, 69% inhibition, P<0.05). Similar effects were also observed in the single‐injury model with oral administration of cilostamide for 2 weeks (100 mg kg−1 bid, 36% inhibition, P<0.01).
Cilostamide inhibited DNA synthesis of cultured VSMC stimulated by foetal calf serum or different kinds of growth factors, but did not affect their migration stimulated by platelet‐derived growth factor (PDGF)‐BB. Cilostamide significantly increased the cyclic AMP concentration of VSMC dose‐dependently.
These results indicate that cilostamide suppresses intimal hyperplasia both in the single‐ and double‐injury models of rat, presumably by inhibiting proliferation rather than migration of VSMC. It is suggested that PDE3 inhibitors might find application in preventing intimal hyperplasia following angioplasty such as percutaneous transluminal coronary angioplasty (PTCA) or stent.

British Journal of Pharmacology (2000) 130, 231–241; doi:10.1038/sj.bjp.0703287
Smooth muscle layer‐dependent distribution of 5‐hydroxytryptamine7 receptor in the porcine myometrium
Authors: Kitazawa Takio , Yamada Yuko , Iwano Hidetomo , Yokota Hiroshi , Yuasa Akira , Taneike Tetsuro 
Published: January 2005

To analyse the mechanisms of muscle layer‐dependent inhibition of porcine myometrial contractility by 5‐hydroxytryptamine (5‐HT), the effects of 5‐HT, 5‐carboxamidotryptamine(5‐CT), 5‐methoxytryptamine (5‐MeOT), forskolin and cyclic adenosine 3′, 5′‐monophosphate (cyclic AMP) analogues on spontaneous and stimulant‐induced contractions were examined in longitudinal (LM) and circular muscles (CM). In addition, accumulation of cyclic AMP by 5‐HT and distribution of 5‐HT7 receptors in LM and CM layers were compared using biochemical and molecular approaches.
5‐HT receptor agonists inhibited the spontaneous contractions of LM and CM (5‐CT>5‐HT>5‐MeOT), but CM was more sensitive than was LM. The inhibition by the agonists was antagonized by methiothepin (100 nM).
Carbachol‐, high‐K+‐, histamine‐ and Ca2+‐induced contractions were inhibited by 5‐HT with different responsivenesses (CM>LM). Even in the presence of 3‐isobutyl‐1‐methylxanthine (IBMX), the inhibition by 5‐HT in the CM was still more conspicuous than that in the LM.
Compared with the CM, the inhibition of spontaneous contraction by forskolin, dibutyryl‐cyclic AMP and 8‐bromo‐cyclic AMP was marked in the LM.
5‐HT (1 nM–1 μM) increased the cyclic AMP in both muscle layers, but the increment in the CM was higher than that in the LM whether IBMX was present or not.
LM and CM layers contained a single class of [3H]‐5‐CT binding sites with a similar Kd value (0.21–0.24 nM). However, Bmax (5‐HT7 receptor concentration) in the CM (120.6 fmol mg−1 protein) was higher than that in the LM (30.4 fmol mg−1 protein).
The molecular study (reverse transcription polymerase chain reaction) demonstrated the expression of 5‐HT7 receptor mRNA in the CM was higher than that in the LM.
These results suggest that the muscle layer‐dependent difference in inhibition by 5‐HT is not restricted to spontaneous contraction but applies to various contractions in the porcine myometrium. Different inhibition of the contractility by 5‐HT is caused by muscle layer‐related accumulation of cyclic AMP (CM>LM), due to smooth muscle‐layer dependent distribution (CM>LM) of 5‐HT7 receptors.

British Journal of Pharmacology (2000) 130, 79–89; doi:10.1038/sj.bjp.0703290
Attenuation of pressure‐induced myogenic contraction and tyrosine phosphorylation by fasudil, a cerebral vasodilator, in rat cerebral artery
Authors: Masumoto Naohiro , Tanabe Yoshiyuki , Saito Maki , Nakayama Koichi 
Published: January 2005

The mechanism by which fasudil inhibits pressure‐induced myogenic contraction was studied with regard to tyrosine phosphorylation in rat cerebral artery. Intracellular Ca2+ concentration ([Ca2+]i) and vessel diameter were simultaneously measured. Total tyrosine phosphorylation level and phosphorylation of tyrosine 419 on pp60src required for its full catalytic activity were immunocytochemically detected in situ.
Fasudil (1–100 μM) partially suppressed the increase in [Ca2+]i, and totally attenuated contraction elicited by pressurization from 10 to 60 mmHg. Furthermore, fasudil (100 μM) significantly attenuated tyrosine phosphorylation and the activity of pp60src augmented in situ by pressure.
Herbimycin A (1–100 nM) and genistein (3–30 μM), tyrosine kinase inhibitors, effectively attenuated the pressure‐induced increase in [Ca2+]i, contraction, tyrosine phosphorylation, and activation of pp60src. Both fasudil and herbimycin A directly inhibited the pp60src activity in a cell free system.
Orthovanadate (100 μM), a tyrosine phosphatase inhibitor, significantly potentiated the pressure‐induced increase in [Ca2+]i and contraction.
Nicardipine (100 nM), a Ca2+ antagonist, completely inhibited pressure‐induced increase in [Ca2+]i and contraction, but affected neither tyrosine phosphorylation nor activity of pp60src in the pressurized arteries.
Arginine‐glycine‐aspartic acid‐serine peptide (1–100 μM) concentration‐dependently reduced the pressure‐induced contraction.
In addition to the hitherto reported vasodilatory actions of fasudil, the present results suggest the inhibition by fasudil of pressure‐induced tyrosine phosphorylation and pp60src activation. The wide spectrum of inhibitory actions of fasudil may contribute to the effective attenuation of the pressure‐induced contraction in the cerebral artery.

British Journal of Pharmacology (2000) 130, 219–230; doi:10.1038/sj.bjp.0703292
Reversal of the vasoconstrictor step of hyperacute xenogeneic rejection of the liver by endothelin antagonists
Authors: Zhang Baimeng , Wen Lanling , Gomola Alexandra , Massault Pierre‐Philippe , Cherruau Brigitte , Houssin Didier , Weill Bernard , Calmus Yvon 
Published: January 2005

The role of endothelin in the initial vasoconstrictor step of hyperacute xenogeneic rejection was investigated.
Isolated rat livers were perfused in recirculation. Perfusion with human sera provided an ex vivo model of hyperacute rejection in a discordant combination.
Perfusion of 10% xenogeneic serum induced a marked (70%) and sustained reduction of the liver flow and induced the release of endothelin into the perfusion medium. In contrast, perfusion of 10% allogeneic serum or of 10% decomplemented human serum induced a weak (25%) and transient reduction of the liver flow and induced the release of minimal amounts of endothelin. The simultaneous administration of BQ 123 and BQ 788, the respective antagonists of ETA and ETB endothelin receptors, or that of bosentan, a mixed ETA/ETB antagonist, antagonized the vasoconstrictor effect of 10% xenogeneic human serum, as well as that of 10−9 M endothelin‐1.
The vasoconstrictor effects of xenogeneic serum on liver circulation are, at least partly, mediated through the release of endothelin by the graft.

British Journal of Pharmacology (2000) 130, 402–408; doi:10.1038/sj.bjp.0703295
Behavioural and physiological effects induced by an infusion of antisense to α2D‐adrenoceptors in the rat
Authors: Robinson E S J , Nutt D J , Jackson H C , Hudson A L 
Published: January 2005

The aim of this study was to investigate the behavioural and physiological effects of an i.c.v. infusion of antisense oligonucleotide to the α2D‐adrenoceptor subtype. Behavioural and physiological parameters were monitored for 2 days before the infusion, throughout the 3‐day infusion period and for 3 days following the end of the infusion.
The antisense infusion resulted in a significant increase in behavioural activity characterized by increased locomotion and grooming scores. Behavioural activity scores of rats treated with antisense to α2D‐adrenoceptors were significantly higher than those of rats treated with vehicle (H2O) or the mismatch toxicity control on day 4 and day 5 and, significantly higher than vehicle controls on day 6.
Body weight gain was significantly reduced in the antisense‐treated rats at the end of the study compared to the vehicle (34%) and mismatch groups (30%), although daily food and water intakes were not significantly different at any time point.
Pupil diameters of rats infused with antisense to α2D‐adrenoceptors were significantly greater than those of animals treated either with vehicle or mismatch oligonucleotide on day 5 of the study. On day 6, the pupil diameters of these animals were still significantly greater than the mismatch group.
In conclusion, an i.c.v. infusion of antisense to the α2D‐adrenoceptor induced behavioural activation in rats, increased pupil diameter and reduced total weight gain. These effects were specific to the antisense‐treated group and were fully reversed post‐infusion.

British Journal of Pharmacology (2000) 130, 153–159; doi:10.1038/sj.bjp.0703296
Modulation of the dinucleotide receptor present in rat midbrain synaptosomes by adenosine and ATP
Authors: Díaz‐Hernández Miguel , Pintor Jesús , Miras‐Portugal M Teresa 
Published: January 2005

Diadenosine polyphosphates activate dinucleotide receptors in rat midbrain synaptic terminals. The agonist with highest affinity at this receptor, diadenosine pentaphosphate (Ap5A), elicits Ca2+ transients at concentrations ranging from 10−7 to 10−3 M with a single‐phase curve and an EC50 value of 56.21±1.82 μM.
Treatment of synaptosomal preparations with alkaline phosphatase (AP) changes the dose‐response control curve into a biphasic one presenting two EC50 values of 6.47±1.25 nM and 11.16±0.83 μM respectively.
The adenosine A1 antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX) reversed the biphasic concentration‐response for Ap5A curve in the presence of AP, to a monophasic one with an EC50 value of 76.05±7.51 μM.
The application of adenosine deaminase produced the same effect as DPCPX, the EC50 value for Ap5A, in the presence of AP being 18.62±4.03 μM.
Activation of the adenosine A1 receptor by means of cyclohexyladenosine (CHA) shifted the dose response curve for Ap5A to the left, resulting in a monophasic curve with an EC50 of 5.01±0.02 pM.
The destruction of extrasynaptosomal nucleotides by AP or the addition of pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS), a broad P2 antagonist compound, enhance maximal effect of the Ap5A up to 55.6% on the dose response curve, thus suggesting a negative modulation by P2 receptors.
In a summary, ATP and adenosine present at the extra‐synaptosomal space, are relevant natural modulators of the dinucleotide receptor, via P2 and adenosine A1 receptors respectively.

British Journal of Pharmacology (2000) 130, 434–440; doi:10.1038/sj.bjp.0703300
Pentaerythrityl tetranitrate attenuates structural changes in conduit arteries evoked by long‐term NO‐synthase inhibition
Authors: Kristek František 
Published: January 2005

The aim of the study was to determine whether the pentaerythrityl tetranitrate (PETN), a tolerance devoid exogenous NO donor could prevent morphological changes in the cardiovascular system evoked by long‐term NO‐synthase inhibition.
Three groups of 10‐week‐old Wistar rats were used: (1) controls, (2) treated by L‐NG‐nitroarginine methyl ester (L‐NAME) in water (50 mg kg−1), and (3) treated by L‐NAME (50 mg kg−1 in water)+PETN (2×50 mg kg−1, using gavage). Blood pressure (BP) was measured by the tail plethysmographic method.
After sacrificing the animals were perfused (120 mmHg) by glutaraldehyde fixative and processed according to standard electron microscopy procedure. Wall thickness (WT), cross sectional area (CSA), inner diameter (ID) of thoracic aorta (TA), carotid (CA) and septal branch of the left descending coronary artery (RS) were measured in light microscopy.
After 6 weeks, the BP was increased to 172±1.7 mmHg (P<0.01) in the L‐NAME group, compared to 127±1.4 mmHg in controls. In L‐NAME+PETN‐treated rats, BP was 163±0.9 mmHg (P<0.01), and significantly lower (P<0.01) in comparison to L‐NAME‐treated rats. Heart weight and heart/body weight ratio was not significantly changed.
In L‐NAME‐treated rats, both WT and CSA were increased in all three arteries (P<0.01). ID was increased only in TA (P<0.01). Wall/diameter ratio (WD) was increased in TA (P<0.01) and CA (P<0.01). In L‐NAME+PETN treated rats, WT was found to be increased only in TA (P<0.01). In comparison to the L‐NAME treated group, WT was decreased in TA (P<0.01), in CA (P<0.01), in RS (P<0.05). CSA was increased only in TA (P<0.01), yet in comparison to the L‐NAME group it was decreased in CA (P<0.01). ID was increased in comparison to both control and L‐NAME treated rats only in TA (P<0.01). WD did not differ from the control value. In comparison to L‐NAME‐treated rats, it was decreased in both TA and CA (P<0.01).
These data suggest that the changes in the cardiovascular system evoked by long‐term NO‐synthase inhibition were attenuated by simultaneous administration of the exogenous donor of nitric oxide–PETN.

British Journal of Pharmacology (2000) 130, 450–456; doi:10.1038/sj.bjp.0703307
Troglitazone prevents and reverses dexamethasone induced insulin resistance on glycogen synthesis in 3T3 adipocytes
Authors: Anil Kumar K L , Marita A R 
Published: January 2005

Troglitazone lowers blood glucose levels in Type II diabetic patients. To evaluate the insulin sensitizing action of troglitazone on glycogen synthesis we have used dexamethasone‐treated 3T3 adipocytes as an in vitro model.
Differentiated 3T3 adipocytes were incubated with 100 nM dexamethasone for 6 days. Troglitazone (1.0 μM) or metformin (1.0 mM) with or without 200 nM insulin was added during the last 4 days. At the end, insulin (100 nM) stimulated glycogen synthesis was determined using 14C‐glucose.
Dexamethasone caused a 50% reduction in glycogen synthesis. Troglitazone caused an approximately 3 fold increase in glycogen synthesis from 43.9±3.4 to 120±16.2 nmols h−1. Under identical conditions metformin had no significant effect.
When cells were incubated with troglitazone and dexamethasone simultaneously for 6 days, troglitazone but not metformin completely prevented dexamethasone‐induced insulin resistance. RU 486 (1.0 μM) also completely prevented the insulin resistance.
Chronic incubation with dexamethasone and insulin resulted in a 73% reduction in glycogen synthesis. In these adipocytes, troglitazone was partially active with glycogen synthesis rising from 23.1±3.0 to 44.4±4.5 nmol h−1, P<0.01 while metformin was inactive.
Troglitazone stimulated 2‐deoxyglucose uptake by 2–3 fold in dexamethasone‐treated adipocytes. Metformin also increased glucose uptake significantly. Troglitazone did not affect insulin binding while a 2 fold increase was observed in normal adipocytes where it exhibited a modest effect.
Since the effect of troglitazone was greater in dexamethasone‐treated adipocytes, troglitazone is likely to act by preventing dexamethasone‐induced alterations which may include (i) binding to glucocorticoid receptor and (ii) effect on glucose uptake.
These data demonstrate the direct insulin sensitizing action of troglitazone on glycogen synthesis and suggest a pharmacological profile different from metformin.

British Journal of Pharmacology (2000) 130, 351–358; doi:10.1038/sj.bjp.0703313
[3H]‐SB‐269970 – A selective antagonist radioligand for 5‐HT7 receptors
Authors: Thomas David R , Atkinson Peter J , Ho Michael , Bromidge Steven M , Lovell Peter J , Villani Anthony J , Hagan Jim J , Middlemiss Derek N , Price Gary W 
Published: January 2005

Binding of the 5‐HT7 receptor antagonist radioligand [3H]‐SB‐269970 to human 5‐HT7(a) receptors expressed in HEK293 cell membranes (h5‐HT7(a)/293) and to guinea‐pig cerebral cortex membranes, was characterized and compared with [3H]‐5‐CT binding.
[3H]‐SB‐269970 (1 nM) showed full association with h5‐HT7(a)/293 membranes after 40 min. Specific binding at equilibrium represented >90% of total binding and was fully reversible by methiothepin (10 μM), full dissociation occurring by 100 min. The association (k+1) and dissociation (k−1) rate constants were 0.05 nM−1min−1 and 0.05 min−1 respectively, giving a KD (k−1/k+1) of 1.0 nM.
[3H]‐SB‐269970 bound saturably and apparently monophasically to both h5‐HT7(a)/293 and guinea‐pig cortex membranes, with KD values of 1.25±0.05 and 1.7±0.3 nM respectively. The Bmax for [3H]‐SB‐269970 to both h5‐HT7(a)/293 and guinea‐pig cortex membranes (5780±380 and 125±8.2 fmoles mg protein−1 respectively) was similar to that for [3H]‐5‐CT (6190±940 and 143±19 fmoles mg protein−1 respectively). These data suggest that, in each tissue, both radioligands labelled the same population of receptors, which appear to be present in an agonist high affinity state.
The profile of compound inhibition of [3H]‐SB‐269970 binding to h5‐HT7(a)/293 and guineapig cortex membranes correlated well (corr. coeff. 0.98) with those for [3H]‐5‐CT binding and were consistent with the profiles reported previously for the human 5‐HT7(a) and guinea‐pig cortex 5‐HT7 receptors using [3H]‐5‐CT. Hill slopes for inhibition of [3H]‐SB‐269970 and [3H]‐5‐CT binding were close to 1, consistent with binding to a single receptor population in both tissues.
[3H]‐SB‐269970 represents the first selective 5‐HT7 antagonist radioligand, which should aid further characterization of 5‐HT7 receptors in recombinant and native tissues and help establish their role in brain function.

British Journal of Pharmacology (2000) 130, 409–417; doi:10.1038/sj.bjp.0703318
Pharmacological characterization of the cardiovascular responses elicited by kinin B1 and B2 receptor agonists in the spinal cord of streptozotocin‐diabetic rats
Authors: Cloutier Frank , Couture Réjean 
Published: January 2005

Kinin receptor agonists and antagonists at the B1 and B2 receptors were injected intrathecally (i.t., at T‐9 spinal cord level) to conscious unrestrained rats and their effects on mean arterial pressure (MAP) and heart rate (HR) were compared in streptozotocin (STZ)‐diabetic rats (65 mg kg−1 STZ, i.p. 3 weeks earlier) and aged‐matched control rats.
The B1 receptor agonist, des‐Arg9‐Bradykinin (BK) (3.2–32.5 nmol), evoked dose‐dependent increases in MAP and tachycardia during the first 10 min post‐injection in STZ‐diabetic rats only. The cardiovascular response to 6.5 nmol des‐Arg9‐BK was reversibly blocked by the prior i.t. injection of antagonists for the B1 receptor ([des‐Arg10]‐Hoe 140, 650 pmol or [Leu8]‐des‐Arg9‐BK, 65 nmol) and B2 receptor (Hoe 140, 81 pmol or FR173657, 81 pmol) or by indomethacin (5 mg kg−1, i.a.).
The i.t. injection of BK (8.1–810 pmol) induced dose‐dependent increases in MAP which were accompanied either by tachycardiac (STZ‐diabetic rats) or bradycardiac (control rats) responses. The pressor response to BK was significantly greater in STZ‐diabetic rats. The cardiovascular response to 81 pmol BK was reversibly blocked by 81 pmol Hoe 140 or 81 pmol FR173657 but not by B1 receptor antagonists nor by indomethacin in STZ‐diabetic rats.
The data suggest that the activation of kinin B1 receptor in the spinal cord of STZ‐diabetic rats leads to cardiovascular changes through a prostaglandin mediated mechanism. Thus, this study affords an accessible model for studying the expression, the pharmacology and physiopathology of the B1 receptor in the central nervous system.

British Journal of Pharmacology (2000) 130, 375–385; doi:10.1038/sj.bjp.0703319
Localization of the nephron site of gentamicin‐induced hypercalciuria in the rat: a micropuncture study
Authors: Parsons P P , Garland H O , Harpur E S 
Published: January 2005

In vivo renal micropuncture techniques were used to locate the nephron site of hypercalciuria induced by acute gentamicin infusion in anaesthetized Sprague Dawley rats. Three series of experiments were conducted. The effect of gentamicin on calcium reabsorption in the proximal tubule (Series I) and loop of Henle (Series II) was investigated using in vivo microperfusion whereas the effect on distal calcium handling (Series III) was studied using in vivo microinfusion.
In all three experimental series, acute systemic gentamicin infusion at 0.28 mg kg−1 min−1 caused significant hypercalciuria within 30 min of commencing drug infusion. Gentamicin had no effect on the rates of urine flow or sodium excretion.
Acute gentamicin infusion had no effect on unidirectional calcium reabsorption in the proximal tubule or loop of Henle despite a simultaneous and highly significant hypercalciuria at the whole kidney level. Net fluid reabsorption was also unaffected by the drug in these nephron segments.
Acute gentamicin infusion significantly increased the urinary recovery of calcium following microinfusion into early distal tubules, whereas urinary calcium recovery was decreased after microinfusion into late distal tubules.
We conclude that acute gentamicin‐induced hypercalciuria is mediated by a decrease in calcium reabsorption in the early distal tubule. Thus, the acute hypercalciuric effect of gentamicin occurs at a different nephron site to the nephrotoxic effects associated with longer‐term administration of the drug. It is, therefore, unlikely that gentamicin‐induced hypercalciuria is involved in the pathogenesis of subsequent proximal tubular cell injury.

British Journal of Pharmacology (2000) 130, 441–449; doi:10.1038/sj.bjp.0703329