bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural requisites of 2‐(p‐chlorophenoxy)propionic acid analogues for activity on native rat skeletal muscle chloride conductance and on heterologously expressed CLC‐1
Authors: Liantonio Antonella , De Luca Annamaria , Pierno Sabata , Didonna Maria Paola , Loiodice Fulvio , Fracchiolla Giuseppe , Tortorella Paolo , Laghezza Antonio , Bonerba Elisabetta , Traverso Sonia , Elia Laura , Picollo Alessandra , Pusch Michael , Camerino Diana Conte 
Published: July 2003

The 2‐(p‐chlorophenoxy)propionic acid (CPP) modulates in a stereoselective manner the macroscopic chloride conductance (gCl), the electrical parameter sustained by the CLC‐1 channel, of skeletal muscle. In order to determine the structural requirements for modulating native gCl and to identify high‐affinity ligands, the effects of newly synthesised CPP analogues have been evaluated on gCl of rat EDL muscle fibres by means of the two‐microelectrode current‐clamp technique.
Each type of the following independent modification of CPP structure led to a three‐ to 10‐fold decrease or to a complete lack of gCl‐blocking activity: replacement of the electron‐attractive chlorine atom of the aromatic ring, substitution of the oxygen atom of the phenoxy group, modification at the chiral centre and substitution of the carboxylic function with a phosphonate one.
The analogues bearing a second chlorophenoxy group on the asymmetric carbon atom showed a significant gCl‐blocking activity. Similar to racemate CPP, the analogue with this group, spaced by an alkyl chain formed by three methylenic groups, blocked gCl by 45% at 100 μM.
These latter derivatives were tested on heterelogously expressed CLC‐1 performing inside‐out patch‐clamp recordings to further define how interaction between drug and channel protein could take place. Depending on the exact chemical nature of modification, these derivatives strongly blocked CLC‐1 with KD values at −140 mV ranging from about 4 to 180 μM.
In conclusion, we identified four molecular determinants pivotal for the interaction with the binding site on muscle CLC‐1 channels: (a) the carboxylic group that confers the optimal acidity and the negative charge; (b) the chlorophenoxy moiety that might interact with a hydrophobic pocket; (c) the chiral centre that allows the proper spatial disposition of the molecule; (d) an additional phenoxy group that remarkably stabilises the binding by interacting with a second hydrophobic pocket.

British Journal of Pharmacology (2003) 139, 1255–1264. doi:10.1038/sj.bjp.0705364
Vascular natriuretic peptide receptor‐linked particulate guanylate cyclases are modulated by nitric oxide–cyclic GMP signalling
Authors: Madhani Melanie , Scotland Ramona S , MacAllister Raymond J , Hobbs Adrian J 
Published: July 2003

The sensitivity of the particulate guanylate cyclase–cyclic guanosine‐3′,5′‐monophosphate (cGMP) system to atrial (ANP) and C‐type (CNP) natriuretic peptides was investigated in aortae and mesenteric small arteries from wild‐type (WT) and endothelial nitric oxide synthase (eNOS) knockout (KO) mice.
ANP and CNP produced concentration‐dependent relaxations of mouse aorta that were significantly attenuated by the natriuretic peptide receptor (NPR)‐A/B antagonist HS‐142‐1 (10−5 M). Both ANP and CNP were more potent in aortae from eNOS KO mice compared to WT.
The potency of ANP and CNP in aortae from WT animals was increased in the presence of the NOS inhibitor, NG‐nitro‐L‐arginine (3 × 10−4 M) and the soluble guanylate cyclase inhibitor 1H‐[1,2,4]oxadiazolol[4,3,a]quinoxalin‐1‐one (5 × 10−6 M).
In contrast, the potency of ANP and CNP in aortae from eNOS KO animals was reduced following pretreatment of tissues with supramaximal concentrations of the NO‐donor, glyceryl trinitrate (3 × 10−5 M, 30 min) or ANP (10−7 M, 30 min).
Responses to acetylcholine in aortae from WT mice (dependent on the release of endothelium‐derived NO) were significantly reduced following pretreatment of tissues with GTN (3 × 10−5 M, 30 min) and ANP (10−7 M, 30 min).
CNP and the NO‐donor, spermine‐NONOate caused concentration‐dependent relaxations of mesenteric small arteries from WT animals that were significantly increased in eNOS KO mice compared to WT. ANP was unable to significantly relax mesenteric arteries from WT or eNOS KO animals.
In conclusion, both NPR‐A‐ and NPR‐B‐linked pGC pathways are modulated by NO–cGMP in murine aorta and mesenteric small arteries and crossdesensitisation occurs between NPR subtypes. The biological activity of endothelium‐derived NO is also influenced by the ambient concentration of NO and natriuretic peptides. Such an autoregulatory pathway may represent an important physiological homeostatic mechanism and link the paracrine activity of NO and CNP with the endocrine functions of ANP and BNP in the regulation of vascular tone and blood pressure.

British Journal of Pharmacology (2003) 139, 1289–1296. doi:10.1038/sj.bjp.0705365
Increased peripheral resistance in heart failure: new evidence suggests an alteration in vascular smooth muscle function
Authors: Ledoux Jonathan , Gee Daniel M , Leblanc Normand 
Published: July 2003

Increased peripheral resistance is a hallmark of chronic heart failure and has been primarily attributed to neurohumoral pathways involving both the renin–angiotensin and sympathetic nervous systems. The increased resistance is thought to serve as a compensatory mechanism to help maintain perfusion to the vital organs by sustaining blood pressure in the fate of a failing heart. Local mechanisms, and in particular endothelial dysfunction, have also been shown to be important contributors in regulating arterial resistance and vascular remodeling in this disease. In this issue of the British Journal of Pharmacology, Gschwend et al. (2003) present new data suggesting that in the absence of a functional endothelium, myogenic constriction of small pressurized mesenteric arteries, an intrinsic property of vascular smooth muscle cells, is enhanced in a coronary artery ligation‐induced myocardial infarction model of congestive heart failure (CHF) in the rat. The increased myogenic tone appears to be tightly linked to angiotensin II type 1 receptors (AT1). The possibility that CHF‐induced stimulation of myogenic constriction is due to the local release of preformed angiotensin II or constitutive upregulation of the AT1 receptor signaling pathways are discussed along with other potential cellular and molecular mechanisms previously suggested to play a role in myogenic reactivity.British Journal of Pharmacology (2003) 139, 1245–1248. doi:10.1038/sj.bjp.0705366
Myogenic constriction is increased in mesenteric resistance arteries from rats with chronic heart failure: instantaneous counteraction by acute AT1 receptor blockade
Authors: Gschwend S , Henning R H , Pinto Y M , de Zeeuw D , van Gilst W H , Buikema H 
Published: July 2003

Increased vascular resistance in chronic heart failure (CHF) has been attributed to stimulated neurohumoral systems. However, local mechanisms may also importantly contribute to set arterial tone. Our aim, therefore, was to test whether pressure‐induced myogenic constriction of resistance arteries in vitro – devoid of acute effects of circulating factors – is increased in CHF and to explore underlying mechanisms.
At 12 weeks after coronary ligation‐induced myocardial infarction or SHAM‐operations in rats, we studied isolated mesenteric arteries for myogenic constriction, determined as the active constriction (% of passive diameter) in response to stepwise increase in intraluminal pressure (20 – 160 mmHg), in the absence and presence of inhibitors of potentially involved modulators of myogenic constriction.
We found that myogenic constriction in mesenteric arteries from CHF rats was markedly increased compared to SHAM over the whole pressure range, the difference being most pronounced at 60 mmHg (24±2 versus 4±3%, respectively, P<0.001).
Both removal of the endothelium as well as inhibition of NO production (L‐NG‐monomethylarginine, 100 μM) significantly increased myogenic constriction (+16 and +25%, respectively), the increase being similar in CHF‐ and SHAM‐arteries (P=NS). Neither endothelin type A (ETA)‐receptor blockade (BQ123, 1 μM) nor inhibition of perivascular (sympathetic) nerve conduction (tetrodotoxin, 100 nM) affected the myogenic response in either group.
Interestingly, increased myogenic constriction in CHF was fully reversed after angiotensin II type I (AT1)‐receptor blockade (candesartan, 100 nM; losartan, 10 μM), which was without effect in SHAM. In contrast, neither angiotensin‐converting enzyme (ACE) inhibition (lisinopril, 1 μM; captopril, 10 μM) or AT2‐receptor blockade (PD123319, 1 μM), nor inhibition of superoxide production (superoxide dismutase, 50 U ml−1), TXA2‐receptor blockade (SQ29,548, 1 μM) or inhibition of cyclooxygenase‐derived prostaglandins (indomethacin, 10 μM) affected myogenic constriction.
Sensitivity of mesenteric arteries to angiotensin II (10 nM – 100 μM) was increased (P<0.05) in CHF (pD2 7.1±0.4) compared to SHAM (pD2 6.2±0.3), while the sensitivity to KCl and phenylephrine was not different.
Our results demonstrate increased myogenic constriction in small mesenteric arteries of rats with CHF, potentially making it an important target for therapy in counteracting increased vascular resistance in CHF. Our results further suggest active and instantaneous participation of AT1‐receptors in increased myogenic constriction in CHF, involving increased sensitivity of AT1‐receptors rather than apparent ACE‐mediated local angiotensin II production.

British Journal of Pharmacology (2003) 139, 1317–1325. doi:10.1038/sj.bjp.0705367
Acute effects of oestrogen receptor subtype‐specific agonists on vascular contractility
Authors: Montgomery Sandra , Shaw Linda , Pantelides Nick , Taggart Michael , Austin Clare 
Published: July 2003

This study shows for the first time that both the putatively selective oestrogen receptor α and oestrogen receptor β agonists PPT (4,4′,4″‐(4‐propyl‐[1H]‐pyrazole‐1,3,5‐triyl) tris‐phenol) and DPN (2,3‐bis(4‐hydroxyphenyl)‐propionitrile) can acutely relax precontracted isolated rat mesenteric arteries at pharmacological (i.e. μM) concentrations. When compared to responses observed to similar concentrations of 17β‐oestrogen obtained on the same tissues, PPT had a significantly greater vasodilatory effect, while DPN had a significantly smaller effect. All responses were rapid being complete within 5 min exposure time. Thus, both PPT and DPN can acutely relax isolated mesenteric arteries with the relative potency of PPT>17β‐oestrogen>DPN.British Journal of Pharmacology (2003) 139, 1249–1253. doi:10.1038/sj.bjp.0705368
Development and characterization of a highly selective neuropeptide Y Y5 receptor agonist radioligand: [125I][hPP1–17, Ala31, Aib32]NPY
Authors: Dumont Yvan , Thakur Mira , Beck‐Sickinger Annette , Fournier Alain , Quirion Rémi 
Published: July 2003

The existence of multiple classes of neuropeptide Y (NPY) receptors (Y1, Y2, Y4, Y5and y6) is now well established. However, one of the major difficulties in the study of these various receptor subtypes is the current lack of highly selective probes to investigate a single receptor class. Up to most recently, this was particularly true for the Y4and Y5subtypes.[hPP1–17, Ala31, Aib32]NPY, the first highly selective Y5agonist, was iodinated using the chloramine T method and purified by high‐pressure liquid chromatography.Binding performed in rat brain homogenates revealed that equilibrium was reached after 120 min (t1/2=21 min) and 60 min (t1/2=12 min) at 25 and 100 pM[125I][hPP1–17, Ala31, Aib32]NPY, respectively.Isotherm saturation binding experiments demonstrated that [125I][hPP1–17, Ala31, Aib32]NPY binds to an apparent single population with high‐affinity (KDof 1.2 and 1.7 nM) and low‐capacity (Bmaxof 14±3 fmol/100,000 cells and 20±5 fmol/mg protein) sites in Y5receptor HEK293‐transfected cells and rat brain membrane homogenates, respectively. No specific [125I][hPP1–17, Ala31, Aib32]NPY binding sites could be detected in Y1, Y2or Y4receptors transfected HEK293 cells, demonstrating the high selectivity of this ligand for the Y5subtype.Competition binding experiments performed in rat brain membrane homogenates and Y5‐receptor transfected HEK293 cells demonstrated that specific [125I][hPP1–17, Ala31, Aib32]NPY binding was competed with high affinity by Y5agonists and antagonists such as [Ala31, Aib32]NPY, [hPP1–17, Ala31, Aib32]NPY, hPP, CGP71683A and JCF109, but not by Y1(BIBP3226), Y2(BIIE0246) and Y1/Y4(GR231118) preferential ligands.Taken together, these data demonstrate that [125I][hPP1–17, Ala31, Aib32]NPY is the first highly selective Y5radioligand to be developed. This new probe should prove most useful for further detailed studies of the molecular and pharmacological properties of this receptor subtype in brain and peripheral tissues.British Journal of Pharmacology(2003)139, 1360–1368. doi:10.1038/sj.bjp.0705376
Mechanisms of action of CHF3381 in the forebrain
Authors: Barbieri Mario , Bregola Gianni , Buzzi Andrea , Marino Silvia , Zucchini Silvia , Stables James P , Bergamaschi Marco , Pietra Claudio , Villetti Gino , Simonato Michele 
Published: July 2003

Aim of this study was to gain insight into the mechanism of action of CHF3381, a novel putative antiepileptic and neuroprotective drug.
CHF3381 blocked NMDA currents in primary cultures of cortical neurons: maximal effect was nearly −80% of the NMDA‐evoked current, with EC50 of approximately 5 μM. This effect was selective, reversible, use‐dependent and elicited at the concentrations reached in the rodent brain after peripheral administration of therapeutic doses.
CHF3381 also inhibited voltage‐gated Na+ currents in an apparently voltage‐dependent manner. However, this effect could be obtained only at relatively high concentrations (100 μM).
Consistent with the mild effects on voltage‐gated Na+ channels, CHF3381 (100 μM) failed to affect electrical stimulation‐evoked glutamate overflow in hippocampal slices. In contrast, the anti‐convulsant agent and Na+ channel blocker lamotrigine (100 μM) inhibited stimulation‐evoked glutamate overflow by approximately 50%.
CHF3381 reduced kindled seizure‐induced c‐fos mRNA levels within the same brain regions, and to a similar level, as the selective NMDA receptor antagonist MK801, providing circumstantial evidence to the idea that CHF3381 blocks NMDA receptors in vivo.
The present mechanistic studies suggest that the primary mechanism of action of CHF3381 in the forebrain is blockade of NMDA receptors. On this basis, this compound may have a potential use in other diseases caused by or associated with a pathologically high level of NMDA receptor activation.

British Journal of Pharmacology (2003) 139, 1333–1341. doi:10.1038/sj.bjp.0705381
Melatonin inhibits nitrate tolerance in isolated coronary arteries
Authors: O'Rourke Stephen T , Hammad Hana , Delagrange Philippe , Scalbert Elizabeth , Vanhoutte Paul M 
Published: July 2003

The present study was designed to test the hypothesis that melatonin inhibits nitrate tolerance in coronary arteries.
Rings of porcine coronary arteries were suspended in organ chambers for isometric tension recording. Nitrate tolerance was induced by incubating the tissues with nitroglycerin (10−4 M) for 90 min, followed by repeated rinsing for 1 h. Control rings that had not been exposed previously to nitroglycerin, but were otherwise treated identically, were studied simultaneously. The rings were contracted with U46619 (1–3 × 10−9 M) and concentration–response curves to nitroglycerin (10−9–10−4 M) were obtained.
Nitrate tolerance was evident by a 15‐ to 20‐fold rightward shift in the concentration–response curve to nitroglycerin in rings with and without endothelium exposed previously to the drug for 90 min. Addition of melatonin (10−9–10−7 M) to the organ chamber during the 90‐min incubation period with nitroglycerin partially inhibited nitrate tolerance in coronary arteries with intact endothelium; however, melatonin had no effect on nitrate tolerance in coronary arteries without endothelium.
The effect of melatonin on nitrate tolerance in coronary arteries with endothelium was abolished by the melatonin receptor antagonist, S20928 (10−6 M). In contrast to melatonin, the selective MT3‐melatonin receptor agonist, 5‐MCA‐NAT (10−8–10−7 M), had no effect on nitrate tolerance in coronary arteries.
The results demonstrate that melatonin, acting via specific melatonin receptors, inhibits nitrate tolerance in coronary arteries and that this effect is dependent on the presence of the vascular endothelium.

British Journal of Pharmacology (2003) 139, 1326–1332. doi:10.1038/sj.bjp.0705383
Malondialdehyde inhibits cardiac contractile function in ventricular myocytes via a p38 mitogen‐activated protein kinase‐dependent mechanism
Authors: Folden David V , Gupta Akanksha , Sharma Avadhesh C , Li Shi‐Yan , Saari Jack T , Ren Jun 
Published: July 2003

Increased oxidative stress plays a significant role in the etiology of cardiovascular disease. Lipid peroxidation, initiated in the presence of hydroxy radicals resulting in the production of malondialdehyde, directly produces oxidative stress. This study was designed to examine the direct impact of malondialdehyde on ventricular contractile function at the single cardiac myocyte level. Ventricular myocytes from adult rat hearts were stimulated to contract at 0.5 Hz, and mechanical and intracellular Ca2+ properties were evaluated using an IonOptix Myocam® system. Contractile properties analyzed included peak shortening amplitude (PS), time‐to‐PS (TPS), time‐to‐90% relengthening (TR90), maximal velocity of shortening/relengthening (±dLdt), and Ca2+‐induced intracellular Ca2+ fluorescence release (CICR) and intracellular Ca2+ decay (τ). p38 mitogen‐activated protein (MAP) kinase phosphorylation was assessed with Western blot.
Our results indicated that malondialdehyde directly depressed PS, ±dLdt and CICR in a concentration‐dependent manner and shortened TPS without affecting TR90 and τ. Interestingly, the malondialdehyde‐induced cardiac mechanical effect was abolished by both the p38 MAP kinase inhibitor SB203580 (1 and 10 μM) and the antioxidant vitamin C (100 μM). Western blot analysis confirmed direct phosphorylation of p38 MAP kinase by malondialdehyde.
These findings revealed a novel role of malondialdehyde and p38 MAP kinase in lipid peroxidation and oxidative stress‐associated cardiac dysfunction.

British Journal of Pharmacology (2003) 139, 1310–1316. doi:10.1038/sj.bjp.0705384
Mild to moderate Crohn's disease – defining the basis for a new treatment algorithm
Authors: Sandborn W. J. , Feagan B. G. 
Published: August 2003

SummaryPreviously, clinicians have had few choices in treating mild to moderate Crohn's disease. They currently treat these Crohn's disease patients with oral mesalamine and antibiotics. This treatment approach is based on the safety of these agents, and the perception that they are effective. This perception regarding efficacy may be influenced by publication bias.This review examines the efficacy and safety data of the conventional corticosteroids, mesalamine, sulfasalazine, budesonide and antibiotics for inducing the remission of mild to moderate Crohn's disease from randomized controlled trials, and proposes an evidence‐based treatment approach.Sulfasalazine has demonstrated modest efficacy when Crohn's disease is confined to the colon. Mesalamine has no clear benefit over placebo in treating active Crohn's disease. Conventional corticosteroids effectively induce remission but are associated with unwanted adverse effects. Budesonide has similar efficacy to conventional steroids with far fewer adverse effects. Antibiotics have not consistently demonstrated efficacy.We propose a new evidence‐based approach which suggests inducing remission of mild to moderate Crohn's disease with budesonide 9 mg/day for patients with ileal and/or right colonic involvement; sulfasalazine for those with disease limited to the colon; and conventional steroids for high disease activity, those who failed budesonide and those with left‐sided disease who are allergic or intolerant to sulfasalazine.
Coping strategies, illness perception, anxiety and depression of patients with idiopathic constipation: a population‐based study
Authors: Cheng C. , Chan A. O. O. , Hui W. M. , Lam S. K. 
Published: August 2003

SummaryBackground: Functional constipation has important psychological elements.Aim: To investigate the prevalence of functional constipation in an Asian population, and the interplay among functional constipation, anxiety/depression, perception and coping strategies.Methods: An interview of 3282 patients was made by telephone survey. Constipation was diagnosed by Rome II criteria. Coping ability and anxiety/depression were assessed by validated questionnaires.Results: Fourteen percent of the interviewees had constipation. Anxiety and depression scores were higher in constipated than in healthy subjects (P < 0.0001 and < 0.0001), and in female than male patients (P = 0.02 and < 0.0001). Patients who were aware of their symptoms perceived greater impact on their lives (P < 0.001). Frequent use of coping strategies associated with lower anxiety scores (P < 0.0001). Female were more frequently aware of the symptoms (P = 0.004), less frequently used coping strategies (P = 0.008). Regression analysis showed that female and high anxiety level were the independent factors for predicting the perception of constipation, whereas anxiety was the only independent factor for predicting the use of coping strategies.Conclusion: Constipation associated with anxiety and depression is prevalent in the general Asian population. Female sex and anxiety are important aetiological factors in constipation, affecting perception and the use of coping strategies.
Meta‐analysis: the relationship between Helicobacter pylori infection and gastro‐oesophageal reflux disease
Authors: Cremonini F. , Di Caro S. , Delgado‐Aros S. , Sepulveda A. , Gasbarrini G. , Gasbarrini A. , Camilleri M. 
Published: August 2003

SummaryBackground: The relationship between Helicobacter pylori infection and its treatment and gastro‐oesophageal reflux disease (GERD) is controversial.Aims: To establish if H. pylori infection is associated with the presence of GERD and if anti‐H. pylori treatment leads to de novo GERD or rebound/exacerbation of GERD.Methods: A search of MEDLINE and EMBASE databases was made. Pooled odds ratios (OR) were calculated for de novo GERD and rebound/exacerbated GERD after anti‐H. pylori therapy in case‐control studies and in therapeutic trials.Results: Fourteen case‐control studies and 10 clinical trials were included. Among case‐control studies, pooled OR for the association between H. pylori negative status and GERD was 1.34 [95% confidence interval (CI) 1.15–1.55]. Among therapeutic trials, pooled OR for the association anti‐H. pylori therapy – GERD was 2.54 (95% CI 1.92–3.37). The OR for de novo GERD was 3.25 (95% CI 2.09–5.33), and for rebound/exacerbated GERD was 2.39 (95% CI 1.75–3.34). Associations were higher among Asian studies than among North American and European studies.Conclusions: This meta‐analysis shows significant association between absence of H. pylori infection and GERD symptoms, and a positive association between anti‐H. pylori therapy and occurrence of both de novo and rebound/exacerbated GERD. The significance of these associations appears to have been inflated by the effect of single trials and by geographical variations.