bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of melatonin on rat pial arteriolar diameter in vivo
Authors: Régrigny Olivier , Delagrange Philippe , Scalbert Elizabeth , Lartaud‐Idjouadiene Isabelle , Atkinson Jeffrey , Chillon Jean‐Marc 
Published: January 2005

Based on our finding that melatonin decreased the lower limit of cerebral blood flow autoregulation in rat, we previously suggested that melatonin constricts cerebral arterioles. The goal of this study was to demonstrate this vasoconstrictor action and investigate the mechanisms involved.
The effects of cumulative doses of melatonin (10−10 to 10−6 M) were examined in cerebral arterioles (30–50 μM) of male Wistar rats using an open skull preparation. Cerebral arterioles were exposed to two doses of melatonin (3×10−9 and 3×10−8 M) in the absence and presence of the mt1 and/or MT2 receptor antagonist, luzindole (2×10−6 M) and the Ca2+‐activated K+ (BKCa) channel blocker, tetraethylammonium (TEA+, 10−4 M). The effect of L‐nitro arginine methyl ester (L‐NAME, 10−8 M) was examined on arterioles after TEA+ superfusion. Cerebral arterioles were also exposed to the BKCa activator, NS1619 (10−5 M), and to sodium nitroprusside (SNP, 10−8 M) in the absence and presence of melatonin (3×10−8 M).
Melatonin induced a dose‐dependent constriction with an EC50 of 3.0±0.1 nM and a maximal constriction of −15±1%. Luzindole abolished melatonin‐induced vasoconstriction. TEA+ induced significant vasoconstriction (−10±2%). No additional vasoconstriction was observed when melatonin was added to the aCSF in presence of TEA+, whereas L‐NAME still induced vasoconstriction (−10±1%). NS1619 induced vasodilatation (+11±1%) which was 50% less in presence of melatonin. Vasodilatation induced by SNP (+12±2%) was not diminished by melatonin.
Melatonin directly constricts small diameter cerebral arterioles in rats. This vasoconstrictor effect is mediated by inhibition of BKCa channels following activation of mt1 and/or MT2 receptors.

British Journal of Pharmacology (1999) 127, 1666–1670; doi:10.1038/sj.bjp.0702714
In vivo B1 kinin‐receptor upregulation. Evidence for involvement of protein kinases and nuclear factor κB pathways
Authors: Campos Maria M , Souza Glória E P , Calixto João B 
Published: January 2005

Intradermal (i.d.) injection of cytokines, IL‐1β and TNFα (5 ng, 60 and 30 min prior) produces a rapid onset up‐regulation of des‐Arg9‐BK‐mediated rat paw oedema. Here we analyse the mechanisms involved in des‐Arg9‐BK‐induced oedema in animals pre‐treated with IL‐1β or TNFα.
Co‐injection of anti‐IL‐1β, anti‐TNFα and anti‐IL‐8 (50 ng) significantly inhibited des‐Arg9‐BK‐induced oedema in animals pre‐treated with IL‐1β (65, 37 and 42%) or TNFα (39, 64, 25%). IL‐1 receptor antagonist (IRA, 100 μg) or IL‐10 (10 ng) inhibited the oedema caused by des‐Arg9‐BK, in rats that had received either IL‐1β (67 and 63%) or TNFα (46 and 35%).
Co‐injection of the PKC inhibitors, staurosporine (10 nmol) or RO 318220 (30 nmol) inhibited des‐Arg9‐BK‐induced paw oedema (44 and 42% for IL‐1β and, 53 and 30% for TNFα, respectively). Genistein (tyrosine kinase inhibitor, 2.5 mg kg−1, s.c.) or PD 098059 (MAP‐kinase inhibitor, 30 nmol) produced marked inhibition of des‐Arg9‐BK‐induced oedema (58 and 39% for IL‐1β and 31 and 35% for TNFα respectively).
The NF‐κB inhibitors TLCK (2 mg kg−1, i.p.) and PDCT (100 mg kg−1, i.p.) significantly inhibited the oedema of des‐Arg9‐BK in IL‐1β (27 and 83%) or TNFα (28 and 80%) pre‐treated animals.
It is concluded that up‐regulation of B1 receptors modulated by IL‐1β or TNFα involves the release of other cytokines, activation of PKC and tyrosine kinase pathways, co‐ordinated with the activation of MAP‐kinase and nuclear factor κB, reinforcing the view that B1 receptors may exert a pivotal role in modulating chronic inflammatory processes.

British Journal of Pharmacology (1999) 127, 1851–1859; doi:10.1038/sj.bjp.0702715
Influence of CGRP (8–37), but not adrenomedullin (22–52), on the haemodynamic responses to lipopolysaccharide in conscious rats
Authors: Gardiner S M , March J E , Kemp P A , Bennett T 
Published: January 2005

The functional involvement of the vasodilator peptides, adrenomedullin (ADM) and calcitonin gene‐related peptide (CGRP), in the haemodynamic sequelae of continuous infusion of lipopolysaccharide (LPS) was assessed in conscious, male, Long Evans rats, by the use of peptide antagonists.
It was demonstrated that ADM (22–52) at a dose of 500 nmol kg−1 h−1 caused significant inhibition of the effects of ADM (1 nmol kg−1), without affecting responses to CGRP (0.1 or 1 nmol kg−1).
Even when the regional vasodilator responses to LPS infusion were enhanced (by pre‐treatment with dexamethasone and the endothelin antagonist, SB 209670, or by pretreatment with SB 209670 and the AT1‐receptor antagonist, losartan), ADM (22–52) had no significant cardiovascular effects. In contrast, the CGRP1‐receptor antagonist, CGRP (8–37), caused small, but significant, inhibitions of the hypotensive and renal and mesenteric vasodilator effects of LPS, but only 6 h after onset of infusion in the presence of dexamethasone and SB 209670.
The results indicate that, in this model of endotoxaemia, the marked regional vasodilatations seen in the presence of dexamethasone and SB 209670 do not involve ADM, but do involve CGRP, albeit only to a small extent.

British Journal of Pharmacology (1999) 127, 1611–1618; doi:10.1038/sj.bjp.0702718
Analysis of the atypical characteristics of adenosine receptors mediating negative inotropic and chronotropic responses of guinea‐pig isolated atria and papillary muscles
Authors: Gardner Neil M , Broadley Kenneth J 
Published: January 2005

Adenosine receptor(s) mediating negative inotropy of paced left atria, isoprenaline‐stimulated paced left atria and papillary muscles, and negative chronotropy of spontaneously beating right atria were characterized.
Isometric tension of guinea‐pig isolated paced left atria and left ventricular papillary muscles and rate of contraction of spontaneously beating right atria were recorded. Papillary muscles were pre‐stimulated with isoprenaline (1×10−8 M). Concentration‐response curves (CRCs) for tension or rate reduction by N6‐cyclopentyladenosine (CPA), the stereoisomers of N6‐(2‐phenylisopropyl)adenosine ((+)‐PIA and (−)‐PIA), 5′‐(N‐carboxamido)adenosine (NECA), N6‐2‐(4‐aminophenyl)ethyladenosine (APNEA) and N6‐(3‐iodobenzyl)adenosine‐5′‐N‐methyuromide (IB‐MECA) revealed a potency order of CPA=(−)‐PIA>NECA in right atria and papillary muscles, which is consistent with involvement of A1‐receptors. The potency order in left atria was CPA=NECA>(−)‐PIA>(+)‐PIA>APNEA, which is not typical of A1 adenosine receptors. Weak activity of APNEA and IB‐MECA discounts involvement of A3 receptors.
pA2 values for the antagonism of CPA by 8(p‐sulfophenyl)theophylline (8‐SPT) were calculated from Schild plots (log concentration‐ratio against log 8‐SPT concentration), the unity slopes of which indicated competitive antagonism. The pA2 value in the papillary muscles was significantly higher than for atrial preparations, indicating a possible difference in receptor characteristics between atrial and papillary muscle responses.
In left and right atria there was a limit to the displacement of the CPA CRCs at higher concentrations of 8‐SPT. The 8‐SPT‐resistant component of the response is suggested to arise from duality of coupling of a common A1 receptor through either different G proteins or G protein subunits to independent transduction pathways. The results with papillary muscles can be explained by a typical A1 receptor coupled to a single transduction pathway.

British Journal of Pharmacology (1999) 127, 1619–1626; doi:10.1038/sj.bjp.0702719
Action of AT1 receptor antagonists on angiotensin II‐induced tone in human isolated subcutaneous resistance arteries
Authors: Garcha Robinder S , Sever Peter S , Hughes Alun D 
Published: January 2005

Human isolated subcutaneous arteries were studied under isometric conditions in a myograph.
Addition of angiotensin II (AII) induced a concentration‐dependent increase in tone in isolated arteries. The active metabolite of candesartan (CV 11974), losartan and the active metabolite of losartan, E‐3174 antagonized AII‐induced tone in a non‐competitive manner, but the AT2 selective antagonist, PD123319, was without effect on responses to AII. The effects of candesartan, losartan and E‐3174 were analysed using a classical model of non‐competitive antagonism and a two‐state receptor model.
Mechanical removal of the endothelium; pre‐incubation with Nω‐nitro‐L‐arginine methyl ester hydrochloride (L‐NAME); pre‐incubation with indomethacin, a cyclo‐oxygenase inhibitor; or pre‐incubation with BQ 485, an endothelin antagonist; had no significant effect on contractions induced by AII.
Our results suggest AII contracts human isolated resistance arteries by an action on AT1 receptors and does not involve release of endothelial factors. Use of a two‐state receptor model successfully described the action of the AT1 antagonists without sacrificing assumptions regarding the competitive nature of binding of these antagonists.

British Journal of Pharmacology (1999) 127, 1876–1882; doi:10.1038/sj.bjp.0702722
Pregnancy reduces brain sigma receptor function
Authors: Bergeron Richard , De Montigny Claude , Debonnel Guy 
Published: January 2005

Sigma (σ) receptors have recently been cloned, though their endogenous ligand(s) remain unidentified. However, some neuroactive steroids, such as progesterone, have a high affinity for these receptors. Some σ ligands, such as DTG, (+)‐pentazocine and DHEA, act as σ ‘agonists’ by potentiating the neuronal response to NMDA. Others, such as haloperidol, NE‐100 and progesterone, act as σ ‘antagonists’ by reversing the potentiations induced by σ ‘agonists’.
We compared the effects of σ ‘agonists’ in four series of female rats: in controls, at day 18 of pregnancy, at day 5 post‐partum, and in ovariectomized rats following a 3‐week treatment with a high dose of progesterone.
In pregnant rats and following a 3‐week treatment with progesterone, 10 fold higher doses of DTG, (+)‐pentazocine and DHEA were required to elicit a selective potentiation of the NMDA response comparable to that obtained in control females. Conversely, at day 5 post‐partum and following the 3‐week treatment with a progesterone and after a 5‐day washout, the potentiation of the NMDA response induced by the σ ‘agonist’ DTG was greater than in control females.
The present data suggest that endogenous progesterone acts as an ‘antagonist’ at σ receptors. The resulting changes in the function of σ receptors during pregnancy and post‐partum may be implicated in emotional phenomena occurring during these periods.

British Journal of Pharmacology (1999) 127, 1769–1776; doi:10.1038/sj.bjp.0702724
Triggering role of nitric oxide in the delayed protective effect of monophosphoryl lipid A in rat heart
Authors: György Katalin , Muller Bernard , Végh Agnes , Kleschyov Andrei L , Stoclet Jean‐Claud 
Published: January 2005

The main objective of the present study was to further evaluate the role of nitric oxide (NO) in delayed cardiac protection against ischaemia‐reperfusion injury induced by monophosphoryl lipid A (MLA).
For this purpose, rats were administered with either 0.5 or 2.5 mg kg−1 MLA (i.p.). Eight or 24 h later, in vivo NO production in the heart was analysed by electron paramagnetic resonance (EPR) spin trapping technique. In parallel experiments, hearts were removed and perfused according to Langendorff. Functional ventricular parameters and incidence of ventricular fibrillation (VF) were determined after 30 min global ischaemic insult (37°C) followed by 30 min reperfusion. Vascular reactivity of aortic rings was also assessed.
Hearts from rats pretreated with 2.5 mg kg−1 MLA for 24 h (but not those from rats treated with 0.5 mg kg−1 MLA for 8 and 24 h, or with 2.5 mg kg−1 MLA for 8 h) exhibited preservation of ventricular function (LVDP, ±dP/dtmax) and a reduced incidence of VF (25% vs 87.5% in vehicle control) during reperfusion. At the cardioprotective dose of 2.5 mg kg−1 (for 8 or 24 h), MLA did not produce alterations of the contractile response of aortic rings to noradrenaline.
An increased formation of NO was detected in hearts removed from rats pretreated with 2.5 mg kg−1 MLA for 8 h, but not in those from rats treated for 24 h (or with 0.5 mg kg−1 MLA).
Pretreatment of the animals with the inhibitors of inducible NO‐synthase, aminoguanidine (2×300 mg kg−1) or L‐N6‐(1‐Iminoethyl)‐lysine (L‐NIL, 10 mg kg−1) abolished both MLA (2.5 mg kg−1)‐induced rise of NO production (observed 8 h after MLA) and cardioprotection (observed 24 h after MLA). However MLA‐induced cardioprotection was not attenuated when the hearts were perfused with aminoguanidine (150 μM) for 30 min before the ischaemic insult.
Altogether, the present data suggest that NO acts as a trigger rather then a direct mediator of the delayed cardioprotective effect of MLA in rat heart.

British Journal of Pharmacology (1999) 127, 1892–1898; doi:10.1038/sj.bjp.0702725
PKCβI mediates the inhibition of P2Y receptor‐induced inositol phosphate formation in endothelial cells
Authors: Chen Bing‐C , Lin Wan‐W 
Published: January 2005

Bovine pulmonary artery endothelium (CPAE) expresses phospholipase C (PLC)‐linked P2Y1 and P2Y2 receptors, for them 2‐methylthio‐ATP (2MeSATP) and UTP are respective agonists. Here, we have investigated the particular protein kinase C (PKC) isoform(s) responsible for the inhibition of P2Y1 and P2Y2 receptor‐evoked inositol phosphate (IP) formation by phorbol 12‐myristate 13‐acetate (PMA).
Although short‐term (20 min) pretreatment of cells with PMA attenuated 2MeSATP‐ and UTP‐induced phosphoinositide (PI) breakdown, this inhibition was lost after 15 h. Preincubation with PMA for 24 h, on the contrary, potentiated 2MeSATP and UTP responses. The IP formation stimulated by NaF was unaltered by PMA pretreatment.
Western blot analysis showed that treatment of CPAE with PMA resulted in a rapid translocation of PKC isoform βI, ε and μ, but not λ, from the cytosol to the membrane fraction.
Pretreatment of the selective PKC inhibitor Ro 31–8220 attenuated the inhibitory effect of PMA on IP formation. Go 6976 (an inhibitor of conventional PKCα, β and γ) and LY 379196 (a selective PKCβ inhibitor) also dose‐dependently inhibited the PMA‐mediated desensitization.
Transfection of PKCβ‐specific antisense oligonucleotide reduced PKCβI protein level and inhibited PMA‐mediated PI reduction.
RT–PCR analysis showed that PMA treatment for 4–24 h up‐regulated P2Y1 and P2Y2 receptors at the mRNA levels.
These results suggest that PKCβI may exert a negative feedback regulation on endothelial P2Y1 and P2Y2 receptor‐mediated PI turnover. The down‐regulation of PKCβI and enhanced P2Y receptor expression together might contribute to the late PI enhancing effect of PMA.

British Journal of Pharmacology (1999) 127, 1908–1914; doi:10.1038/sj.bjp.0702727
Antisense down‐regulation of thymidylate synthase to suppress growth and enhance cytotoxicity of 5‐FUdR, 5‐FU and Tomudex in HeLa cells
Authors: Ferguson Peter J , Collins Olga , Dean Nicholas M , DeMoor Janice , Sha‐Li Chen , Vincent Mark D , Koropatnick James 
Published: January 2005

Thymidylate synthase (TS), the key enzyme in de novo synthesis of thymidine, is an important target for antitumour chemotherapy. It was hypothesized that antisense oligonucleotide down‐regulation of TS mRNA would decrease TS levels and enhance the cytotoxicity of inhibitors of TS, including the pyrimidine analogues 5‐fluorouracil (5‐FU) and 5‐fluorodeoxyuridine (5‐FUdR), and the folate analogue Tomudex (ICI D1694; N‐(5‐[N‐(3,4‐dihydro‐2‐methyl‐4‐oxoquinazolin‐6‐ylmethyl)‐N‐methylamino]‐2‐theonyl‐L‐glutamic acid).
2′‐Methoxyethoxylated, phosphorothioated 20‐mer oligodeoxynucleotides (ODNs), complementary to various sequences in TS mRNA, were synthesized, along with control oligomers consisting of the same, respective bases in randomized order, against which all the biological effects were compared. Following a 6‐h transfection of HeLa cells using polycationic liposome at 3 μg ml−1, ODN 83 (50 nM), complementary to a region in the 3′‐untranslated region of the TS mRNA, decreased TS mRNA levels by approximately 70% within 24 h. ODN 83 also decreased TS enzyme activity, as measured by binding of TS to radiolabelled 5‐fluorodeoxyuridine monophosphate. In addition to inhibiting proliferation by up to approximately 40%, ODN 83 enhanced the cytotoxicity of Tomudex or 5‐FU, added 1 day following transfection, by 50–60%. ODN 83 also enhanced sensitivity to 5‐FUdR by 70%, but did not affect the toxicity of cisplatin, chlorambucil, melphalan, doxorubicin, ionizing radiation, paclitaxel, or irinotecan.
These data indicate that antisense ODN down‐regulation of TS can inhibit human tumour cell proliferation and enhance the efficacy of TS‐targeted drugs.

British Journal of Pharmacology (1999) 127, 1777–1786; doi:10.1038/sj.bjp.0702728
Effects of indoramin in rat vas deferens and aorta: concomitant α1‐adrenoceptor and neuronal uptake blockade
Authors: Pupo André S , Cavenaghi Daniela L C , Campos Marcelo , Morais Paola de Lucena , Jurkiewicz Neide H , Jurkiewicz Aron 
Published: January 2005

The actions of the α1‐adrenoceptor antagonist indoramin have been examined against the contractions induced by noradrenaline in the rat vas deferens and aorta taking into account a putative neuronal uptake blocking activity of this antagonist which could result in self‐cancelling actions.
Indoramin behaved as a simple competitive antagonist of the contractions induced by noradrenaline in the vas deferens and aorta yielding pA2 values of 7.38±0.05 (slope=0.98±0.03) and 6.78±0.14 (slope=1.08±0.06), respectively.
When the experiments were repeated in the presence of cocaine (6 μM) the potency (pA2) of indoramin in antagonizing the contractions of the vas deferens to noradrenaline was increased to 8.72±0.07 (slope=1.10±0.05) while its potency remained unchanged in the aorta (pA2=6.69±0.12; slope=1.04±0.05).
In denervated vas deferens, indoramin antagonized the contractions to noradrenaline with a potency similar to that found in the presence of cocaine (8.79±0.07; slope=1.09±0.06).
It is suggested that indoramin blocks α1‐adrenoceptors and neuronal uptake in rat vas deferens resulting in Schild plots with slopes not different from unity even in the absence of selective inhibition of neuronal uptake. As a major consequence of this double mechanism of action, the pA2 values for this antagonist are underestimated when calculated in situations where the neuronal uptake is active, yielding spurious pKB values.

British Journal of Pharmacology (1999) 127, 1832–1836; doi:10.1038/sj.bjp.0702735
Eukaliuric diuresis and natriuresis in response to the KATP channel blocker U37883A: Micropuncture studies on the tubular site of action
Authors: Huang Dan Y , Osswald Hartmut , Vallon Volker 
Published: January 2005

Systemic application of U37883A, a blocker of ATP sensitive potassium (KATP) channels, elicits diuresis and natriuresis without significantly altering urinary potassium excretion.
To elucidate tubular sites of action upstream to the distal nephron, micropuncture experiments were performed in nephrons with superficial glomeruli of anaesthetized Munich‐Wistar‐Frömter rats during systemic application of U37883A (1, 5 or 15 mg kg−1 i.v.).
The observed eukaliuric diuresis and natriuresis in response to U37883A at 15 mg kg−1 was accompanied by an increase in early distal tubular flow rate (VED) from 10–18 nl min−1 reflecting a reduction in fractional reabsorption of fluid up to this site (FR‐fluid) of 13%. The latter proposed an effect on water‐permeable segments such as the proximal tubule which could fully account for the observed reduction in fractional reabsorption of Na+ up to the early distal tubule (FR‐Na+) of 8% and the increase in early distal tubular Na+ concentration ([Na+]ED) from 35–51 mM whereas [K+]ED was left unaltered.
In comparison, furosemide (3 mg kg−1 i.v.), which acts in the water‐impermeable thick ascending limb, elicited diuresis, natriuresis and kaliuresis which were associated with a fall in FR‐Na+ of 10% with no change in FR‐fluid, and a rise in [Na+]ED from 42–117 mM and [K+]ED from 1.2–5.7 mM with no change in VED.
Direct late proximal tubular fluid collections confirmed a significant inhibition of fluid reabsorption in proximal convoluted tubule in response to systemic application of U37883A.
These findings suggest that the diuretic and natriuretic effect upstream to the distal tubule in response to systemic application of U37883A involves actions on water‐permeable segments such as the proximal convoluted tubule.

British Journal of Pharmacology (1999) 127, 1811–1818; doi:10.1038/sj.bjp.0702742
Stereoselective interaction of thiopentone enantiomers with the GABAA receptor
Authors: Cordato D J , Chebib M , Mather L E , Herkes G K , Johnston G A R 
Published: January 2005

As pharmacokinetic differences between the thiopentone enantiomers seem insufficient to explain the ∼2 fold greater potency for CNS effects of (−)‐S‐ over (+)‐R‐thiopentone, this study was performed to determine any enantioselectivity of thiopentone at the GABAA receptor, the primary receptor for barbiturate hypnotic effects.
Two electrode voltage clamp recording was performed on Xenopus laevis oocytes expressing human GABAA receptor subtype α1β2γ2 to determine relative differences in potentiation of the GABA response by rac‐, (+)‐R‐ and (−)‐S‐thiopentone, and rac‐pentobarbitone. Changes in the cellular environment pH and in GABA concentrations were also evaluated.
With 3 μM GABA, the EC50 values were (−)‐S‐thiopentone (mean 26.0±s.e.mean 3.2 μM, n=9 cells) >rac‐thiopentone (35.9±4.2 μM, n=6, P=0.1) >(+)‐R‐thiopentone (52.5±5.0 μM, n=8, P<0.02) >rac‐pentobarbitone (97.0±11.2 μM, n=11, P<0.01). Adjustment of environment pH to 7.0 or 8.0 did not alter the EC50 values for (+)‐R‐ or (−)‐S‐thiopentone.
Uninjected oocytes responded to >100 μM (−)‐S‐ and R‐thiopentone. This direct response was abolished by intracellular oocyte injection of 1,2‐bis(2‐aminophenoxy)ethane‐N,N,N1,N1‐tetraacetic acid (BAPTA), a Ca2+ chelating agent. With BAPTA, the EC50 values were (−)‐S‐thiopentone (20.6±3.2 μM, n=8) <(+)‐R‐thiopentone (36.2±3.2 μM, n=9, P<0.005).
(−)‐S‐thiopentone was found to be ∼2 fold more potent than (+)‐R‐thiopentone in the potentiation of GABA at GABAA receptors expressed on Xenopus oocytes. This is consistent with the differences in potency for CNS depressant effects found in vivo.

British Journal of Pharmacology (1999) 128, 77–82; doi:10.1038/sj.bjp.0702744