bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oxaliplatin induces hyperexcitability at motor and autonomic neuromuscular junctions through effects on voltage‐gated sodium channels
Authors: Webster Richard G , Brain Keith L , Wilson Richard H , Grem Jean L , Vincent Angela 
Published: October 2005

Oxaliplatin, an effective cytotoxic treatment in combination with 5‐fluorouracil for colorectal cancer, is associated with sensory, motor and autonomic neurotoxicity. Motor symptoms include hyperexcitability while autonomic effects include urinary retention, but the cause of these side‐effects is unknown. We examined the effects on motor nerve function in the mouse hemidiaphragm and on the autonomic system in the vas deferens.
In the mouse diaphragm, oxaliplatin (0.5 mM) induced multiple endplate potentials (EPPs) following a single stimulus, and was associated with an increase in spontaneous miniature EPP frequency. In the vas deferens, spontaneous excitatory junction potential frequency was increased after 30 min exposure to oxaliplatin; no changes in resting Ca2+ concentration in nerve terminal varicosities were observed, and recovery after stimuli trains was unaffected.
In both tissues, an oxaliplatin‐induced increase in spontaneous activity was prevented by the voltage‐gated Na+ channel blocker tetrodotoxin (TTX). Carbamazepine (0.3 mM) also prevented multiple EPPs and the increase in spontaneous activity in both tissues. In diaphragm, β‐pompilidotoxin (100 μM), which slows Na+ channel inactivation, induced multiple EPPs similar to oxaliplatin's effect. By contrast, blockers of K+ channels (4‐aminopyridine and apamin) did not replicate oxaliplatin‐induced hyperexcitability in the diaphragm.
The prevention of hyperexcitability by TTX blockade implies that oxaliplatin acts on nerve conduction rather than by effecting repolarisation. The similarity between β‐pompilidotoxin and oxaliplatin suggests that alteration of voltage‐gated Na+ channel kinetics is likely to underlie the acute neurotoxic actions of oxaliplatin.

British Journal of Pharmacology (2005) 146, 1027–1039. doi:10.1038/sj.bjp.0706407
Rat tissue kallikrein releases a kallidin‐like peptide from rat low‐molecular‐weight kininogen
Authors: Hilgenfeldt Ulrich , Stannek Christina , Lukasova Martina , Schnölzer Martina , Lewicka Sabina 
Published: October 2005

The kallikrein–kinin system is subdivided into the plasma and tissue–kallikrein–kinin system, with bradykinin (BK) and kallidin (KAL) (Lys0‐bradykinin) as functional peptides. This occurs in both humans and other mammals. Both peptides are released by plasma and tissue–kallikrein. BK, but not KAL, has been detected in rats until now. One can explain this observation by the structural differences found in the sequence of rat high‐ and low‐molecular kininogen containing an Arg‐residue instead of a Lys‐residue in front of the N‐terminus of the BK sequence. Nevertheless, we were able to measure a kallidin‐like peptide (KLP), in rat plasma and urine, using a specific KAL antiserum.
In order to confirm our data, we isolated low‐molecular‐weight kininogen from rat plasma and incubated it with purified rat glandular kallikrein. The generated peptide was retained on a high‐pressure liquid chromatography column and displaced by an excess of angiotensin I. The KLP‐containing fraction was identified with the KLP radioimmunoassay. A specific ion signal with a mass to charge ratio (m/z) of 1216.73 was detected with matrix‐assited laser desorption/ionization mass spectrometry.
As proposed earlier, the structure of this peptide is Arg1‐KAL, instead of Lys1‐KAL. The structural similarity between the Lys‐ and the Arg‐residue explains the high crossreactivity (80%) of KLP with the specific KAL antibody.
The incubation of KLP with angiotensin‐converting enzyme yields two molecules with masses of 913.4 and 729.3 containing the sequence H–Arg–Arg–Pro–Pro–Gly–Phe–Ser–Pro–OH and H–Arg–Arg–Pro–Pro–Gly–Phe–OH. The enzymatic cleavage could be inhibited by captopril.
The data suggest that in rats, as in other mammals, the tissue kallikrein–kinin system mediates its physiological effects via a kallidin‐like peptide, which is Arg1‐kallidin (Arg0‐bradykinin).

British Journal of Pharmacology (2005) 146, 958–963. doi:10.1038/sj.bjp.0706409
ETA and ETB receptors differentially modulate afferent and efferent arteriolar responses to endothelin
Authors: Inscho Edward W , Imig John D , Cook Anthony K , Pollock David M 
Published: October 2005

The segment‐specific actions of endothelin peptides and agonists have not been thoroughly investigated in the renal microcirculation. The current studies were performed to assess the relative contribution of ETA and ETB receptors to the renal pre‐ and postglomerular arteriolar responses to ET‐1.
Experiments determined the effect of selective ETA (A‐127722; 30 nM) and ETB (A‐192621; 30 nM) receptor blockade, on arteriolar responses to ET‐1 concentrations of 1 pM to 10 nM in rat kidneys using the isolated juxtamedullary nephron technique. Renal perfusion pressure was set at 110 mmHg.
Baseline afferent arteriolar diameter was similar in all groups and averaged 17.8±0.6 μm (n=14). In control experiments (n=6), ET‐1 produced significant concentration‐dependent decreases in arteriolar diameter, with 10 nM ET‐1 decreasing diameter by 85±1%.
Selective blockade of ETA receptors (n=6) prevented ET‐1‐mediated vasoconstriction, except at concentrations of 1 and 10 nM. Similarly, the vasoconstrictor profile was right shifted during selective ETB receptor blockade (n=4). Combined ETA and ETB receptor blockade (n=5) completely abolished afferent arteriolar diameter responses to ET‐1.
ETB selective agonists (S6c and IRL‐1620) produced disparate responses. S6c produced a concentration‐dependent vasoconstriction of afferent arterioles. In contrast, S6c produced a concentration‐dependent dilation of efferent arterioles that could be blocked with an ETB receptor antagonist. IRL‐1620, another ETB agonist, was less effective at altering afferent or efferent diameter and produced a small reduction in pre‐ and postglomerular arteriolar diameter.
These data demonstrate that both ETA and ETB receptors participate in ET‐1‐mediated vasoconstriction of afferent arterioles. ETB receptor stimulation provides a significant vasodilatory influence on the efferent arteriole. Furthermore, since selective ETA and ETB receptor antagonists abolished preglomerular vasoconstrictor responses at lower ET‐1 concentrations, these data support a possible interaction between ETA and ETB receptors in the control of afferent arteriolar diameter.

British Journal of Pharmacology (2005) 146, 1019–1026. doi:10.1038/sj.bjp.0706412
Neurally released ATP mediates endothelium‐dependent hyperpolarization in the circular smooth muscle cells of chicken anterior mesenteric artery
Authors: Draid Marwan , Shiina Takahiko , El‐Mahmoudy AbuBakr , Boudaka Ammar , Shimizu Yasutake , Takewaki Tadashi 
Published: October 2005

The object of the present study was to clarify the neurotransmitter(s) controlling membrane responses to electrical field stimulation (EFS) in the circular smooth muscle cells of first‐order branches of chicken anterior mesenteric artery.EFS (five pulses at 20 Hz, 1 ms) evoked a hyperpolarization of amplitude −21.6±1.2 mV, total duration 21.8±1.2 s and latency 641.7±81.9 ms. The response was tetrodotoxin‐sensitive and nonadrenergic noncholinergic (NANC) in nature.The NANC response was blocked by the nonspecific purinergic antagonist, suramin, indicating that the response is mediated by the neurotransmitter adenosine 5′‐triphosphate (ATP).Either desensitization or blockade of P2Y receptor with its putative agonist 2‐methylthioATP (1 μMfor 30 min) or with its antagonist cibacron blue F3GA (10 μM), respectively, abolished the purinergic hyperpolarization. PPADS at concentrations up to 100 μMhad no effect on the EFS‐induced response, indicating that this response is mediated through P2Y, but not P2X, receptor. In addition, the response was completely abolished by two specific P2Y1 receptor antagonists, namely, MRS 2179 (300 nM) and A3P5PS (10 μM).Removal of the endothelium abolished the purinergic hyperpolarization, which was converted, in some preparations, to a small depolarization, indicating that the hyperpolarizing response is endothelium‐dependent.The present study suggests that in first‐order branches of chicken anterior mesenteric artery, ATP released from perivascular nerves may diffuse to the endothelium‐activating P2Y1 receptor to induce release of an inhibitory substance that mediates hyperpolarization in the circular smooth muscle.British Journal of Pharmacology(2005)146, 983–989. doi:10.1038/sj.bjp.0706413
Endothelial dysfunction in the streptozotocin‐induced diabetic apoE‐deficient mouse
Authors: Ding Hong , Hashem Michael , Wiehler William B , Lau Winnie , Martin Jacqueline , Reid Julianne , Triggle Chris 
Published: October 2005

Endothelial dysfunction plays a role in the development of atherosclerosis and diabetes‐associated vascular disease and, in the streptozotocin (STZ)‐induced apoE‐deficient diabetic mouse, we report that, when compared to the citrate (CIT)‐treated nondiabetic apoE‐deficient control, acetylcholine (Ach)‐mediated endothelium‐dependent relaxation was reduced in the small mesenteric arteries (SMA) and the plaque‐prone regions of the aorta from the STZ‐diabetic mouse.
In the SMA the component of Ach‐mediated relaxation that was attributed to nitric oxide (NO) from STZ‐treated diabetic apoE‐deficient mice was enhanced; however, the endothelium‐derived hyperpolarizing factor (EDHF)‐mediated component was reduced. The EDHF component was assessed by determining the component of the Ach‐mediated response that was resistant to the combination of the NO synthase (NOS) inhibitor N‐nitro‐L‐arginine methyl ester, cyclooxygenase inhibitor, indomethacin, and soluble guanylate cyclase inhibitor, ODQ, and inhibited by the combination of the intermediate conductance KCa (IKCa) inhibitor TRAM‐34 and the small‐conductance KCa (SKCa) inhibitor apamin.
Endothelial NOS was increased but SK2, SK3 and connexin (Cx) 37 mRNA expressions were significantly (P<0.05) decreased in the SMA from STZ‐treated apoE‐deficient mice compared to the CIT‐treated controls. There was no difference in the IKCa expression or in Cx 40, 43 and 45 mRNA levels between STZ‐ and CIT‐treated mice.
The microvasculature of STZ‐induced apoE‐deficient mice developed endothelial dysfunction, which may be linked to a decrease in the contribution of the EDHF component due to a decrease in SK2 and 3 and Cx 37 expression.

British Journal of Pharmacology (2005) 146, 1110–1118. doi:10.1038/sj.bjp.0706417
Effects of urea pretreatment on the binding properties of adenosine A1receptors
Authors: May Lauren T , Sexton Patrick M , Christopoulos Arthur 
Published: October 2005

The effect of denaturation and/or extraction of nonintegral membrane proteins by 7 Murea on the binding of the antagonist [3H]cyclopentyl‐1,3‐dipropylxanthine 8 dipropyl‐2,3 ([3H]DPCPX), and the agonists adenosine, (−)‐N6‐(2‐phenylisopropyl)‐adenosine (R‐PIA) andN6‐cyclohexyladenosine (CHA), was investigated at human A1adenosine receptors stably expressed in CHO cells.Pretreatment with urea caused a 56% reduction in membrane proteins. Compared to controls, the use of adenosine deaminase (ADA), 100 μM5′‐guanylylimidodiphosphate (Gpp(NH)p) or urea each caused equivalent increases in specific [3H]DPCPX binding.Neither the binding kinetics nor the affinity of [3H]DPCPX were significantly different in urea‐pretreated compared to ADA‐pretreated membranes.At 25°C in ADA‐pretreated membranes, the competition isotherms for R‐PIA and CHA were characterized by two affinity states. Gpp(NH)p (100 μM) reduced, but did not abolish, the value of the high‐affinity dissociation constant. Similar results were obtained after treatment with urea for R‐PIA, whereas the high‐affinity state for CHA was abolished.At 37°C, urea pretreatment, but not 100 μMGpp(NH)p, abolished high‐affinity agonist competition binding. There was no significant effect of any of the treatments on the low‐affinity agonist binding state.In urea‐pretreated membranes, exogenously added adenosine competed according to a simple mass‐action model with a pKLof 5.66±0.05 (n=3).Compared to the more common approaches of ADA treatment and/or use of guanine nucleotides, our findings suggest that urea pretreatment represents an inexpensive and useful approach for investigating the binding properties of adenosine A1ligands (including adenosine) to the G protein‐uncoupled form of the receptor.British Journal of Pharmacology(2005)146, 1119–1129. doi:10.1038/sj.bjp.0706419
Improvement of age‐related endothelial dysfunction by simvastatin: effect on NO and COX pathways
Authors: De Sotomayor Maria Álvarez , Pérez‐Guerrero Concepción , Herrrera Ma Dolores , Jimenez Luis , Marín Roberto , Marhuenda Elisa , Andriantsitohaina Ramaroson 
Published: October 2005

The effects of oral administration of the HMG‐CoA reductase inhibitor, simvastatin (SV), on age‐related endothelial dysfunction were investigated in the aorta of male Wistar rats.
Adult (12–14 weeks) and old (60–80 weeks) rats were treated daily for 12 weeks with either vehicle or SV (1 mg kg−1). In old rats, SV treatment did not significantly affect systolic blood pressure and LDL‐cholesterol, but it reduced plasma cholesterol, triglycerides and oxidised LDL though it did not affect total antioxidant status.
SV improved endothelium‐dependent relaxation to acetylcholine and A‐23187 in vessels from aged, but not adult, rats. This effect was linked to a greater NO vasodilatation via an increased expression of endothelial NO‐synthase. A mechanism sensitive to superoxide dismutase and catalase also accounts for enhanced endothelial vasodilatation.
Finally, SV did not affect the release of prostacyclin, but it inhibited the generation of thromboxane (TX) A2 from COX‐2 isoform. The effect of the latter was sensitive to the Tp receptor antagonist, ICI‐192,605.
The present study provides evidence that oral administration of SV improves endothelial dysfunction in the aorta from aged rats by mechanisms associated with enhanced NO vasodilatation, reduced release of TXA2 from cyclo‐oxygenase, and increased antioxidant properties of the vessel wall. These data underscore a new therapeutic perspective for SV in age‐related endothelial dysfunction.

British Journal of Pharmacology (2005) 146, 1130–1138. doi:10.1038/sj.bjp.0706420
Nongenomic responses to 17β‐estradiol in male rat mesenteric arteries abolish intrinsic gender differences in vascular responses
Authors: Keung Wendy , Vanhoutte Paul M , Man Ricky Y K 
Published: October 2005

The aim of the present study was to investigate the gender differences in the acute effects of 17β‐estradiol on the rat superior mesenteric artery.
Isometric tension was measured in rings of mesenteric arteries from both male and female Sprague–Dawley rats.
Relaxation to acetylcholine was not significantly different between arteries (with endothelium) from male and female rats in the absence or presence of 17β‐estradiol. After blockade of endothelium‐dependent hyperpolarizations with apamin (0.3 μM) plus charybdotoxin (0.1 μM), acute exposure to 17β‐estradiol (1 nM) for 30 min resulted in enhancement of relaxation to acetylcholine in arteries from male but not female rats.
After acute exposure to 17β‐estradiol, mesenteric arteries from male rats were more sensitive to sodium nitroprusside than arteries from female rats.
Contractions of mesenteric arteries to phenylephrine and 9,11‐dideoxy‐11α,9α‐epoxymethanoprostaglandin F2α (U46619) were greater in arteries from male rats than female rats. This difference was not detected after acute exposure to 17β‐estradiol.
In preparations without endothelium, the enhancement of relaxation and reduction in contraction in arteries from male rats were preserved.
These results suggest that there exists a gender difference in the response to the acute nongenomic modulatory effect of 17β‐estradiol in rat mesenteric arteries. Arteries from male rats seem to be more sensitive to the modulatory effects of 17β‐estradiol than arteries from female rats. The effect appears to be mainly at the level of the vascular smooth muscles.

British Journal of Pharmacology (2005) 146, 1148–1155. doi:10.1038/sj.bjp.0706422
Hydrogen peroxide is an endothelium‐dependent contracting factor in rat renal artery
Authors: Gao Yu‐Jing , Lee Robert M K W 
Published: October 2005

In addition to endothelium‐derived relaxing factor and hyperpolarizing factor, vascular endothelium also modulates smooth muscle tone by releasing endothelium‐derived contracting factor(s) (EDCF), but the identity of EDCF remains obscure. We studied here the involvement of hydrogen peroxide (H2O2) in endothelium‐dependent contraction (EDC) of rat renal artery to acetylcholine (ACh).
ACh (10−6, 10−5, and 10−4 M) induced a transient contraction of rat renal artery with intact endothelium in a concentration‐related manner, but not in the artery with endothelium removed. In phenylephrine‐precontracted renal arteries, ACh induced an endothelium‐dependent relaxation response at lower concentrations (10−8–10−6 M), and a relaxation followed by a contraction at higher concentrations (10−5 M). Inhibition of nitric oxide synthase by Nω‐nitro‐L‐arginine (10−4 M) enhanced the EDC to ACh.
Catalase (1000 U ml−1) reduced the EDC to ACh. H2O2 (10−6, 10−5, and 10−4 M) induced a similar transient contraction of the renal arteries as ACh, but in an endothelium‐independent manner. Inhibition of NAD(P)H oxidase and cyclooxygenase by diphenylliodonium chloride and diclofenac greatly attenuated ACh‐induced EDC, while inhibition of xanthine oxidase (allopurinol) and cytochrome P450 monooxygenase (17‐octadecynoic acid) did not affect the contraction. Antagonist of thromboxane A2 and prostaglandin H2 receptors (SQ 29548) and thromboxane A2 synthase inhibitor (furegrelate) attenuated the contraction to ACh and to H2O2.
In isolated endothelial cells, ACh (10−5 M) induced a transient H2O2 production detected with a fluorescence dye sensitive to H2O2 (2′,7′‐dichlorofluorescein diacetate). The peak concentration of H2O2 was 5.1 × 10−4 M at 3 min and was prevented by catalase.
Taken together, these results show that ACh triggers H2O2 production through NAD(P)H oxidase activation in the endothelial cells, and that ACh and H2O2 share the same signaling pathway in causing smooth muscle contraction. Therefore, H2O2 is most likely the EDCF in rat renal artery in response to ACh stimulation.

British Journal of Pharmacology (2005) 146, 1061–1068. doi:10.1038/sj.bjp.0706423
Contractile effects of 5‐hydroxytryptamine and 5‐carboxamidotryptamine in the equine jejunum
Authors: Delesalle Cathérine , Deprez Piet , Schuurkes Jan A J , Lefebvre Romain A 
Published: October 2005

The use of human prokinetic drugs in colic horses leads to inconsistent results. This might be related to differences in gastrointestinal receptor populations. The motor effects of 5‐hydroxytryptamine (5‐HT; serotonin) on the equine mid‐jejunum were therefore studied. Longitudinal muscle preparations were set up for isotonic measurement.5‐HT induced tonic contractions with superimposed phasic activity; these responses were not influenced by tetrodotoxin and atropine, suggesting a non‐neurogenic, non‐cholinergic pathway.The 5‐HT receptor antagonists GR 127935 (5‐HT1B,D), ketanserin (5‐HT2A), SB 204741 (5‐HT2B), RS 102221 (5‐HT2C), granisetron (5‐HT3), GR 113808 (5‐HT4) and SB 269970 (5‐HT7) had no influence on the 5‐HT‐induced response; the 5‐HT1Areceptor antagonists NAN 190 (pKb=8.13±0.06) and WAY 100635 (pKb=8.69±0.07), and the 5‐HT1,2,5,6,7receptor antagonist methysergide concentration‐dependently inhibited the 5‐HT‐induced contractile response.The 5‐HT1,7receptor agonist 5‐carboxamidotryptamine (5‐CT) induced a contractile response similar to that of 5‐HT; its effect was not influenced by tetrodotoxin and atropine, and SB 269970, but antagonised by WAY 100635. 8‐OHDPAT, buspiron and flesinoxan, which are active at rat and human 5‐HT1Areceptors, had no contractile influence.These results suggest that the contractile effect of 5‐HT in equine jejunal longitudinal muscle is due to interaction with muscular 5‐HT receptors, which cannot be characterised between the actually known classes of 5‐HT receptors.British Journal of Pharmacology(2006)147, 23–35. doi:10.1038/sj.bjp.0706431
Rapid assessment of maternal activity among rural Indian mothers (Pune Maternal Nutrition Study)
Authors: Kanade AN , Rao S , Yajnik CS , Margetts BM , Fall CHD 
Published: October 2005

AbstractObjectiveTo develop an activity questionnaire for objective and rapid assessment of maternal habitual physical activity with the aim of describing its relationship with birth size.DesignProspective observational study.SettingSix villages near Pune, Maharashtra, India.SubjectsSeven hundred and ninety-seven rural Indian mothers were studied after excluding abortions and termination of pregnancies, foetal anomalies, etc.MethodPrincipal components analysis (PCA) was used to identify a few leading questions from an elaborate questionnaire involving 36 questions related to 14 typical maternal activities.ResultsOn the basis of high loading (>0.8), PCA identified three activities, i.e. farming, fetching water and washing clothes. Questions and sub-questions related to these activities only were considered for defining an activity score for rapid assessment. Validation of this new activity score, with the score based on the elaborate questionnaire, showed 70% sensitivity as well as specificity. New activity scores showed strong inverse relationships similar to those observed using the elaborate questionnaire, at early as well as late gestation, with neonatal head circumference (P=0.001 and 0.055) and mid-arm circumference (P=0.02 and 0.03).ConclusionsSimple questionnaires, based on leading activities identified by PCA, can be as informative as longer and detailed questionnaires. This method has potential for adaptation, especially in rural communities in developing countries.
Dietary Westernisation: conceptualisation and measurement in Mauritius
Authors: Uusitalo U , Sobal J , Moothoosamy L , Chitson P , Shaw J , Zimmet P , Tuomilehto J 
Published: October 2005

AbstractObjectivesThe aims of the study were to provide information that will contribute to conceptualising what is called ‘dietary Westernisation’, and to provide an example of measuring it on an individual level.DesignFood consumption frequency and demographic data on adults in Mauritius were examined in 1988, 1992 and 1998. In 1992, a 24-hour recall was also included. The cross-sectional samples consisted of 1115 (age 25–74 years) Mauritians in 1987/88, 1917 (age 30–74 years) in 1992 and 2239 (age 20–74 years) in 1998. Principal components analysis was carried out on daily consumption frequencies of 10 indicator foods (white rice, white bakery bread, pulses, processed meat, poultry, fresh/frozen fish, butter, margarine, whole milk and skimmed/low-fat milk). Correlations between dietary patterns and selected food consumption frequencies were examined in each survey year.ResultsFour dietary patterns were identified as being related to dietary Westernisation. The Traditional dietary pattern was characterised by higher consumption frequencies of Indian breads, salted/smoked fish and sugar-sweetened tea. The Western dietary pattern was characterised by higher consumption frequencies of cakes/pastries, meat and many Western fast foods like burgers, but, surprisingly, also by brown bread, breakfast cereals and salad. The Bread/butter dietary pattern predominantly described more frequent consumption of bread compared with rice. The Margarine/milk dietary pattern was inconsistently related with staple foods. Younger, educated and wealthier Mauritians appeared to adopt Western dietary patterns earlier.ConclusionsThis study suggests that relatively few indicator foods are needed for measuring dietary Westernisation. Dietary Westernisation in a non-Western country may also include shifts towards voluntary consumption of healthier foods.