bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beta 3‐adrenoceptor stimulation induces vasorelaxation mediated essentially by endothelium‐derived nitric oxide in rat thoracic aorta
Authors: Trochu Jean‐Noël , Leblais Véronique , Rautureau Yohann , Bévérelli Fabrizio , Le Marec Hervé , Berdeaux Alain , Gauthier Chantal 
Published: January 2005

The relaxant effects of isoprenaline may result from activation of another β‐adrenoceptor subtype in addition to β1 and β2. This study evaluated the role of a third β‐adrenoceptor subtype, β3, in β‐adrenoceptor‐induced relaxation of rat thoracic aorta by isoprenaline.
Isoprenaline produced a concentration‐dependent relaxation of phenylephrine pre‐contracted rings of the thoracic aorta (pD2=7.46±0.15; Emax=85.9±3.4%), which was partially attenuated by endothelium removal (Emax=66.5±6.3%) and administration of the nitric oxide (NO) synthase inhibitor, L‐NG‐monomethyl arginine (L‐NMMA) (Emax=61.3±7.9%).
In the presence of nadolol, a β1‐ and β2‐adrenoceptor antagonist, isoprenaline‐induced relaxation persisted (Emax=55.6±5.3%), but occurred at higher concentrations (pD2=6.71±0.10) than in the absence of nadolol and lasted longer.
Similar relaxant effects were obtained with two β3‐adrenoceptor agonists: SR 58611 (a preferential β3‐adrenoceptor agonist), and CGP 12177 (a partial β3‐adrenoceptor with β1‐ and β2‐adrenoceptor antagonistic properties). SR 58611 caused concentration‐dependent relaxation (pD2=5.24±0.07; Emax=59.5±3.7%), which was not modified by pre‐treatment with nadolol but antagonized by SR 59230A, a β3‐adrenoceptor antagonist. The relaxation induced by SR 58611 was associated with a 1.7 fold increase in tissue cyclic GMP content.
Both relaxation and the cyclic GMP increase induced by SR 58611 were greatly reduced by endothelium removal and in the presence of L‐NMMA.
We conclude that in the rat thoracic aorta, β3‐adrenoceptors are mainly located on endothelial cells, and act in conjuction with β1‐ and β2‐adrenoceptors to mediate relaxation through activation of an NO synthase pathway and subsequent increase in cyclic GMP levels.

British Journal of Pharmacology (1999) 128, 69–76; doi:10.1038/sj.bjp.0702797
The effects of endomorphin‐1 and endomorphin‐2 in CHO cells expressing recombinant μ‐opioid receptors and SH‐SY5Y cells
Authors: Harrison C , McNulty S , Smart D , Rowbotham D J , Grandy D K , Devi L A , Lambert D G 
Published: January 2005

Endomorphin‐1 and ‐2 (E‐1/E‐2) have been proposed as endogenous ligands for the μ‐opioid receptor. The aims of this study are to characterize the binding of E‐1/E‐2 and the subsequent effects on cyclic AMP formation and [Ca2+]i levels in SH‐SY5Y and Chinese hamster ovary (CHO) cells expressing endogenous and recombinant μ‐opioid receptors.
E‐1 displaced [3H]‐diprenorphine ([3H]‐DPN) binding in CHOμ and SH‐SY5Y membranes with pKi values of 8.02±0.09 and 8.54±0.13 respectively. E‐2 displaced [3H]‐DPN binding in CHOμ and SH‐SY5Y cells with pKi values of 7.82±0.11 and 8.43±0.13 respectively. E‐1/E‐2 bound weakly to CHOδ and CHOκ membranes, with IC50 values of greater than 10 μM.
In CHOμ cells, E‐1/E‐2 inhibited forskolin (1 μM) stimulated cyclic AMP formation with pIC50 values of 8.03±0.16 (Imax=53.0±9.3%) and 8.15±0.24 (Imax=56.3±3.8%) respectively. In SH‐SY5Y cells E1/E2 inhibited forskolin stimulated cyclic AMP formation with pIC50 values of 7.72±0.13 (Imax=46.9±5.6%) and 8.11±0.31 (Imax=40.2±2.8%) respectively.
E‐1/E‐2 (1 μM) increased [Ca2+]i in fura‐2 loaded CHOμ cell suspensions in a thapsigargin sensitive and naloxone reversible manner. Mean increases observed were 106±28 and 69±6.7 nM respectively. In single adherent cells E‐1/E‐2 (1 μM) increased [Ca2+]i with a mean 340/380 ratio change of 0.81±0.09 and 0.40±0.08 ratio units respectively. E‐1/E‐2 failed to increase intracellular calcium in CHOδ, CHOκ and SH‐SY5Y cells.
These data show that E‐1/E‐2 bind with high affinity and selectivity to μ‐opioid receptors and modulate signal transduction pathways typical of opioids. This provides further evidence that these two peptides may be endogenous ligands at the μ‐opioid receptor.

British Journal of Pharmacology (1999) 128, 472–478; doi:10.1038/sj.bjp.0702798
The effect of body temperature on myocardial protection conferred by ischaemic preconditioning or the selective adenosine A1receptor agonist GR79236, in an anaesthetized rabbit model of myocardial ischaemia and reperfusion
Authors: Sheldrick A , Gray K M , Drew G M , Louttit J B 
Published: January 2005

The cardioprotective effect of N‐[(1S, trans)‐2‐hydroxycyclopentyl]adenosine (GR79236), an adenosine A1receptor agonist, was compared with that produced by ischaemic preconditioning in an anaesthetized rabbit model of myocardial ischaemia and reperfusion. In addition, we examined the effect of different body core temperatures on GR79236‐ or ischaemic preconditioning‐induced cardioprotection when administered prior to ischaemia, and on cardioprotection induced by GR79236 administered 10 min prior to the onset of reperfusion.When rabbits were subjected to 30 min occlusion of the left coronary artery, followed by 2 h reperfusion, GR79236 (3×10−8 mol kg−1i.v. (10.5 μg kg−1i.v.)) or ischaemic preconditioning (5 min ischaemia followed by 5 min reperfusion), administered or applied 10 min prior to the occlusion, significantly limited the development of infarction. The cardioprotective effect of ischaemic preconditioning was significantly greater than that seen after administration of GR79236. Pre‐treatment with the selective adenosine A1receptor antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX, 3.3×10−6 mol kg−1(1 mg kg−1i.v.)), prevented the cardioprotective effect of GR79236, but not that of ischaemic preconditioning.Maintaining body core temperature at 38.5°C rather than at 37.0°C did not influence infarct size in control groups of rabbits, but reduced the cardioprotective effect of GR79236 when administered 10 min prior to occlusion or 10 min prior to the onset of reperfusion. The cardioprotective effect of ischaemic preconditioning was not temperature‐dependent.In conclusion, myocardial protection conferred by GR79236 in anaesthetized rabbits is mediatedviaadenosine A1receptors. Myocardial protection can be conferred when GR79236 is administered before the onset of ischaemiaorreperfusion, and is reduced when body core temperature is maintained at 38.5°C rather than at 37.0°C. In contrast, myocardial protection conferred by ischaemic preconditioning is not reduced by adenosine A1receptor blockade, or by maintaining body core temperature at 38.5°C rather than at 37.0°C. These findings point to distinct differences in the mechanisms of induction of myocardial protection by adenosine A1receptor agonist and ischaemic preconditioning. They also highlight the need for careful control of body core temperature when investigating the phenomenon of cardioprotection.British Journal of Pharmacology(1999)128, 385–395; doi:10.1038/sj.bjp.0702799
Inhibition of the current of heterologously expressed HERG potassium channels by imipramine and amitriptyline
Authors: Teschemacher Anja G , Seward Elizabeth P , Hancox Jules C , Witchel Harry J 
Published: January 2005

Tricyclic antidepressants (TCAs) are associated with cardiovascular side effects including prolongation of the QT interval of the ECG. In this report we studied the effects of two TCAs (imipramine and amitriptyline) on ionic current mediated by cloned HERG potassium channels.
Voltage clamp measurements of HERG currents were made from CHO cells transiently transfected with HERG cDNA. HERG‐encoded potassium channels were inhibited in a reversible manner by both imipramine and amitriptyline. HERG tail currents (IHERG) following test pulses to +20 mV were inhibited by imipramine with an IC50 of 3.4±0.4 μM (mean±s.e.mean) and a Hill coefficient of 1.17±0.03 (n=5). 3 μM amitriptyline inhibited IHERG by 34±6% (n=3). The inhibition showed only weak voltage dependence.
Using an ‘envelope of tails’ comprised of pulses to +20 mV of varying durations, the τ of activation was found to be 155±30 ms for control and 132±26 ms for 3 μM imipramine (n=5). Once maximal channel activation was achieved after 320 ms (as demonstrated by maximal tail currents), further prolongation of depolarization did not increase imipramine‐mediated HERG channel inhibition.
Taking current measurements every second during a 10 s depolarizing pulse from −80 mV to 0 mV, block was observed during the first pulse in the presence of imipramine and the level of IHERG block was similar throughout the pulse (n=5).
A three pulse protocol (two depolarizing pulses to +20 mV separated by 20 ms at −80 mV) revealed that imipramine did not significantly alter the kinetics of IHERG inactivation. The τ of inactivation was 8±2 ms and 5.6±0.4 ms (n=5) in the absence and presence of 3 μM imipramine, respectively, and currents inactivated to a similar extent.
Our data are consistent with TCAs causing components of block of the HERG channel in both the closed and open states. Any component of open channel block occurs rapidly upon depolarization. Inhibition of IHERG by the prototype TCAs imipramine and amitriptyline may suggest a mechanism for QT prolongation associated with risks of arrhythmia and sudden death that accompany high concentrations of TCAs following overdose.

British Journal of Pharmacology (1999) 128, 479–485; doi:10.1038/sj.bjp.0702800
Pro‐oxidant challenge in vivo provokes the onset of NIDDM in the insulin resistant obese Zucker rat
Authors: Laight David W , Desai Kaushik M , Gopaul Nitin K , Änggård Erik E , Carrier Martin J 
Published: January 2005

We investigated the ability of an acute pro‐oxidant challenge in vivo to deteriorate glycaemic control and insulin action in the obese Zucker rat, a model of insulin resistance associated with oxidant stress. In obese animals, the daily administration for 1 week of hydroquinone (HQ) in combination with L‐buthionine sulphoximine (BSO), elevated fasting plasma glycaemia and insulinaemia and markedly aggravated i.v. glucose‐stimulated hyperinsulinaemia without significantly affecting i.v. glucose tolerance, suggesting exacerbated insulin resistance. Intermediate effects on hyperinsulinaemia in obese animals were determined with HQ treatment alone while BSO treatment alone had no effect. In contrast, none of the pro‐oxidant treatments affected age‐matched, insulin sensitive, lean Zucker rats. Our data therefore demonstrate for the first time, a vulnerability to deterioration in insulin action in an established insulin resistant state following an environmental pro‐oxidative insult. This may have relevance in the conversion of insulin resistance syndrome (IRS) to non‐insulin dependent diabetes mellitus (NIDDM).British Journal of Pharmacology (1999) 128, 269–271; doi:10.1038/sj.bjp.0702801
Curcumin inhibits Th1 cytokine profile in CD4+ T cells by suppressing interleukin‐12 production in macrophages
Authors: Kang B Y , Song Y J , Kim K ‐M , Choe Y K , Hwang S Y , Kim T S 
Published: January 2005

Interleukin‐12 (IL‐12) plays a central role in the immune system by driving the immune response towards T helper 1 (Th1) type responses which are characterized by high IFN‐γ and low IL‐4 production. In this study we investigated the effects of curcumin, a natural product of plants obtained from Curcuma longa (turmeric), on IL‐12 production by mouse splenic macrophages and the subsequent ability of these cells to regulate cytokine production by CD4+ T cells.
Pretreatment with curcumin significantly inhibited IL‐12 production by macrophages stimulated with either lipopolysaccharide (LPS) or head‐killed Listeria monocytogenes (HKL).
Curcumin‐pretreated macrophages reduced their ability to induce IFN‐γ and increased the ability to induce IL‐4 in Ag‐primed CD4+ T cells. Addition of recombinant IL‐12 to cultures of curcumin‐pretreated macrophages and CD4+ T cells restored IFN‐γ production in CD4+ T cells.
The in vivo administration of curcumin resulted in the inhibition of IL‐12 production by macrophages stimulated in vitro with either LPS or HKL, leading to the inhibition of Th1 cytokine profile (decreased IFN‐γ and increased IL‐4 production) in CD4+ T cells.
These findings suggest that curcumin may inhibit Th1 cytokine profile in CD4+ T cells by suppressing IL‐12 production in macrophages, and points to a possible therapeutic use of curcumin in the Th1‐mediated immune diseases.

British Journal of Pharmacology (1999) 128, 380–384; doi:10.1038/sj.bjp.0702803
Functional expression of a cDNA encoding a human ecto‐ATPase
Authors: Mateo Jesús , Harden T Kendall , Boyer José L 
Published: January 2005

The metabolism of extracellular nucleotides plays an important role in nucleotide signalling mediated by P2 receptors. The nucleotide sequence encoding a putative human ecto‐ATPase named CD39L1 was reported recently. However, the biological activity of this protein has not been established.
Based on the sequence of CD39L1 we isolated from mRNA from human ECV‐304 cells a sequence encoding a 495 amino acid protein that is identical to CD39L1, with the exception that this sequence contains a 23 amino acid stretch in the putative extracellular loop that is missing in CD39L1. Partial sequence of a genomic DNA clone indicates that the CD39L1 gene corresponds to an alternative spliced form of the human ecto‐ATPase.
Stable expression of isolated sequence in NIH‐3T3 mouse fibroblasts conferred a marked nucleotide hydrolytic activity consistent with the activity of an ecto‐ATPase.
The human ecto‐ATPase hydrolyzed all naturally occurring nucleoside triphosphates in a Ca2+‐ or Mg2+‐dependent manner. Nucleoside diphosphates were hydrolyzed at a rate approximately 5% of that of the corresponding triphosphates. The apparent Km and Vmax values were: 394±62 μM and 107±7 nmol Pi min−1 106 cells−1 for the hydrolysis of ATP, and 102±33 μM and 4±0.4 nmol Pi min−1 106 cells−1 for the hydrolysis of ADP, respectively.
In conclusion, we report here the cloning and functional expression of a human ecto‐ATPase. The study of the biochemical properties and the regulatory mechanisms of ecto‐ATPases of defined sequence will be valuable in the definition of their role in nucleotide signalling.

British Journal of Pharmacology (1999) 128, 396–402; doi:10.1038/sj.bjp.0702805
Cloning and preliminary pharmacological characterization of the anaphylatoxin C5a receptor in the rabbit
Authors: Bachvarov Dimcho R , Houle Steeve , Bachvarova Magdalena , Bouthillier Johanne , St‐Pierre Serge A , Fukuoka Yoshihiro , Ember Julia A , Marceau François 
Published: January 2005

The rabbit receptor for C5a was cloned from a genomic library and found to be 79.5% identical to the human homologue, the highest degree of similarity found so far in nonprimate laboratory animals.
The rabbit C5a receptor stably expressed in RBL cells binds human 125I‐C5a (2 nM). Unlabelled C5a and the C‐terminal analogue N‐acetyl‐Tyr‐Ser‐Phe‐Lys‐Pro‐Met‐Pro‐Leu‐D‐Ala‐Arg (Ac‐YSFKPMPLaR) were found to be competitors of that binding, the peptide analogue retaining approximately 0.1% of the affinity of human C5a.
The order of potency human C5a>Ac‐YSFKPMPLaR was conserved in bioassays based on rabbits (relaxation of the isolated portal vein and pulmonary artery; acute in vivo neutropenia), but with a decreasing potency gap between the two compounds, a likely consequence of the resistance to peptidases of the analogue.
The molecular definition of the rabbit C5a receptor evidenced a high preservation degree of sequence and pharmacologic properties relative to the human ortholog receptor, thus defining a set of molecular tools for the investigation of the role of C5a in physiologic and pathologic models based on the rabbit (e.g. atherosclerosis, inflammation).

British Journal of Pharmacology (1999) 128, 321–326; doi:10.1038/sj.bjp.0702812
Vasoconstriction of intrapulmonary arteries to P2‐receptor nucleotides in normal and pulmonary hypertensive newborn piglets
Authors: McMillan M R , Burnstock G , Haworth S G 
Published: January 2005

The vasoconstrictor responses of isolated intrapulmonary arteries (IPA) to P2‐receptor agonists was investigated during adaptation to extrauterine life in the normal piglet and the effect of pulmonary hypertension was studied following exposure of newborn animals to chronic hypobaric hypoxia (51 kPa) for 3 days.
At resting tone, α,β‐methyleneATP (α,β‐meATP) (P2X‐receptor agonist) contracted intrapulmonary arteries from adult, but not immature pigs, and repeated application desensitized the response.
Adenosine 5′‐triphosphate (ATP) induced endothelium‐independent relaxation at low concentrations at all ages, a variable contractile response to high concentrations developed by 3 days, becoming larger and consistent by 14 days of age.
Uridine 5′‐triphosphate (UTP) evoked a contractile response in normal intrapulmonary arteries from foetal to adult life, the magnitude of the response increasing with age. Endothelial removal and pre‐incubation with Nω‐nitro‐L‐arginine methyl ester (L‐NAME) (100 μM) increased the contractile response of adult vessels.
Pre‐incubation with α,β‐meATP (100 μM), increased the contractile response to UTP in both newborn and adult vessels. ATP‐induced relaxations were reduced in newborn vessels but there was no effect on the responses of adult vessels.
Responses to UTP, ATP and α,β‐meATP of intrapulmonary arteries from newborn piglets exposed to chronic hypobaric hypoxia for 3 days were normal.
In summary, UTP elicited marked vasoconstriction of porcine IPA at all ages. UTP and ATP responses were consistent with activation of the P2Y4‐receptor recently identified in vascular smooth muscle by others. α,β‐meATP induced a small vasoconstriction in the adult probably via the P2X1‐receptor. Responses remained normal in neonatal pulmonary hypertension.

British Journal of Pharmacology (1999) 128, 549–555; doi:10.1038/sj.bjp.0702814
Vasodilatation of intrapulmonary arteries to P2‐receptor nucleotides in normal and pulmonary hypertensive newborn piglets
Authors: McMillan M R , Burnstock G , Haworth S G 
Published: January 2005

The vasodilator responses of isolated intrapulmonary arteries (IPA) to P2‐receptor agonists were investigated during adaptation to extrauterine life in the piglet. The effect of pulmonary hypertension on the normal response was determined after exposing newborn animals to chronic hypobaric hypoxia (51 kPa) for 3 days.
Adenosine 5′‐triphosphate (ATP), 2‐methylthioATP (2‐meSATP), adenosine 5‐O‐(2‐thiodiphos‐phate) (ADPβS) and uridine 5′‐triphosphate (UTP) induced a relaxation in normal newborn piglet IPA pre‐contracted with prostaglandin F2α (PGF2α). The relaxations were not affected by removal of the endothelium. The responses to ATP and ADPβS increased significantly with age.
The relaxation responses of IPA to ATP, 2‐meSATP and ADPβS continued to increase normally after birth in an hypoxic environment.
The results of the study show that vasodilatation of porcine intrapulmonary vessels to nucleotides increased during development from foetus to adult; that the vasodilatation to purines was mediated by P2Y‐receptors on the vascular smooth muscle rather than on the endothelium; and that the P2Y‐receptor mediated relaxation of IPA remained normal in the pulmonary hypertensive neonate.

British Journal of Pharmacology (1999) 128, 543–548; doi:10.1038/sj.bjp.0702815
Troglitazone and pioglitazone attenuate agonist‐dependent Ca2+ mobilization and cell proliferation in vascular smooth muscle cells
Authors: Asano Michiko , Nakajima Toshiaki , Iwasawa Kuniaki , Morita Toshihiro , Nakamura Fumitaka , Imuta Hiroyuki , Chisaki Keigo , Yamada Nobuhiro , Omata Masao , Okuda Yukichi 
Published: January 2005

The effects of troglitazone and pioglitazone on agonist‐induced Ca2+ mobilization and cell proliferation were studied using fluorescent Ca2+ indicator fura‐2 AM and incorporation of [3H]‐thymidine in rat aortic smooth muscle cells. The patch clamp techniques were also employed.
Vasopressin and platelet‐derived growth factor‐BB (PDGF) caused a transient elevation in [Ca2+]i by Ca2+ mobilization from intracellular stores, followed by a sustained rise due to Ca2+ entry. Nicardipine partly inhibited the sustained phase, but La3+ completely abolished it.
Troglitazone and pioglitazone did not significantly affect the transient rise elicited by these agonists, but preferentially inhibited the sustained phase of [Ca2+]i.
Under voltage clamp conditions, troglitazone and pioglitazone inhibited voltage‐dependent L‐type Ca2+ current (ICa·L). They also inhibited nonselective cation channels (Icat) elicited by vasopressin in a concentration‐dependent manner. The half maximal inhibitory concentrations of troglitazone on ICa·L and Icat were 4.6 and 5.7 μM, respectively. On the other hand, nifedipine and nicardipine did not inhibit Icat.
Vasopressin and PDGF increased incorporation of [3H]‐thymidine, and nifedipine and nicardipine partly suppressed it. However, the inhibitory effects of La3+ and exclusion of extracellular Ca2+ were more potent than the Ca2+ blocking agents. Troglitazone and pioglitazone also inhibited it concentration‐dependently.
These results suggest that troglitazone and pioglitazone preferentially inhibited agonist (vasopressin and PDGF)‐induced Ca2+ entry and proliferation in rat vascular smooth muscle cells, where the inhibitory effects of thiazolidinediones on ICa·L and Icat might be partly involved. Thus, thiazolidinediones may exert hypotensive and antiatherosclerotic effects.

British Journal of Pharmacology (1999) 128, 673–683; doi:10.1038/sj.bjp.0702818
Activity profiles of dalargin and its analogues in μ‐, δ‐ and κ‐opioid receptor selective bioassays
Authors: Pencheva Nevena , Pospišek Jan , Hauzerova Linda , Barth Tomislav , Milanov Peter 
Published: January 2005

To elucidate the structural features ensuring action of [D‐Ala2, Leu5]‐enkephalyl‐Arg (dalargin), a series of dalargin analogues were tested for their effectiveness in depressing electrically‐evoked contractions of the guinea‐pig myenteric plexus‐longitudinal muscle preparations (μ‐ and κ‐opioid receptors) and the vasa deferentia of the hamster (δ‐opioid receptors), mouse (μ‐, δ‐ and κ‐opioid receptors), rat (similar to μ‐opioid receptors) and rabbit (κ‐opioid receptors). The naloxone KB values in the myenteric plexus were also obtained.
[L‐Ala2]‐dalargin was 19 times less potent than dalargin, and its pharmacological activity was peptidase‐sensitive. The ratio of δ‐activity to μ‐activity for [L‐Ala2]‐dalargin was 6.78, and KB was 7.9 nM. This emphasizes the role that D‐configuration of Ala2 plays in determining the active folding of dalargin molecule as well as in conferring resistance to peptidases.
[Met5]‐dalargin was equipotent to dalargin in the myenteric plexus, but was more potent in the vasa deferentia of hamster and mouse (KB=5.5 nM). Leu5 and the interdependence of Leu5 and D‐Ala2 are of importance for the selectivity of dalargin for μ‐opioid receptors.
Dalarginamide was more potent and selective for μ‐opioid receptors than dalargin, whilst dalarginethylamide, though equipotent to dalarginamide in the myenteric plexus, was more potent at δ‐opioid receptors (KB=5.0 nM). [D‐Phe4]‐dalarginamide and N‐Me‐[D‐Phe4]‐dalarginamide were inactive indicating the contribution of L‐configuration of Phe4 to the pharmacological potency of dalargin.
N‐Me‐[L‐Phe4]‐dalarginamide possessed the highest potency and selectivity for μ‐opioid receptors (the ratio of δ‐activity to μ‐activity was 0.00053; KB=2.6 nM). The CONH2 terminus combined with the N‐methylation of L‐Phe4 increased the potency and selectivity of dalargin for μ‐opioid receptors.

British Journal of Pharmacology (1999) 128, 569–576; doi:10.1038/sj.bjp.0702825