bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison of the effects of L‐NAME, 7‐NI and L‐NIL on carrageenan‐induced hindpaw oedema and NOS activity
Authors: Handy Rachel L C. , Moore Philip K. 
Published: January 2005

Intraplantar injection of carrageenan (150 μl, 1–3% w/v) in the rat resulted in a dose‐related increase in hindpaw weight (oedema) characterized by a rapid ‘early’ phase (up to 2.5 h) response followed by a more sustained ‘late’ phase (2–6 h) response. No change in weight of either the contralateral (i.e. noninjected) hindpaw or hindpaws injected with saline was observed.
Six hours after intraplantar injection of carrageenan (1–3% w/v) hindpaw constitutive (i.e. calcium‐dependent) nitric oxide synthase (cNOS) activity (determined ex vivo as the conversion of radiolabelled L‐arginine to radiolabelled citrulline) was increased (e.g. 2% w/v; 0.64±0.08 pmol citrulline mg−1 protein 15 min−1 c.f. 0.08±0.04 pmol citrulline mg−1 protein 15 min−1 in saline‐injected, control animals, n=4, P<0.05). Carrageenan injection also resulted in the appearance in hindpaw homogenates of inducible (i.e. calcium‐independent) nitric oxide synthase (iNOS, e.g. 2% w/v; 0.67±0.14 pmol citrulline mg−1 protein 15 min−1, n=4). Hindpaw cyclic GMP concentration was also significantly increased 6 h after intraplantar injection of carrageenan (e.g. 2% w/v; 379.6±26.8 fmol mg−1 protein c.f. 261.8±42.2 fmol mg−1 protein, in saline‐injected, control animals, n=4, P<0.05).
Pretreatment (5–25 mg kg−1, i.p., 30 min before carrageenan, 2% w/v) of animals with L‐NG nitro arginine methyl ester (L‐NAME; isoform nonselective inhibitor of NOS) or 7‐nitro indazole (7‐NI; inhibitor of neuronal NOS, nNOS) caused dose‐related inhibition of both the early (2 h) and late (6 h) phase hindpaw oedema, associated with reduced hindpaw iNOS and cNOS activity and cyclic GMP concentration in animals killed at 6 h. Administration of 7‐NI (5–25 mg kg−1, i.p.) to animals 2.5 h after intraplantar carrageenan (2% w/v) injection (i.e. at the end of the early phase oedema response) produced dose‐related inhibition of the late phase response.
Pretreatment (5–25 mg kg−1, i.p., 30 min before carrageenan, 2% w/v) of animals with L‐N6‐iminoethyllysine (L‐NIL, selective inhibitor of iNOS) (5–25 mg kg−1) failed to affect the early phase hindpaw oedema response but did produce a dose‐related inhibition of the late phase oedema. L‐NIL pretreatment also inhibited the carrageenan‐induced increase in both hindpaw iNOS and cNOS activity as well as the rise in hindpaw cyclic GMP concentration.
The present experiments demonstrate an anti‐inflammatory effect of 7‐NI as evidenced by inhibition of carrageenan‐induced hindpaw oedema in the rat. Inhibition of nNOS (early phase) and iNOS (late phase) at the site of inflammation most probably accounts for the anti‐inflammatory activity observed. These data suggest a role for nitric oxide synthesized by the nNOS isoform (most probably within sensory nerves) in this model of inflammation.

British Journal of Pharmacology (1998) 123, 1119–1126; doi:10.1038/sj.bjp.0701735
The protective effects of CP‐060S on ischaemia‐ and reperfusion‐induced arrhythmias in anaesthetized rats
Authors: Koga Takaki , Fukazawa Masanori , Suzuki Yoshiyuki , Akima Michitaka , Adachi Yuichiro , Tamura Kazuhiko , Kato Tatsuya , Kuromaru Osamu 
Published: January 2005

CP‐060S is a novel sodium and calcium overload inhibitor, and is also characterized as a calcium channel blocker. As these activities have each been shown independently to ameliorate ischaemia damage in the myocardium, the combination may synergistically exert cardioprotection. In this study, therefore, the protective effect of CP‐060S against ischaemia‐ and reperfusion‐induced arrhythmia was evaluated in anesthetized rats.
Rats were anaesthetized with pentobarbitone, and the left anterior descending coronary artery was occluded for either 5 min with subsequent reperfusion (a reperfusion‐induced arrhythmia model) or 30 min without (an ischaemia‐induced arrhythmia model). All drugs were intravenously administered 1 min before the onset of occlusion.
In the reperfusion‐induced arrhythmia model, the animals in the vehicle‐treated group exhibited ventricular tachycardia (VT) in 100%, ventricular fibrillation (VF) in 89%, and death caused by sustained VF in 56%. CP‐060S (30–300 μg kg−1) dose‐dependently suppressed the incidences of arrhythmias. Significant decreases occurred at 100 μg kg−1 in VF (incidence: 42%) and mortality (8%), and at 300 μg kg−1 in VT (50%), VF (33%) and mortality (8%). This protective effect of CP‐060S was 10 times more potent than that of a pure calcium channel blocker, diltiazem (30–1000 μg kg−1) we tested, in terms of effective dose ranges. As both drugs decreased myocardial oxygen consumption estimated by rate‐pressure product to a similar extent, the calcium channel blocking activity of CP‐060S would not seem to be sufficient to explain its potency.
In the same model, co‐administration of ineffective doses of diltiazem (300 μg kg−1) and a sodium and calcium overload inhibitor, R56865 (100 μg kg−1), produced significant suppression of VT (incidence: 62%), VF (46%) and mortality (8%). By contrast, co‐administration of R56865 at the same dose with CP‐060S (300 μg kg−1) did not add to the effect of a single treatment of CP‐060S.
In the ischaemia‐induced arrhythmia model, CP‐060S (300 μg kg−1) significantly decreased the incidence of VF from 75% to 29%, whereas diltiazem (1 mg kg−1) was ineffective.
These results suggest that CP‐060S inhibits both ischaemia‐ and reperfusion‐induced arrhythmia. The combination of the calcium channel blocking effect and the calcium overload inhibition was hypothesized to contribute to these potently protective effects.

British Journal of Pharmacology (1998) 123, 1409–1417; doi:10.1038/sj.bjp.0701742
Early effects of acute γ‐radiation on vascular arterial tone
Authors: Bourlier Virginie , Diserbo Michel , Joyeux Marie , Ribuot Christophe , Multon Eric , Gourmelon Patrick , Verdetti Jean 
Published: January 2005

To determine the acute effects of irradiation on the functionality of vessel, rat aortic rings were mounted in an organ bath for isometric tension measurements and irradiated (60Co, 1 Gy min−1, 15 min).
Irradiation, which is without effect on non‐contracted or endothelium‐denuded vessels, led to an immediate and reversible increase in vascular tone on (−)‐phenylephrine (1 μM)‐precontracted aortic rings. The tension reached a plateau about 5 min after the beginning of irradiation.
The maximal radiation‐induced contraction occurred on aortic rings relaxed by acetylcholine (ACh) (1 μM). In this condition, the addition of catalase (1000 u ml−1), which reduces hydrogen peroxide, and DMSO (0.1% v/v), which scavenges hydroxyl radical, had no influence on tension level while superoxide dismutase (SOD) (100 u ml−1), a superoxide anion scavenger, reduced the observed contraction. A similar result was obtained in the presence of indomethacin (10 μM), a cyclo‐oxygenase blocker.
Pretreatment of rings with the nitric oxide synthase inhibitor, Nω‐nitro‐L‐arginine methyl ester (L‐NAME) (10–100 μM) inhibited the radiation‐induced contraction.
This effect was dose rate‐dependent and even occurred for a very low dose rate (0.06 Gy min−1).
The present results indicate that γ‐radiation induces an instantaneous vascular tone increase that is endothelium and dose rate‐dependent. This effect is (i) maximal when nitric oxide (NO) is produced, (ii) greatly reduced by SOD and (iii) inhibited by L‐NAME, suggesting a major involvement of complexes between NO and superoxide anion.

British Journal of Pharmacology (1998) 123, 1168–1172; doi:10.1038/sj.bjp.0701744
Effect of some cyclooxygenase inhibitors on the increase in guanosine 3′:5′‐cyclic monophosphate induced by NO‐donors in human whole platelets
Authors: Failli Paola , Cecchi Enrica , Tosti‐Guerra Cristina , Mugelli Alessandro , Laffi Giacomo , Zilletti Lucilla , Giotti Alberto 
Published: January 2005

The effect of the NSAIDs indomethacin, indoprofen, diclofenac and acetylsalicylic acid on the increase in guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) induced by nitric oxide‐donor agents was tested in human whole platelets and in platelet crude homogenate.
In whole platelets, indomethacin reduced the increase in cyclic GMP induced by the nitric oxide‐donors (NO‐donors) sodium nitroprusside (NaNP) and S‐nitroso‐N‐acetylpenicillamine (SNAP) in a dose‐dependent way, its IC50 being 13.7 μm and 15.8 μm, respectively.
Of the other cyclooxygenase inhibitors tested, only indoprofen reduced the increase in cyclic GMP induced by both NO‐donors in a dose‐dependent way (IC50=32.7 μm, NaNP and 25.0 μm, SNAP), while acetylsalicylic acid (up to 1000 μm) and diclofenac (up to 100 μm) were ineffective.
However, in platelet crude homogenate neither indomethacin nor indoprofen reduced the cyclic GMP production.
Indomethacin (10 μm), indoprofen (30 μm), diclofenac (100 μm) and acetylsalicylic acid (1000 μm) showed a comparable efficacy in inhibiting platelet thromboxane B2 (TXB2) production, suggesting that the inhibitory effect of indomethacin and indoprofen on the increase in cyclic GMP induced by both NO‐donors was not mediated by inhibition of cyclooxygenase.
In vitro, the NSAIDs analysed did not interfere with nitrite production of SNAP.
The unhomogeneous behaviour of NSAIDs on the increase in cyclic GMP induced by NO‐donors in whole platelets may contribute to the different pharmacological and toxicological characteristics of the drugs, providing new knowledge on the effect of indomethacin and indoprofen.

British Journal of Pharmacology (1998) 123, 1457–1463; doi:10.1038/sj.bjp.0701745
α1L‐Adrenoceptor mediation of smooth muscle contraction in rabbit bladder neck: a model for lower urinary tract tissues of man
Authors: Shannon Kava M. , Blue David R. , Vimont Rachel L. , Clarke David E. , Ford Anthony P. D. W. 
Published: January 2005

The α1‐adrenoceptor population mediating contractile responses to noradrenaline (NA) in smooth muscles of the bladder neck from rabbit (RBN) has been characterized by use of quantitative receptor pharmacology.
Experiments with several ‘key’ α1‐adrenoceptor antagonists of varying subtype selectivities (RS‐17053, BMY 7378, indoramin, 5‐methylurapidil, prazosin, REC 15/2739, SNAP 5089, terazosin, WB 4101, tamsulosin, (+)‐cyclazosin and RS‐100329) were conducted. Schild regression analyses yielded affinity (mean pKb) estimates of 7.1, 6.2, 8.6, 8.6, 8.4, 9.3, 7.0, 7.4, 8.9, 10.0, 7.1 and 9.3, respectively, although deviations from unit Schild regression slope question the robustness of data for RS‐17053 and SNAP 5089.
The nature of antagonism by these agents and the profile of affinity determinations generated together suggest that a single α1‐adrenoceptor subtype mediates contractile responses of RBN to NA. Additional studies with phenylephrine indicated also an agonist‐independence of this profile. Pharmacologically, this profile was reminiscent of that described as ‘α1L’ ‐adrenoceptor, which has been shown to mediate contractions of several tissues including lower urinary tract (LUT) tissues of man. Furthermore, a similarity was noticed between the ‘α1L’ ‐adrenoceptor described here in RBN and the rabbit and human cloned α1a‐adrenoceptor (based on data from both whole cell radioligand binding at 37°C and [3H]‐inositol phosphates accumulation assays), characterizations of which have been published elsewhere.
In conclusion, the RBN appears to provide a predictive pharmacological assay for the study of NA‐induced smooth muscle contraction in LUT tissues of man.

British Journal of Pharmacology (1998) 123, 1359–1366; doi:10.1038/sj.bjp.0701748
Endothelial dysfunction and metabolic control in streptozotocin‐induced diabetic rats
Authors: Rodríguez‐Mañas Leocadio , Angulo Javier , Peiró Concepción , Llergo José L. , Sánchez‐Ferrer Alberto , López‐Dóriga Pedro , Sánchez‐Ferrer Carlos F. 
Published: January 2005

The aim of this work was to study the influence of the metabolic control, estimated by the levels of glycosylated haemoglobin in total blood samples (HbA1c), in developing vascular endothelial dysfunction in streptozotocin‐induced diabetic rats. Four groups of animals with different levels of insulin treatment were established, by determining HbA1c values in 5.5 to 7.4%, 7.5 to 9.4%, 9.5 to 12% and >12%, respectively.
The parameters analysed were: (1) the endothelium‐dependent relaxations to acetylcholine (ACh) in isolated aorta and mesenteric microvessels; (2) the vasodilator responses to exogenous nitric oxide (NO) in aorta; and (3) the existence of oxidative stress by studying the influence of the free radical scavenger superoxide dismutase (SOD) on the vasodilator responses to both ACh and NO.
In both isolated aortic segments and mesenteric microvessels, the endothelium‐mediated concentration‐dependent relaxant responses elicited by ACh were significantly decreased when the vessels were obtained from diabetic animals but only with HbA1c values higher than 7.5%. There was a high correlation between HbA1c levels and the impairment of ACh‐induced relaxations, measured by pD2 values.
The concentration‐dependent vasorelaxant responses to NO in endothelium‐denuded aortic segments were significantly reduced only in vessels from diabetic animals with HbA1c values higher than 7.5%. Again, a very high correlation was found between the HbA1c values and pD2 for NO‐evoked responses.
In the presence of SOD, the responses to ACh or NO were only increased in the segments from diabetic rats with HbA1c levels higher than 7.5%, but not in those from non‐diabetic or diabetic rats with a good metabolic control (HbA1c levels <7.5%).
These results suggest the existence of: (1) a close relation between the degree of endothelial dysfunction and the metabolic control of diabetes, estimated by the levels of HbA1c; and (2) an increased production of superoxide anions in the vascular wall of the diabetic rats, which is also related to the metabolic control of the disease.

British Journal of Pharmacology (1998) 123, 1495–1502; doi:10.1038/sj.bjp.0701749
The role of central melanocortin receptors in the activation of the hypothalamus‐pituitary‐adrenal‐axis and the induction of excessive grooming
Authors: Von Frijtag Josefien C. , Croiset Gerda , Hendrik Gispen Willem , Adan Roger A. H. , Wiegant Victor M. 
Published: January 2005

In accord with previous studies intracerebroventricular (i.c.v.) injections of ACTH1‐24 (1 μg) induced a display of excessive grooming, and increased the plasma concentrations of ACTH and corticosterone. Pituitary‐adrenal activation was blocked by pretreatment with dexamethasone, indicating that the effect of the (i.c.v.) injected peptide was not caused by a peripheral effect on the adrenal cortex.
Doses of 1 and 3 μg of a non‐selective melanocortin‐3/4‐receptor antagonist (SHU 9119), or of 5 and 10 μg of a selective melanocortin‐4‐receptor antagonist ([D‐Arg8]ACTH4‐10), coadministered (i.c.v.) with 1 μg ACTH1‐24, inhibited the ACTH1‐24‐induced activation of the hypothalamus‐pituitary‐adrenal‐axis and excessive grooming.
In addition, several doses of the selective melanocortin‐3‐receptor agonist Lys‐γ2‐MSH were centrally administered, but neither neuroendocrine, nor excessive grooming responses were observed.
These results imply that the melanocortin‐4‐receptor, and not the melanocortin‐3‐receptor, is involved in the ACTH1‐24‐induced rise in plasma levels of ACTH and corticosterone, and excessive grooming.

British Journal of Pharmacology (1998) 123, 1503–1508; doi:10.1038/sj.bjp.0701750
Acetylcholine modulation of high‐voltage‐activated calcium channels in the neurones acutely dissociated from rat paratracheal ganglia
Authors: Murai Yoshinaka , Ishibashi Hitoshi , Akaike Norio , Ito Yushi 
Published: January 2005

The modulation of high‐voltage‐activated (HVA) Ca2+ channels by acetylcholine (ACh) was studied in the paratracheal ganglion cells acutely dissociated from 2‐week‐old Wistar rats by use of the nystatin perforated patch recording configuration under voltage‐clamp conditions.
ACh inhibited the HVA Ca2+ currents in a concentration‐ and voltage‐dependent manner.
The inhibition was mimicked by a muscarinic agonist, oxotremorine. Pirenzepine and methoctramine produced parallel shifts to the right in the ACh concentration‐response curves. Schild analysis of the ACh concentration‐ratios yield pA2 values for pirenzepine and methoctramine of 6.85 and 8.57, respectively, suggesting the involvement of an M2 receptor.
Nifedipine, ω‐conotoxin‐GVIA and ω‐conotoxin‐MVIIC reduced the HVA ICa by 16.8, 59.2 and 6.3%, respectively. A current insensitive to all of these Ca2+ antagonists, namely ‘R‐type’, was also observed. The results indicated the existence of L‐, N‐, P/Q‐, and R‐type Ca2+ channels.
The ACh‐sensitive current component was markedly reduced in the presence of ω‐conotoxin‐GVIA, but not with both nifedipine and ω‐conotoxin‐MVIIC. ACh also inhibited the R‐type HVA ICa remaining in saturating concentrations of nifedipine, ω‐conotoxin‐GVIA and ω‐conotoxin‐MVIIC.
The inhibitory effect of ACh was prevented by pretreatment with pertussis toxin.
It was concluded that ACh selectively reduces both the N‐ and R‐type Ca2+ channels, by activating pertussis toxin sensitive G‐protein through the M2 muscarinic receptor in paratracheal ganglion cells.

British Journal of Pharmacology (1998) 123, 1441–1449; doi:10.1038/sj.bjp.0701753
Evidence for the existence of [3H]‐trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore
Authors: Morin Didier , Elimadi Aziz , Sapena Rosa , Crevat Aimé , Carrupt Pierre‐Alain , Testa Bernard , Tillement Jean‐Paul 
Published: January 2005

Trimetazidine is an anti‐ischaemic drug effective in different experimental models but its mechanism of action is not fully understood. Data indicate that mitochondria could be the main target of this drug. The aim of this work was to investigate the binding of [3H]‐trimetazidine on a purified preparation of rat liver mitochondria.
[3H]‐trimetazidine binds to two populations of mitochondrial binding sites with Kd values of 0.96 and 84 μm. The total concentration of binding sites is 113 pmol mg−1 protein. Trimetazidine binding sites are differently distributed. The high‐affinity ones are located on the outer membranes and represent only a small part (4%) of total binding sites, whereas the low‐affinity ones are located on the inner membranes and are more abundant (96%) with a Bmax=108 pmol mg−1 protein.
Drug displacement studies with pharmacological markers for different mitochondrial targets showed that [3H]‐trimetazidine binding sites are different from previously described mitochondrial sites.
The possible involvement of [3H]‐trimetazidine binding sites in the regulation of the mitochondrial permeability transition pore (MTP), a voltage‐dependent channel sensitive to cyclosporin A, was investigated with mitochondrial swelling experiments. Trimetazidine inhibited the mitochondrial swelling induced by Ca2+ plus tert‐butylhydroperoxide (t‐BH). This effect was concentration‐dependent with an IC50 value of 200 μm.
Assuming that trimetazidine effectiveness may be related to its structure as an amphiphilic cation, we compared it with other compounds exhibiting the same chemical characteristic both for their ability to inhibit MTP opening and to displace [3H]‐trimetazidine bound to mitochondria. Selected compounds were drugs known to interact with various biological membranes.
A strong correlation between swelling inhibition potency and low‐affinity [3H]‐trimetazidine binding sites was observed: r=0.907 (n=24; P<0.001).
These data suggest that mitochondrial sites labelled with [3H]‐trimetazidine may be involved in the MTP inhibiton.

British Journal of Pharmacology (1998) 123, 1385–1394; doi:10.1038/sj.bjp.0701755
Binding of KATP channel modulators in rat cardiac membranes
Authors: Löffler‐Walz Cornelia , Quast Ulrich 
Published: January 2005

The binding of [3H]‐P1075, a potent opener of adenosine‐5′‐triphosphate‐(ATP)‐sensitive K+ channels, was studied in a crude heart membrane preparation of the rat, at 37°C.
Binding required MgATP. In the presence of an ATP‐regenerating system, MgATP supported [3H]‐P1075 binding with an EC50 value of 100 μm and a Hill coefficient of 1.4.
In saturation experiments [3H]‐P1075 binding was homogeneous with a KD value of 6±1 nm and a binding capacity (Bmax) of 33±3 fmol mg−1 protein.
Upon addition of an excess of unlabelled P1075, the [3H]‐P1075‐receptor complex dissociated in a mono‐exponential manner with a dissociation rate constant of 0.13±0.01 min−1. If a bi‐molecular association mechanism was assumed, the dependence of the association kinetics on label concentration gave an association rate constant of 0.030±0.003 nm−1 min−1. From the kinetic experiments the KD value was calculated as 4.7±0.6 nm.
Openers of the ATP‐sensitive K+ channel belonging to different structural classes inhibited specific [3H]‐P1075 binding in a monophasic manner to completion; an exception was minoxidil sulphate where maximum inhibition was 68%. The potencies of the openers in this assay agree with published values obtained in rat cardiocytes and are on average 3.5 times lower than those determined in rat aorta.
Sulphonylureas, such as glibenclamide and glibornuride and the sulphonylurea‐related carboxylate, AZ‐DF 265, inhibited [3H]‐P1075 binding with biphasic inhibition curves. The high affinity component comprised about 60% of the curves with the IC50 value of glibenclamide being ∼amp;90 nm; affinities for the low affinity component were in the μm concentration range. The fluorescein derivative, phloxine B, showed a monophasic inhibition curve with an IC50 value of 6 μm, a maximum inhibition of 94% and a Hill coefficient of 1.5.
It is concluded that binding studies with [3H]‐P1075 are feasible in rat heart membranes in the presence of MgATP and of an ATP‐regenerating system. The pharmacological profile of the [3H]‐P1075 binding sites in the cardiac preparation, which probably contains sulphonylurea receptors (SURs) from cardiac myocytes (SUR2A) and vascular smooth muscle cells (SUR2B), differs from that expected for SUR2A and SUR2B.

British Journal of Pharmacology (1998) 123, 1395–1402; doi:10.1038/sj.bjp.0701756