bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cibenzoline, an ATP‐sensitive K+ channel blocker, binds to the K+‐binding site from the cytoplasmic side of gastric H+,K+‐ATPase
Authors: Tabuchi Yoshiaki , Yashiro Hiroaki , Hoshina Satomi , Asano Shinji , Takeguchi Noriaki 
Published: January 2005

Cibenzoline, (±)‐2‐(2,2‐diphenylcyclopropyl‐2‐imidazoline succinate, has been clinically used as one of the Class I type antiarrhythmic agents and also reported to block ATP‐sensitive K+ channels in excised membranes from heart and pancreatic β cells. In the present study, we investigated if this drug inhibited gastric H+,K+‐ATPase activity in vitro.
Cibenzoline inhibited H+,K+‐ATPase activity of permeabilized leaky hog gastric vesicles in a concentration‐dependent manner (IC50: 201 μM), whereas no effect was shown on Na+,K+‐ATPase activity of dog kidney (IC50: >1000 μM). Similarly, cibenzoline inhibited H+,K+‐ATPase activity of HEK‐293 cells (human embryonic kidney cell line) co‐transfected with rabbit gastric H+,K+‐ATPase α‐ and β‐subunit cDNAs (IC50: 183 μM).
In leaky gastric vesicles, inhibition of H+,K+‐ATPase activity by cibenzoline was attenuated by the addition of K+ (0.5 – 5 mM) in a concentration‐dependent manner. The Lineweaver‐Burk plot of the H+,K+‐ATPase activity shows that cibenzoline increases Km value for K+ without affecting Vmax, indicating that this drug inhibits H+,K+‐ATPase activity competitively with respect to K+.
The inhibitory effect of H+,K+‐ATPase activity by cibenzoline with normal tight gastric vesicles did not significantly differ from that with permeabilized leaky gastric vesicles, indicating that this drug reacted to the ATPase from the cytoplasmic side of the membrane.
These findings suggest that cibenzoline is an inhibitor of gastric H+,K+‐ATPase with a novel inhibition mechanism, which inhibits gastric H+,K+‐ATPase by binding its K+‐recognition site from the cytoplasmic side.

British Journal of Pharmacology (2001) 134, 1655–1662; doi:10.1038/sj.bjp.0704422
Prostanoid EP1‐ and TP‐receptors involved in the contraction of human pulmonary veins
Authors: Walch Laurence , De Montpreville Vincent , Brink Charles , Norel Xavier 
Published: January 2005

To characterize the prostanoid receptors (TP, FP, EP1 and/or EP3) involved in the vasoconstriction of human pulmonary veins, isolated venous preparations were challenged with different prostanoid‐receptor agonists in the absence or presence of selective antagonists.
The stable thromboxane A2 mimetic, U46619, was a potent constrictor agonist on human pulmonary veins (pEC50=8.60±0.11 and Emax=4.61±0.46 g; n=15). The affinity values for two selective TP‐antagonists (BAY u3405 and GR32191B) versus U46619 were BAY u3405: pA2=8.94±0.23 (n=3) and GR32191B: apparent pKB=8.25±0.34 (n=3), respectively. These results are consistent with the involvement of TP‐receptor in the U46619 induced contractions.
The two EP1‐/EP3‐ agonists (17‐phenyl‐PGE2 and sulprostone) induced contraction of human pumonary veins (pEC50=8.56±0.18; Emax=0.56±0.24 g; n=5 and pEC50=7.65±0.13; Emax=1.10±0.12 g; n=14, respectively). The potency ranking for these agonists: 17‐phenyl‐PGE2>sulprostone suggests the involvement of an EP1‐receptor rather than EP3. In addition, the contractions induced by sulprostone, 17‐phenyl‐PGE2 and the IP‐/EP1‐ agonist (iloprost) were blocked by the DP‐/EP1‐/EP2‐receptor antagonist (AH6809) as well as by the EP1 antagonist (SC19220).
PGF2α induced small contractions which were blocked by AH6809 while fluprostenol was ineffective. These results indicate that FP‐receptors are not implicated in the contraction of human pulmonary veins.
These data suggest that the contractions induced by prostanoids involved TP‐ and EP1‐receptors in human pulmonary venous smooth muscle.

British Journal of Pharmacology (2001) 134, 1671–1678; doi:10.1038/sj.bjp.0704423
Effect of ABT‐627 (A‐147627), a potent selective ETA receptor antagonist, on the cardiopulmonary profile of newborn lambs with surgically‐induced diaphragmatic hernia
Authors: Kavanagh Mélanie , Battistini Bruno , Jean Sonia , Crochetière Josiane , Fournier Louis , Wessale Jerry , Opgenorth Terry J , Cloutier Raymond , Major Diane 
Published: January 2005

Postnatal mortality in isolated congenital diaphragmatic hernia (CDH) is mainly related to the associated pulmonary hypertension (PH) and to right‐to‐left shunting.
Endothelins (ETs) are potent vasoconstrictors and pro‐mitogenic peptides. Strong evidences support their participation in CDH and in the etiology of PH via the activation of ETA receptors (ETA‐Rs).
Evaluation of the effect of ABT‐627, a selective non‐peptidic ETA‐R antagonist, given from −15 to 210 min post‐delivery (1 mg kg−1 bolus +0.01 mg kg−1 h−1 infusion, i.v.), was conducted in the lamb model of CDH.
Severity of CDH was assessed in comparison to untreated controls (n=5). Untreated CDH lambs (n=7) had a higher mean pulmonary arterial pressure (MPAP; P<0.0001), lower mean blood pressure (MBP; P=0.0004), higher MPAP / MBP ratio (P<0.0001), lower arterial pH (P<0.0001), higher paCO2 (P<0.0001), lower paO2 (P<0.0001) and lower post‐ductal pulsatile SaO2 (P<0.0001) than untreated controls.
Treated controls (n=7) showed a higher MPAP, lower MBP, higher MPAP/MBP ratio, lower arterial pH, higher paCO2, lower paO2, lower post‐ductal pulsatile SaO2 and lower plasmatic ir‐ET ratios compared to untreated controls (P<0.0001).
Treated CDH lambs (n=8) showed a higher MBP (P<0.0001), lower MPAP / MBP ratio (P<0.0001), higher arterial pH (P<0.0001), lower paCO2 (P<0.0001), higher paO2 (P=0.0228), higher post‐ductal pulsatile SaO2 (P=0.0016) and lower plasmatic ir‐ET ratios (P=0.0247) when compared to untreated CDH lambs.
These observations revealed that, although acute perinatal treatment with a selective non‐peptidic ETA‐R antagonist had some adverse effects in controls, it attenuated the progressive cardiopulmonary deterioration that occurred after birth in CDH lambs.

British Journal of Pharmacology (2001) 134, 1679–1688; doi:10.1038/sj.bjp.0704424
Haeme oxygenase‐1 and cardiac anaphylaxis
Authors: Ndisang Joseph Fomusi , Wang Rui , Vannacci Alfredo , Marzocca Cosimo , Fantappiè Ornella , Mazzanti Roberto , Mannaioni Pier Francesco , Masini Emanuela 
Published: January 2005

Haeme oxygenase (HO) is an enzyme mainly localized in the smooth endoplasmic reticulum and involved in haeme degradation and in the generation of carbon monoxide (CO). Here we investigate (1) whether the inducible isoform of HO (HO‐1) is expressed in the isolated heart of the guinea‐pig and (2) the functional significance of HO‐1 on the response to antigen in isolated hearts taken from actively sensitized guinea‐pigs.
Both the HO‐1 expression and activity are consistently increased in hearts from guinea‐pigs pretreated with hemin, an HO‐1 inducer (4 mg kg−1 i.p., 18 h before antigen challenge). The administration of the HO‐1 inhibitor zinc‐protoporphyrin IX (ZnPP‐IX, 50 μmol kg−1, i.p., 6 h before hemin) abolished the increase of both the HO‐1 expression and activity.
In vitro challenge with the specific antigen of hearts from actively sensitized animals evokes a positive inotropic and chronotropic effect, a coronary constriction followed by dilation and an increase in the amount of histamine in the perfusates. In hearts from hemin‐pretreated animals, antigen challenge did not modify the heart rate and the force of contraction; the coronary outflow was significantly increased and a diminution of the release of histamine was observed. The patterns of cardiac anaphylaxis were fully restored in hearts from animals treated with ZnPP‐IX 6 h before hemin.
In isolated hearts perfused with a Tyrode solution gassed with 100% CO for 5 min and successively reoxygenated, the response to antigen was similar to that observed in hearts from hemin‐pretreated animals.
Pretreatment with hemin or the exposure to exogenous CO were linked to an increase in cardiac cyclic GMP levels and to a decrease of tissue Ca2+ levels.
The study demonstrates that overexpression of HO‐1 inhibits cardiac anaphylaxis through the generation of CO which, in turn, decreases the release of histamine through a cyclic GMP‐ and Ca2+‐dependent mechanism.

British Journal of Pharmacology (2001) 134, 1689–1696; doi:10.1038/sj.bjp.0704427
[Gly14]‐Humanin improved the learning and memory impairment induced by scopolamine in vivo
Authors: Mamiya Takayoshi , Ukai Makoto 
Published: January 2005

Humanin is a very recently discovered 24 amino acid linear polypeptide, which protects against cell death induced by either familial Alzheimer's disease mutant of amyloid precursor protein, presenilin‐1 or presenilin‐2 in vitro. However, it has remained uncertain whether humanin is a useful drug for the animal model of learning and memory deficit. In this study, we evaluated the effects of [Gly14]‐humanin, a more potent humanin analogue, on the scopolamine HBr (1 mg kg−1 s.c.)‐induced impairment of spontaneous alternation behaviour in the Y‐maze, an index of short‐term memory in mice. [Gly14]‐Humanin (1000 pmol 5 μl−1 i.c.v.) reversed the impairment without affecting the number of arm entries. These results suggest that (I) [Gly14]‐humanin is a beneficial drug for the impairment of learning and memory and (II) it modulates the learning and memory function mediated via cholinergic systems in mice.British Journal of Pharmacology (2001) 134, 1597–1599; doi:10.1038/sj.bjp.0704429
Evidence for the presence of A1 adenosine receptors in the aorta of spontaneously hypertensive rats
Authors: Fahim Mohammed , Mustafa Syed Jamal 
Published: January 2005

Isolated aortic rings (endothelium‐intact and ‐denuded) from spontaneously hypertensive (SHR) and Wistar‐Kyoto (WKY) rats were used in this study to examine the vasoactive effects of various adenosine analogues.
In phenylephrine contracted aortic rings, concentration‐response curves were constructed by cumulative additions (10−11 – 10−5 M) of (2S)‐N6‐[2‐endo‐Norbornyl] adenosine (ENBA), N6‐cyclopentyladenosine (CPA), R‐N6‐(2‐phenylisopropyl) adenosine (R‐PIA), 2‐p‐(‐2‐carboxyethyl) phenethylamino‐5′‐N‐thylcarboxamido adenosine (CGS‐21680).
A non‐specific adenosine receptor agonist 2‐chloroadenosine (CAD) resulted in biphasic response with a small contraction at lower concentrations (10−9 – 10−8 M) followed by a significant relaxation at higher concentration in endothelium‐intact SHR tissues, suggesting presence of both A1 and A2 adenosine receptors in SHR aorta. However, only relaxation was observed in WKY.
Contractile response in SHR had the following rank order of potency: ENBA>CPA>R‐PIA>CAD. The relaxation response in SHR and WKY had the following rank order of potency: CGS 21680>CAD>R‐PIA>CPA>ENBA.
Removal of endothelium abolished the adenosine analogue induced contractions in SHR aorta and attenuated the vasorelaxation responses in the WKY and SHR.
The contractile response in SHR was abolished by A1 adenosine receptor antagonist N6‐endonorbornan‐2‐yl‐9‐methyladenine (N‐0861). A2 adenosine receptor antagonist, 3,7‐dimethyl‐1‐proparglyxanthine (DMPX) did not affect the contraction response of adenosine analogues.
Endothelium‐dependent contractions elicited by A1 receptor agonists were blocked by indomethacin and by free radical scavengers.
These data suggest that the contractile response to adenosine analogues in SHR aorta is probably mediated by free radicals which are generated through the increased cyclo‐oxygenase activity occurring in the vascular endothelium of SHR but not the WKY rats.

British Journal of Pharmacology (2001) 134, 1760–1766; doi:10.1038/sj.bjp.0704433
A study of the mechanisms involved in the neurotoxic action of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) on dopamine neurones in mouse brain
Authors: Colado M Isabel , Camarero Jorge , Mechan Annis O , Sanchez Veronica , Esteban Blanca , Elliott J Martin , Green A Richard 
Published: January 2005

Administration of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) to mice produces acute hyperthermia and long‐term degeneration of striatal dopamine nerve terminals. Attenuation of the hyperthermia decreases the neurodegeneration. We have investigated the mechanisms involved in producing the neurotoxic loss of striatal dopamine.
MDMA produced a dose‐dependent loss in striatal dopamine concentration 7 days later with 3 doses of 25 mg kg−1 (3 h apart) producing a 70% loss.
Pretreatment 30 min before each MDMA dose with either of the N‐methyl‐D‐aspartate antagonists AR‐R15896AR (20, 5, 5 mg kg−1) or MK‐801 (0.5 mg kg−1×3) failed to provide neuroprotection.
Pretreatment with clomethiazole (50 mg kg−1×3) was similarly ineffective in protecting against MDMA‐induced dopamine loss.
The free radical trapping compound PBN (150 mg kg−1×3) was neuroprotective, but it proved impossible to separate neuroprotection from a hypothermic effect on body temperature.
Pretreatment with the nitric oxide synthase (NOS) inhibitor 7‐NI (50 mg kg−1×3) produced neuroprotection, but also significant hypothermia. Two other NOS inhibitors, S‐methyl‐L‐thiocitrulline (10 mg kg−1×3) and AR‐R17477AR (5 mg kg−1×3), provided significant neuroprotection and had little effect on MDMA‐induced hyperthermia.
MDMA (20 mg kg−1) increased 2,3‐dihydroxybenzoic acid formation from salicylic acid perfused through a microdialysis tube implanted in the striatum, indicating increased free radical formation. This increase was prevented by AR‐R17477AR administration. Since AR‐R17477AR was also found to have no radical trapping activity this result suggests that MDMA‐induced neurotoxicity results from MDMA or dopamine metabolites producing radicals that combine with NO to form tissue‐damaging peroxynitrites.

British Journal of Pharmacology (2001) 134, 1711–1723; doi:10.1038/sj.bjp.0704435
Comparison of the contractile and calcium‐increasing properties of platelet‐activating factor and endothelin‐1 in the rat mesenteric artery and vein
Authors: Claing Audrey , Shbaklo Hadia , Plante Mirco , Bkaily Ghassan , D'Orléans‐Juste Pedro 
Published: January 2005

In the present study, the properties of endothelin‐1 (ET‐1) and platelet‐activating factor (PAF) in inducing contraction and increased intracellular‐free calcium level in rat mesenteric arteries and veins were studied. Furthermore, measurements of cytosolic ([Ca]c) and nuclear ([Ca]n) Ca2+ were performed by confocal microscopy.
PAF, at a concentration of 1 μM, and the selective ETB agonists, IRL‐1620 and sarafotoxin S6C (100 nM), induced a marked constriction and increase in [Ca]i in the mesenteric vein but not in the artery. On the other hand, endothelin‐1 (1–100 nM) induced a significant concentration‐dependent nifedipine‐insensitive increase in tension and [Ca]i in both arteries and veins.
Those responses to endothelin‐1 were significantly reduced by the ETA receptor antagonist, BQ‐123 (10−6 M), on both types of vessels, whereas the selective ETB receptor antagonist, BQ‐788, inhibited only the venous responses. The mixed ETA/ETB receptor antagonist, SB 209670, reduced the ET‐1‐induced venous responses to the same level of that found in presence of BQ‐123 or BQ‐788. However, concomitant applications of BQ‐123 and BQ‐788 reduced the vasoconstriction below to that induced by ETA or ETB blockade without further affecting [Ca]i.
PAF and the selective ETB agonists IRL‐1620, induced a sustained increase of [Ca]c and [Ca]n solely in venous cells and ET‐1 in both arterial and venous smooth muscle cells.
Thus, PAF increases total intracellular calcium concentration and tension on the smooth muscle cells from venous origin only. Furthermore, ET‐1‐induced vasoactive as well as [Ca]i and [Ca]n increasing effects are mediated by distinct receptors on venous and arterial smooth muscles.

British Journal of Pharmacology (2002) 135, 433–443; doi:10.1038/sj.bjp.0704441
Comparison of the affinity of β‐blockers for two states of the β1‐adrenoceptor in ferret ventricular myocardium
Authors: Lowe Martin D , Lynham James A , Grace Andrew A , Kaumann Alberto J 
Published: January 2005

We compared the potency of 11 clinically available β‐blockers as antagonists of the positive inotropic effects of (−)‐isoprenaline and CGP12177 on ferret ventricular myocardium.
(−)‐CGP12177, (−)‐pindolol and (−)‐alprenolol were non‐conventional partial agonists with intrinsic activity of 0.7, 0.2 and 0.1 respectively.
All β‐blockers antagonized in a concentration‐dependent and surmountable manner the positive inotropic effects of both (−)‐isoprenaline and CGP12177. The potency of each β‐blocker was consistently higher against (−)‐isoprenaline than against CGP12177. Two groups of β‐blockers were identified. In one group the difference between the pKB values of blockade against (−)‐isoprenaline and CGP12177 was 1.1–1.6 log units ((−)‐alprenolol, (−)‐pindolol, (−)‐bupranolol, nadolol and carvedilol). In the other group the pKB difference was of 2.1–3.0 log units ((−)‐atenolol, metoprolol, bisoprolol, sotalol, (−)‐propranolol and (−)‐timolol).
The β‐blockers competed with (−)‐[125I]‐cyanopindolol for binding to ventricular β1‐adrenoceptors. The binding affinities correlated with the corresponding blocking potencies against (−)‐isoprenaline. On average the pKi values were 0.5 log units smaller than the pKB values against (−)‐isoprenaline but 1.6 log units greater than the pKB values against CGP12177.
In ferret ventricle the effects of (−)‐isoprenaline appear to be antagonized by β‐blockers through the state of the β1‐adrenoceptor for which (−)‐[125I]‐cyanopindolol and β‐blockers have high affinity. The cardiostimulant effects of CGP12177 appear to be mediated through a low‐affinity state of the β1‐adrenoceptor for which β‐blockers have low affinity.

British Journal of Pharmacology (2002) 135, 451–461; doi:10.1038/sj.bjp.0704450
Redox/ROS regulation of lipopolysaccharide‐induced mitogen‐activated protein kinase (MAPK) activation and MAPK‐mediated TNF‐α biosynthesis
Authors: Haddad J J , Land S C 
Published: January 2005

Redox and ROS regulation of MAPK‐mediated TNF‐α biosynthesis is not well characterized. It was hypothesized that the involvement of the MAPK pathway in regulating LPS‐mediated TNF‐α secretion is redox‐dependent, NF‐κB‐sensitive and attenuated by N‐acetyl‐L‐cysteine (NAC) and other antioxidants.
In alveolar epithelial cells, LPS induced a time‐ and dose‐dependent phosphorylation of MAPKp38. This was associated with the activation of MAPK‐activated protein kinase, which phosphorylated the small heat‐shock protein, Hsp27.
MAPKp38 inhibition (SB‐203580) abrogated LPS‐induced TNF‐α production. MAPKERK blockade (PD‐98059) attenuated TNF‐α secretion, an effect synergistically amplified in the presence of SB‐203580.
Regulation of NF‐κB by selective inhibitors revealed that this pathway is partially involved in regulating LPS‐mediated TNF‐α secretion. Whereas the proteasome inhibitor, MG‐132, had no effect on LPS‐mediated TNF‐α production, CAPE, sulfasalazine and SN‐50, a cell‐permeant NF‐κB inhibitor, attenuated but did not abrogate TNF‐α biosynthesis.
LPS up‐regulated ROS, an effect abrogated by 4′‐hydroxy‐3′‐methoxy‐acetophenone and NAC, which reduced TNF‐α secretion, induced the accumulation of GSH, reduced the concentration of GSSG, and blockaded the phosphorylation/activation of MAPKp38 pathway.
ROS induced MAPKp38 phosphorylation and selective antioxidants, including the permeant GSH precursor, γ‐GCE, reduced ROS‐dependent MAPKp38 phosphorylation.
These results indicate that the MAPK pathway and MAPK‐mediated regulation of TNF‐α production is redox‐dependent, GSH‐mediated and requires, at least in part, a NF‐κB/ROS‐sensitive mechanism.

British Journal of Pharmacology (2002) 135, 520–536; doi:10.1038/sj.bjp.0704467
Pharmacological profiles of a novel opioid receptor‐like1 (ORL1) receptor antagonist, JTC‐801
Authors: Yamada Hideki , Nakamoto Hiromitsu , Suzuki Yasunori , Ito Takao , Aisaka Kazuo 
Published: January 2005

Pharmacological effects of a novel opioid receptor‐like1 (ORL1) receptor antagonist, [N‐(4‐amino‐2‐methylquinolin‐6‐yl)‐2‐(4‐ethylphenoxymethyl) benzamide monohydrochloride] (JTC‐801), were examined in in vitro and in vivo.
JTC‐801 inhibited the binding of [3H]‐nociceptin to human ORL1 receptors expressed in HeLa cells with a Ki value of 44.5 nM.
JTC‐801 completely antagonized the suppression of nociceptin on forskolin‐induced accumulation of cyclic AMP (IC50 : 2.58 μM) using ORL1 receptor expressing HeLa cells in vitro.
In in vivo, when given intravenously at dosages of 0.01 mg kg−1 and above, or orally at dosages 1 mg kg−1 and above, JTC‐801 antagonized the nociceptin‐induced allodynia in mice.
Effects of JTC‐801 on various nociceptive models were examined. In mouse hot‐plate test, JTC‐801 prolonged escape response latency (ERL) to exposed heat stimulus with minimum effective doses (MED) of 0.01 mg kg−1 by i.v. or 1 mg kg−1 by p.o.
In the rat formalin test, JTC‐801 reduced both the first and second phases of the nociceptive response with MED of 0.01 mg kg−1 by i.v. administration or 1 mg kg−1 by p.o. administration. This anti‐nociceptive action of JTC‐801 was not inhibited by naloxone (10 mg kg−1, s.c.).
We have demonstrated that JTC‐801 antagonizes the ORL1 receptor response, and that JTC‐801 has efficacious and potent anti‐nociceptive effects in acute pain animal models not only by intravenous injection but also oral administration. These results suggest that JTC‐801 may represent a new class of analgesics.

British Journal of Pharmacology (2002) 135, 323–332; doi:10.1038/sj.bjp.0704478
Behavioural and biochemical evidence for interactions between Δ9‐tetrahydrocannabinol and nicotine
Authors: Valjent Emmanuel , Mitchell Jennifer M , Besson Marie‐Jo , Caboche Jocelyne , Maldonado Rafael 
Published: January 2005

Behavioural and pharmacological effects of Δ9‐tetrahydrocannabinol (THC) and nicotine are well known. However, the possible interactions between these two drugs of abuse remain unclear in spite of the current association of cannabis and tobacco in humans.
The present study was designed to analyse the consequences of nicotine administration on THC‐induced acute behavioural and biochemical responses, tolerance and physical dependence.
Nicotine strongly facilitated hypothermia, antinociception and hypolocomotion induced by the acute administration of THC. Furthermore, the co‐administration of sub‐threshold doses of THC and nicotine produced an anxiolytic‐like response in the light–dark box and in the open‐field test as well as a significant conditioned place preference. Animals co‐treated with nicotine and THC displayed an attenuation in THC tolerance and an enhancement in the somatic expression of cannabinoid antagonist‐precipitated THC withdrawal.
THC and nicotine administration induced c‐Fos expression in several brain structures. Co‐administration of both compounds enhanced c‐Fos expression in the shell of the nucleus accumbens, central and basolateral nucleus of the amygdala, dorso‐lateral bed nucleus of the stria terminalis, cingular and piriform cortex, and paraventricular nucleus of the hypothalamus.
These results clearly demonstrate the existence of a functional interaction between THC and nicotine. The facilitation of THC‐induced acute pharmacological and biochemical responses, tolerance and physical dependence by nicotine could play an important role in the development of addictive processes.

British Journal of Pharmacology (2002) 135, 564–578; doi:10.1038/sj.bjp.0704479