bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of anion secretion in Calu‐3 human airway epithelial cells by 7,8‐benzoquinoline
Authors: Cuthbert A W , MacVinish L J 
Published: September 2003

Cultured epithelial monolayers of Calu‐3 human airway cells were used to measure anion secretion in response to a number of phenanthrolines and benzoquinolines, using short‐circuit current measurements. Calu‐3 cells are derived from serous cells of submucosal glands of the airways and are a target for conditions in which muco‐ciliary clearance is compromised.
Compounds studied were 5,6‐benzoquinoline, 5‐chloro‐1,10‐phenanthroline, 7,8‐benzoquinoline, 5‐nitro‐1,10‐phenanthroline, benzo[c]cinnoline and 1,10‐phenanthroline, which gave EC50 values of 34, 48, 123, 235, 192 and 217 μM, respectively. Of these, 7,8‐benzoquinoline was chosen for further detailed study. Concentration–response relationships for all the compounds had Hill slopes greater than 1.
Permeabilisation of the apical surface of epithelia with nystatin in the presence of an apical to basolateral potassium ion gradient reduced the EC50 for 7,8‐benzoquinoline to 31	μM and altered the Hill slope to close to 1.
Using apically permeabilised epithelia it was shown that 7,8‐benzoquinoline activates an intermediate‐conductance calcium‐sensitive potassium channel (KCNN4) and a cAMP‐sensitive potassium channel (KCNQ1/KCNE3) in the basolateral epithelial membranes.
7,8‐Benzoquinoline was shown to increase chloride conductance of apical epithelial membranes, presumed to be by activation of the cystic fibrosis transmembrane conductance regulator.
7,8‐Benzoquinoline had a minor effect on cAMP accumulation in Calu‐3 cells, probably by inhibition of phosphodiesterase, which may contribute to its effect on CFTR‐ and cAMP‐sensitive potassium channels.
The usefulness of these novel actions in promoting secretion in airway submucosal glands is discussed.

British Journal of Pharmacology (2003) 140, 81–90. doi:10.1038/sj.bjp.0705403
Galanin and neuropeptide Y reduce cholinergic transmission in the heart of the anaesthetised mouse
Authors: Smith‐White Margaret A , Iismaa Tiina P , Potter Erica K 
Published: September 2003

This study investigated the effects of galanin (GAL) on inhibition of cholinergic (vagal) activity in the mouse heart using control galanin knockout (GAL‐KO) and GAL‐1R receptor knockout (GAL‐1R‐KO) mice.
In pentobarbitone anaesthetised mice, supramaximal stimulation every 30 s of the vagus nerve innervating the heart, increased pulse interval (PI) by approximately 50 ms or decreased heart rate by approximately 100 beats min−1. This response was attenuated by intravenous administration of GAL (dose ranged from 0.8 to 13 nmol kg−1) in a dose‐dependent manner.
In GAL‐KO mice, the magnitude of inhibition of the increase in PI (ΔPI) following a bolus dose of GAL was not different from the ΔPI in control mice, and neuropeptide Y (NPY), previously shown to attenuate vagal inhibitory activity in mice, evoked a comparative inhibition of ΔPI in GAL‐KO mice.
In GAL‐1R‐KO mice, an intravenous, bolus injection of GAL had no inhibitory effect on vagal activity.
In control mice, stimulation of the sympathetic nerve at 25 V, 10 Hz for 2 min in the presence of propranolol evoked a long‐lasting attenuation of ΔPI. The inhibitory effect on ΔPI was reduced in the presence of the NPY Y2 antagonist, BIIE0246.
In GAL‐1R‐KO mice, stimulation of the sympathetic nerve in the presence of propranolol evoked an attenuation of ΔPI not significantly different from the response in control mice in the presence of BIIE0246. Following administration of BIIE0246 in GAL‐1R‐KO mice, the inhibition of ΔPI that followed stimulation of the sympathetic nerve was abolished.
These findings support the view that the nerve terminals of parasympathetic neurons in the mouse heart possess both GAL‐1R and NPY Y2 receptors which, when activated, reduce acetylcholine release.

British Journal of Pharmacology (2003) 140, 170–178. doi:10.1038/sj.bjp.0705404
Inhibition of leukotriene synthesis with MK‐886 prevents a rise in blood pressure and reduces noradrenaline‐evoked contraction in L‐NAME‐treated rats
Authors: Stanke‐Labesque Françoise , Hardy Gaëlle , Caron Françoise , Cracowski Jean‐Luc , Bessard Germain 
Published: September 2003

Long‐term treatment of rats with Nω‐nitro‐L‐arginine methyl ester (L‐NAME) induces hypertension associated with inflammatory and vascular changes. Leukotrienes are proinflammatory vasoactive products that are suspected to be involved in the pathogenesis of hypertension. We investigated, in rats chronically treated with L‐NAME, the involvement of leukotrienes in the in vivo regulation of blood pressure and the in vitro contraction elicited by noradrenaline in isolated aorta.
Rats were randomly assigned to four groups and orally treated for 3 weeks with L‐NAME (1 mg ml−1), L‐NAME (1 mg ml−1) plus the leukotriene biosynthesis inhibitor MK‐886 (0.1 mg ml−1), MK‐886 (0.1 mg ml−1) alone or vehicle (Methocel, 0.1%). All the drugs were added to the drinking fluid.
The mean arterial blood pressure (MABP) increased significantly in L‐NAME‐treated rats (173.3±9.4 mmHg (n=25)) vs Methocel‐treated rats (110.7±4.8 mmHg (n=11), P<0.001). Chronic treatment with MK‐886 prevented this rise in MABP.
Aortic rings with or without endothelium were suspended in organ baths for recording isometric changes in response to noradrenaline. Pretreatment with either MK‐886 (10 μM), the CysLT1 receptor antagonist MK571 (1 μM) or the dual CysLT1/CysLT2 receptor antagonist BAY‐u9773 (0.1 μM) reduced (P<0.05) noradrenaline‐induced contractions in intact aortic rings from L‐NAME‐treated rats only.
Noradrenaline (0.3 μM) induced a two‐fold increase in cysteinyl leukotriene (CysLT) release (measured by enzyme immunoassay) in intact aortic rings from L‐NAME‐treated rats only.
These data suggested (1) a role for the 5‐lipoxygenase pathway in the regulation of blood pressure in L‐NAME‐treated rats and (2) the involvement of endothelial CysLTs in noradrenaline‐induced contraction in aorta from L‐NAME‐treated rats.

British Journal of Pharmacology (2003) 140, 186–194. doi:10.1038/sj.bjp.0705405
Dexamethasone improves vascular hyporeactivity induced by LPS in vivo by modulating ATP‐sensitive potassium channels activity
Authors: D'Emmanuele Di Villa Bianca R , Lippolis L , Autore G , Popolo A , Marzocco S , Sorrentino L , Pinto A , Sorrentino R 
Published: September 2003

Septic shock represents an important risk factor for patients critically ill. This pathology has been largely demonstrated to be a result of a myriad of events. Glucocorticoids represent the main pharmacological therapy used in this pathology.
Previously we showed that ATP‐sensitive potassium (KATP) channels are involved in delayed vascular hyporeactivity in rats (24 h after Escherichia coli lipopolysaccharide (LPS) injection). In LPS‐treated rats, we observed a significant hyporeactivity to phenylephrine (PE) that was reverted by glybenclamide (GLB), and a significant increase in cromakalim (CRK)‐induced hypotension.
We evaluated the effect of dexamethasone (DEX 8 mg kg−1 i.p.) whether on hyporeactivity to PE or on hyperreactivity to CRK administration, in vivo, in a model of LPS (8 × 106 U kg−1 i.p.)‐induced endotoxemia in urethane‐anaesthetised rats.
DEX treatment significantly reduced, in a time‐dependent manner, the increased hypotensive effect induced by CRK in LPS‐treated rats. This effect was significantly (P<0.05) reverted by the glucocorticoid receptor antagonist RU38486 (6.6 mg kg−1 i.p.).
GLB‐induced hypertension (40 mg kg−1 i.p.), in LPS‐treated rats, was significantly inhibited by DEX if administered at the same time of LPS.
Simultaneous administration of DEX and LPS to rats completely abolished the hyporeactivity to PE observed after 24 h from LPS injection.
In conclusion, our results suggest that the beneficial effect of DEX in endotoxemia could be ascribed, at least in part, to its ability to interfere with KATP channel activation induced by LPS. This interaction may explain the improvement of vascular reactivity to PE, mediated by DEX, in LPS‐treated rats, highlighting a new pharmacological activity to the well‐known anti‐inflammatory properties of glucocorticoids.

British Journal of Pharmacology (2003) 140, 91–96. doi:10.1038/sj.bjp.0705406
Role of L‐citrulline transport in nitric oxide synthesis in rat aortic smooth muscle cells activated with LPS and interferon‐γ
Authors: Wileman Samantha M , Mann Giovanni E , Pearson Jeremy D , Baydoun Anwar R 
Published: September 2003

L‐citrulline, a coproduct of nitric oxide synthase (NOS)‐catalysed metabolism of L‐arginine to nitric oxide (NO), is an important intermediate of the urea cycle and a precursor for L‐arginine biosynthesis in vascular cells.
In the present study, we have examined the characteristics of L‐citrulline transport, regulation by lipopolysaccharide (LPS) and interferon‐γ (IFN‐γ) and the ability of L‐citrulline to sustain NO synthesis in rat cultured aortic smooth muscle cells.
L‐citrulline transport was saturable with an apparent Km=1.6±0.2 mM and Vmax=5.9±0.6 pmol μg−1 protein min−1. Transport was pH‐insensitive, partially Na+‐dependent and markedly inhibited by substrates selective for amino‐acid transport systems L and N but not by L‐arginine or substrates for systems A, ASC, xc‐ or XAG. Moreover, transport was not altered in cells treated with LPS (100 μg ml−1) and IFN‐γ (50 U ml−1) for 0–24 h.
Unlike L‐arginine, L‐citrulline could not sustain maximal NO production in cells expressing iNOS.
Our findings provide the first evidence in vascular smooth muscle cells that L‐citrulline transport is mediated via a low‐affinity carrier with characteristics resembling systems L and N. Moreover, in L‐arginine‐deprived rat aortic smooth muscle cells, L‐citrulline cannot sustain maximal NO release via iNOS.

British Journal of Pharmacology (2003) 140, 179–185. doi:10.1038/sj.bjp.0705407
Capacitative calcium entry as a pulmonary specific vasoconstrictor mechanism in small muscular arteries of the rat
Authors: Snetkov Vladimir A , Aaronson Philip I , Ward Jeremy P T , Knock Gregory A , Robertson Tom P 
Published: September 2003

The effect of induction of capacitative Ca2+ entry (CCE) upon tone in small (i.d. 200–500 μm) intrapulmonary (IPA), mesenteric (MA), renal (RA), femoral (FA), and coronary arteries (CA) of the rat was examined.
Following incubation of IPA with 100 nM thapsigargin (Thg) in Ca2+‐free physiological salt solution (PSS), a sustained contraction was observed upon reintroduction of 1.8 mM Ca2+, which was unaffected by either diltiazem (10 μM) or the reverse mode Na+/Ca2+ antiport inhibitor KB‐R7943 (10 μM). An identical protocol failed to elicit contraction in MA, RA, or CA, while a small transient contraction was sometimes observed in FA.
The effect of this protocol on the intracellular Ca2+ concentration ([Ca2+]i) was assessed using Fura PE3‐loaded IPA, MA, and FA. Reintroduction of Ca2+ into the bath solution following Thg treatment in Ca2+‐free PSS caused a large, rapid, and sustained increase in [Ca2+]i in all the three types of artery.
100 nM Thg induced a slowly developing noisy inward current in smooth muscle cells (SMC) isolated from IPA, which was due to an increase in the activity of single channels with a conductance of ∼30 pS. The current had a reversal potential near 0 mV in normal PSS, and persisted when Ca2+‐dependent K+ and Cl− currents were blocked; it was greatly inhibited by 1 μM La3+, 1 μM Gd3+, and the IP3 receptor antagonist 2‐APB (75 μM), and by replacement of extracellular cations by NMDG+.
In conclusion, depletion of intracellular Ca2+ stores with Thg caused capacitative Ca2+ entry in rat small muscular IPA, MA, and FA. However, a corresponding contraction was observed only in IPA. CCE in IPA was associated with the development of a small La3+‐ and Gd3+‐sensitive current, and an increased Mn2+ quench of Fura PE‐3 fluorescence. These results suggest that although CCE occurs in a number of types of small arteries, its coupling to contraction appears to be of particular importance in pulmonary arteries.

British Journal of Pharmacology (2003) 140, 97–106. doi:10.1038/sj.bjp.0705408
17β‐Estradiol regulates the expression of endothelin receptor type B in the heart
Authors: Nuedling Simone , Eickels Martin van , Alléra Axel , Doevendans Pieter , Meyer Rainer , Vetter Hans , Grohé Christian 
Published: September 2003

Little is known about the interaction of 17β‐estradiol (E2) and the vasoactive endothelin system in the heart. Endothelin signaling is activated in a failing heart and may contribute to myocardial dysfunction and remodeling. Therefore, we investigated the regulation of proteins of the endothelin system (ppET‐1, ECE and ETA‐R and ETB‐R) in the hearts of female spontaneously hypertensive rats (SHR) with respect to E2.
Relative expression levels of the respective cardiac mRNA obtained from sham‐operated, ovariectomized and ovariectomized E2‐substituted SHR were quantified by real‐time PCR. Ovariectomy led to a significant upregulation of the ETB‐R mRNA (2.6±0.8‐fold) in the left ventricular myocardium, which was not attendant with an alteration of ETA‐R, ECE and ppET‐1 mRNA expression.
An upregulation of the relative expression level of ETB‐R protein due to ovariectomy was also demonstrated by radioligand binding assay.
Upregulation of both ETB‐R mRNA and ETB‐R protein expression was completely inhibited by E2 replacement.
To confirm these results in in vitro experiments, we quantified the mRNA of ET‐R subtypes from isolated cardiomyocytes in the presence and absence of E2 (10−8 M, 24 h). Our data showed a markedly downregulated level of ETB‐R mRNA in cardiomyocytes stimulated with E2. ETB‐R downregulation was not attendant with the alteration of ETA‐R, ECE and ppET‐1 mRNA expression.
Taken together, these data demonstrate that estrogen regulates the expression of ETB‐R in rat ventricular myocardium in vivo and in vitro. These observations may help to understand gender‐based differences found in cardiovascular disease.

British Journal of Pharmacology (2003) 140, 195–201. doi:10.1038/sj.bjp.0705409
Aminoguanidine prevents age‐related aortic stiffening in Fisher 344 rats: aortic impedance analysis
Authors: Chang Kuo‐Chu , Hsu Kwan‐Lih , Peng Ying‐I , Lee Fong‐Chu , Tseng Yung‐Zu 
Published: September 2003

We determined the effects of long‐term treatment with aminoguanidine (AG), an inhibitor of advanced glycation end products, on the mechanical properties of the arterial system in aged Fisher 344 rats, using the aortic impedance analysis.
Normotensive rats were treated from 18 to 24 months with AG (1 g/l−1 in drinking water) and compared with a control group. Pulsatile aortic pressure and flow signals were measured and then subjected to Fourier transformation for the analysis of aortic input impedance. Wave transit time was determined using the impulse response function of the filtered aortic input impedance spectra.
With no alteration in body weight, rats treated with AG had decreased heart weight compared with the aged untreated controls.
AG did not affect arterial blood pressure; however, the age‐related increase in total peripheral resistance was prevented by AG.
AG retarded the age‐related decline in aortic distensibility, as evidenced by a reduction of 25.2% in aortic characteristic impedance and an increase of 28.1% in wave transit time.
Meanwhile, the increase in wave reflection factor in aging rats was reduced by 32.3% by AG. Both the increased wave transit time and the decreased wave reflection factor suggest that AG may prevent the age‐related augmentation in systolic loading condition for the left ventricle coupled to the arterial system.
We conclude that long‐term treatment with AG may impart significant protection against aortic stiffening and cardiac hypertrophy in aged Fisher 344 rats.

British Journal of Pharmacology (2003) 140, 107–114. doi:10.1038/sj.bjp.0705410
2′, 3′‐O‐(2,4,6,Trinitrophenyl)‐ATP and A‐317491 are competitive antagonists at a slowly desensitizing chimeric human P2X3 receptor
Authors: Neelands Torben R , Burgard Edward C , Uchic Marie E , McDonald Heath A , Niforatos Wende , Faltynek Connie R , Lynch Kevin J , Jarvis Michael F 
Published: September 2003

Rapid desensitization of ligand‐gated ion channel receptors can alter the apparent activity of receptor modulators, as well as make detection of fast‐channel activation difficult. Investigation of the antagonist pharmacology of ATP‐sensitive homomeric P2X3 receptors is limited by agonist‐evoked fast‐desensitization kinetics.
In the present studies, chimeric receptors were created using the coding sequence for the N‐terminus and the first transmembrane domain of either the nondesensitizing human P2X2a or fast‐desensitizing P2X3 receptor joined to the sequence encoding the extracellular loop, second transmembrane domain, and C‐terminus of the other receptor (designated P2X2–3 and P2X3–2, respectively). These clones were stably transfected into 1321N1 astrocytoma cells for biophysical and pharmacological experiments using both electrophysiological and calcium‐imaging methods.
Chimeric P2X2–3 and P2X3–2 receptors were inwardly rectifying and agonist responses showed desensitization properties similar to the wild‐type human P2X2a and P2X3 receptors, respectively.
The P2X2–3 chimera displayed an agonist pharmacological profile similar to the P2X3 wild‐type receptor being activated by low concentrations of both ATP and α,β‐meATP. In contrast, the P2X3–2 chimera had markedly reduced sensitivity to both agonists.
The P2X3 receptor antagonists TNP‐ATP and A‐317491 were shown to be potent, competitive antagonists of the P2X2–3 chimera (Ki=2.2 and 52.1 nM, respectively), supporting the hypothesis that rapid receptor desensitization can mask the competitive antagonism of wild‐type homomeric P2X3 receptors.

British Journal of Pharmacology (2003) 140, 202–210. doi:10.1038/sj.bjp.0705411
Role of cannabinoid CB1 receptors and tumor necrosis factor‐α in the gut and systemic anti‐inflammatory activity of SR 141716 (Rimonabant) in rodents
Authors: Croci Tiziano , Landi Marco , Galzin Anne‐Marie , Marini Pietro 
Published: September 2003

We investigated the effect of the cannabinoid CB1 receptor antagonist, SR 141716, on indomethacin‐induced small intestine inflammation and Escherichia coli lipopolysaccharide (LPS)‐induced plasma TNF‐α (TNF) release in comparison to the cannabinoid CB2 receptor antagonist, SR 144528, in rodents.
In rats, indomethacin induced significant ulcer formation in the small intestine; this was accompanied by an increase in tissue TNF levels and myeloperoxidase (MPO) activity. SR 141716 prevented the ulcers and the rise in TNF levels (ID50 3.3, 0.4 mg kg−1, respectively) and MPO activity. SR 144528 prevented intestinal ulcers only.
The effect of SR 141716 against indomethacin‐induced ulcers and increase of plasma TNF levels after LPS was also studied in wild‐type and CB1 receptor knockout mice. Indomethacin induced intestinal ulcers in mice, but not tissue TNF production and MPO activity. SR 141716 reduced the ulcers to a similar extent in wild‐type and CB1 receptor knockout mice. In rats and wild‐type mice, but not in CB1 receptor knockout mice, SR 141716 inhibited the LPS‐induced increase in plasma TNF levels.
These findings provide evidence that the indomethacin model of intestinal lesions differs in rat and mouse and support the existence of several mechanisms for the antiulcer activity of SR141716, the most important involving the inhibition of TNF production. The potent anti‐inflammatory activity of SR141716 in rodents indicated its potential therapeutic interest in chronic immune‐inflammatory diseases.

British Journal of Pharmacology (2003) 140, 115–122. doi:10.1038/sj.bjp.0705412
Dexamethasone enhances interaction of endogenous Annexin 1 with L‐selectin and triggers shedding of L‐selectin in the monocytic cell line U‐937
Authors: De Coupade Catherine , Solito Egle , Levine Jon D 
Published: September 2003

L‐selectin, constitutively expressed by leukocytes, is involved in the initial binding of leukocytes to activated endothelium. Anti‐inflammatory drugs like glucocorticoids can induce shedding of L‐selectin, but the mechanism is still unknown. Annexin 1, a protein whose synthesis and externalization/secretion are induced during the inflammatory response, has been proposed as a mediator of the anti‐inflammatory actions of glucocorticoids.
The monocytic cell line U‐937 strongly expresses Annexin 1 after 24 h of phorbol 12‐myristate 13‐acetate (PMA, 1 nM) treatment and externalizes/releases the protein after additional 16 h of dexamethasone (1 μM) treatment.
This study investigated the possible regulation of cell surface L‐selectin shedding by endogenous Annexin 1, and its role in glucocorticoid‐induced L‐selectin shedding in the U‐937 cell line.
PMA‐ and dexamethasone treatment‐induced L‐selectin shedding was potentially mediated by Annexin 1, since neutralizing antibodies against Annexin 1 reduced dexamethasone‐ and Annexin 1‐induced shedding.
Immunoprecipitation and binding assays provided support for the suggestion that this effect could be mediated by an interaction between externalized Annexin 1 and L‐selectin. Such interaction involved the N‐terminal domain of Annexin 1 and was calcium‐dependent. Confocal microscopy studies demonstrated increased colocalization of Annexin 1 and L‐selectin on the cell surface.
Overall, our study provides new insights into the potential role of endogenous ANXA1 as a mediator of dexamethasone‐induced L‐selectin shedding, which may contribute to the anti‐inflammatory activity of glucocorticoids.

British Journal of Pharmacology (2003) 140, 133–145. doi:10.1038/sj.bjp.0705413
Relationship between peroxisome proliferator‐activated receptors (PPARα and PPARγ) and endothelium‐dependent relaxation in streptozotocin‐induced diabetic rats
Authors: Kanie Noriyasu , Matsumoto Takayuki , Kobayashi Tsuneo , Kamata Katsuo 
Published: September 2003

The aim of the present study was to investigate the causal relationship between peroxisome proliferator‐activated receptor (PPAR) and endothelium‐dependent relaxation in streptozotocin (STZ)‐induced diabetic rats.
Acetylcholine (ACh)‐induced endothelium‐dependent relaxation was significantly weaker in diabetic rats than in age‐matched controls. The decreased relaxation in diabetes was improved by the chronic administration of bezafibrate (30 mg kg−1, p.o., 4 weeks).
The expressions of the mRNAs for PPARα and PPARγ were significantly decreased in STZ‐induced diabetic rats (compared with the controls) and this decrease was restored partially, but not completely, by the chronic administration of bezafibrate.
Superoxide dismutase activity in the aorta was not significantly different between diabetic rats and bezafibrate‐treated diabetic rats.
The expression of the mRNA for the p22phox subunit of NAD(P)H oxidase was significantly higher in diabetics than in controls, but it was lower in bezafibrate‐treated diabetic rats than in nontreated diabetic rats. Although the expression of the mRNA for prepro ET‐1 (ppET‐1) was markedly increased in diabetic rats (compared with controls), this increase was prevented to a significant extent by the chronic administration of bezafibrate.
These results suggest that downregulations of PPARα and PPARγ may lead to an increased expression of ppET‐1 mRNA in diabetic states and this increment may trigger endothelial dysfunction.

British Journal of Pharmacology (2003) 140, 23–32. doi:10.1038/sj.bjp.0705414