bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tachykinin NK2 receptors and enhancement of cholinergic transmission in the inflamed rat colon: an in vivo motility study
Authors: Carini F , Lecci A , Tramontana M , Giuliani S , Maggi C A 
Published: January 2005

In the gastrointestinal tract, tachykinin NK2 receptors are localized both on smooth muscle and nerve fibres. NK2 receptor antagonists reduce exaggerated intestinal motility in various diarrhoea models but the site of action contributing to this effect is unknown. In this study we investigated the effects of atropine (1.4 μmol kg−1, i.v.), hexamethonium (13.5 μmol kg−1, i.v.), and nepadutant (0.1 μmol kg−1, i.v.), a selective tachykinin NK2 receptor antagonist, on distension (0.5 and 1 ml)‐, or irritation (acetic acid, 0.5 ml of 7.5% v v−1)‐induced motility in the rat distal colon in vivo. The effects of atropine, hexamethonium or Nω‐nitro‐L‐argininemethylester (L‐NAME, 1.85 μmol kg−1, i.v.) on [βAla8]NKA(4‐10) (10 nmol kg−1, i.v.)‐induced colonic contractions were also investigated.
When the colonic balloon was filled with a subthreshold volume (0.5 ml), the intraluminal instillation of acetic acid triggered a high‐amplitude phasic colonic motility which was partially reduced by nepadutant and suppressed by either hexamethonium or atropine. Filling of the balloon with 1 ml evoked reflex (hexamethonium‐sensitive), atropine‐sensitive phasic colonic motility: nepadutant had no significant effect on the distension‐evoked motility.
Neither hexamethonium nor atropine significantly reduced [βAla8]NKA(4‐10)‐induced colonic contractions, whereas nepadutant suppressed them. Following L‐NAME pretreatment, [βAla8]NKA(4‐10)‐induced colonic contractions were inhibited by both atropine and hexamethonium. In hexamethonium‐pretreated animals, an atropine‐sensitive component of [βAla8]NKA(4‐10)‐induced colonic contractions was also evident.
These results indicate that the application of irritants onto the colonic mucosa induces the release of endogenous tachykinins which enhance excitatory cholinergic mechanisms through the stimulation of NK2 receptors.

British Journal of Pharmacology (2001) 133, 1107–1113; doi:10.1038/sj.bjp.0704164
Pharmacological characterization of muscarinic receptors in mouse isolated urinary bladder smooth muscle
Authors: Choppin A , Eglen R M 
Published: January 2005

The pharmacological characteristics of muscarinic receptors in the male mice urinary bladder smooth muscle were studied.
(+)‐Cis‐dioxolane, oxotremorine‐M, acetylcholine, carbachol and pilocarpine induced concentration‐dependent contractions of the urinary bladder smooth muscle (pEC50=6.6±0.1, 6.9±0.1, 6.7±0.1, 5.8±0.1 and 5.8±0.1, EMax=3.2±0.8 g, 2.7±0.4 g, 1.0±0.1 g, 2.7±0.3 and 0.9±0.2 g, respectively, n=4). These contractions were competitively antagonized by a range of muscarinic receptor antagonists (pKB values): atropine (9.22±0.09), pirenzepine (6.85±0.08), 4‐DAMP (8.42±0.14), methoctramine (5.96±0.05), p‐F‐HHSiD (7.48±0.09), tolterodine (8.89±0.13), AQ‐RA 741 (7.04±0.12), s‐secoverine (8.21±0.09), zamifenacin (8.30±0.17) and darifenacin (8.70±0.09).
In this tissue, the pKB values correlated most favourably with pKi values for these compounds at human recombinant muscarinic M3 receptors. A significant correlation was also noted at human recombinant muscarinic m5 receptors given the poor discriminative ability of ligands between M3 and m5 receptors.
In recontraction studies, in which the muscarinic M3 receptor population was decreased, and conditions optimized to study M2 receptor activation, methoctramine exhibited an affinity estimate consistent with muscarinic M3 receptors (pKB=6.23±0.14; pA2=6.16±0.03).
Overall, these data study suggest that muscarinic M3 receptors are the predominant, if not the exclusive, subtype mediating contractile responses to muscarinic agonists in male mouse urinary bladder smooth muscle.

British Journal of Pharmacology (2001) 133, 1035–1040; doi:10.1038/sj.bjp.0704165
Combination of miglitol, an anti‐diabetic drug, and nicorandil markedly reduces myocardial infarct size through opening the mitochondrial KATP channels in rabbits
Authors: Minatoguchi Shinya , Wang Ningyuan , Uno Yoshihiro , Arai Masazumi , Hashimoto Kazuaki , Hashimoto Yasuko , Chen Xue‐Hai , Takemura Genzou , Fujiwara Hisayoshi 
Published: January 2005

The anti‐diabetic drug miglitol, an α‐glucosidase inhibitor, which is currently used clinically, reduces myocardial infarct size by reducing the glycogenolytic rate through inhibition of the α‐1,6‐glucosidase of glycogen‐debranching enzyme in the heart. Nicorandil, a KATP channel opener with a nitrate‐like effect, which is also currently used clinically, also reduces the infarct size. Therefore, we hypothesized that combination of nicorandil and submaximal dose of miglitol could markedly reduce myocardial infarct size more than miglitol or nicorandil alone, and investigated the mechanism for the infarct size‐reducing effect.
Japanese white rabbits without collateral circulation were subjected to 30 min coronary occlusion followed by 48 h reperfusion. Pre‐ischaemic treatment with submaximal dose of miglitol (5 mg kg−1, i.v.) and nicorandil alone (100 μg kg−1 min−1 5 min) moderately reduced the infarct size as a percentage of area at risk (24±4 and 25±4%, respectively), and 10 mg kg−1 of miglitol markedly reduced the infarct size (15±2%) compared with the controls (42±2%). Combination of 5 mg kg−1 of miglitol and nicorandil (100 μg kg−1 min−1 5 min), and 10 mg kg−1 of miglitol and nicorandil (100 μg kg−1 min−1 5 min) significantly reduced the infarct size (13±4 and 12±3%, respectively) more than miglitol or nicorandil alone.
Pretreatment with 5HD completely abolished the infarct size‐reducing effect of 10 mg kg−1 of miglitol alone (36±7%) and that of combination of 5 mg kg−1 of miglitol and nicorandil (46±2%).
Combination of nicorandil and submaximal dose of miglitol markedly reduced the myocardial infarct size more than miglitol or nicorandil alone. This effect was suggested to be related to the opening of mitochondrial KATP channels.

British Journal of Pharmacology (2001) 133, 1041–1046; doi:10.1038/sj.bjp.0704166
A comparison of allergen and polycation induced cutaneous responses in the rabbit
Authors: Jones Helen , Paul William , Page Clive P 
Published: January 2005

Allergic inflammatory responses contribute to the symptoms of a number of diseases including atopic dermatitis, asthma and rhinitis. Cationic proteins are released from inflammatory cells and levels are known to be raised in disease states.
Using an in vivo model of acute inflammation, we investigated the characteristics of cutaneous responses to antigen (Alternaria tenuis, AT) and poly‐L‐lysine (PLL, used as a paradigm for cationic proteins). We aimed to compare the inflammatory profile of cationic polypeptides and the allergic response and to identify similarities and differences between these responses.
Responses to intradermal injection of the polycation, PLL and antigen were compared using radiolabelled protein (125I‐bovine serum albumin, BSA) and cells (111In‐neutrophils, PMN) to study plasma exudation (PE) and PMN accumulation (PMNA) in the skin of AT sensitized rabbits.
Both PLL and antigen caused dose‐related increases in PE and PMNA. PE (and PMNA) responses to PLL were prolonged (up to 3 h), as were those to antigen. This is in contrast to PE responses to fMLP which were maximal at 45 min.
In immunized animals, treated with colchicine (1 mg kg−1 i.v.), PE responses to the directly acting mediator, bradykinin (BK), were not affected, whereas PE responses to the neutrophil dependent mediator, f‐met‐leu‐phe (fMLP), were significantly (P<0.01) reduced. Antigen‐induced PE responses were significantly (50, 500 (P<0.05); 200 (P<0.01) p.n.u. site−1) inhibited by colchicine, but PLL‐induced responses were not significantly affected.
We conclude that although PLL‐induced responses had a similar time course to those of antigen, some differences were observed between responses, which indicate that although polycations may contribute to allergic responses, these two responses are produced by distinct mechanisms.

British Journal of Pharmacology (2001) 133, 1181–1189; doi:10.1038/sj.bjp.0704172
Rho‐dependent inhibition of the induction of connective tissue growth factor (CTGF) by HMG CoA reductase inhibitors (statins)
Authors: Eberlein Michael , Heusinger‐Ribeiro Juliane , Goppelt‐Struebe Margarete 
Published: January 2005

It was supposed that inhibitors of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG CoA) reductase (statins) might inhibit the expression of the fibrosis‐related factor CTGF (connective tissue growth factor) by interfering with the isoprenylation of Rho proteins.
The human renal fibroblast cell line TK173 was used as an in vitro model system to study the statin‐mediated modulation of the structure of the actin cytoskeleton and of the expression of CTGF mRNA.
Incubation of the cells with simvastatin or lovastatin time‐dependently and reversibly changed cell morphology and the actin cytoskeleton with maximal effects observed after about 18 h.
Within the same time period, statins reduced the basal expression of CTGF and interfered with CTGF induction by lysophosphatidic acid (LPA) or transforming growth factor beta. Simvastatin and lovastatin proved to be much more potent than pravastatin (IC50 1–3 μM compared to 500 μM).
The inhibition of CTGF expression was prevented when the cells were incubated with mevalonate or geranylgeranylpyrophosphate (GGPP) but not by farnesylpyrophosphate (FPP). Specific inhibition of geranylgeranyltransferase‐I by GTI‐286 inhibited LPA‐mediated CTGF expression whereas an inhibitor of farnesyltransferases FTI‐276 was ineffective.
Simvastatin reduced the binding of the small GTPase RhoA to cellular membranes. The effect was prevented by mevalonate and GGPP, but not FPP.
These data are in agreement with the hypothesis that interference of statins with the expression of CTGF mRNA is primarily due to interference with the isoprenylation of RhoA, in line with previous studies, which have shown that RhoA is an essential mediator of CTGF induction.
The direct interference of statins with the synthesis of CTGF, a protein functionally related to the development of fibrosis, may thus be a novel mechanism underlying the beneficial effects of statins observed in renal diseases.

British Journal of Pharmacology (2001) 133, 1172–1180; doi:10.1038/sj.bjp.0704173
Haemodynamic effects of the bacterial quorum sensing signal molecule, N‐(3‐oxododecanoyl)‐L‐homoserine lactone, in conscious, normal and endotoxaemic rats
Authors: Gardiner S M , Chhabra S R , Harty C , Williams P , Pritchard D I , Bycroft B W , Bennett T 
Published: January 2005

N‐acylhomoserine lactones (AHLs) are small, diffusible signalling molecules, employed by Gram‐negative bacteria to coordinate gene expression with cell population density. Recent in vitro findings indicate that AHLs may function as virulence determinants per se, through modification of cytokine production by eukaryotic cells, and by stimulating the relaxation of blood vessels.
In the present study, we assessed the influence of AHLs on cardiovascular function in conscious rats, and draw attention to the ability of the N‐(3‐oxododecanoyl)‐L‐homoserine lactone (3‐oxo‐C12‐HSL), a signal molecule produced by P. aeruginosa, to cause marked bradycardia. This bradycardic effect was blocked by atropine and atenolol, and did not occur in vitro. Furthermore, modification of the acyl side chain length resulted in the loss of activity, whereas removal of the homoserine lactone ring, did not. The bradycardic effect of 3‐oxo‐C12‐HSL was also observed in endotoxaemic animals, albeit attenuated.
In normal rats, 3‐oxo‐C12‐HSL caused initial mesenteric and hindquarters vasoconstriction, but only slight, and delayed signs of vasodilatation in the renal and mesenteric vascular beds. Furthermore, administration of 3‐oxo‐C12‐HSL (pre‐treatment or 2 h post‐treatment) together with LPS, did not modify the established regional haemodynamic effects of the LPS, 6 h after the onset of its infusion.
Our observations do not provide any clear evidence for an ability of 3‐oxo‐C12‐HSL to modify the haemodynamic responses to LPS infusion. However, they are not inconsistent with the hypothesis that some of the cardiovascular sequelae of bacterial infection may be modulated by an influence of bacterial quorum sensing signalling molecules on the host.

British Journal of Pharmacology (2001) 133, 1047–1054; doi:10.1038/sj.bjp.0704174
Treatment of hippocampal neurons with cyclosporin A results in calcium overload and apoptosis which are independent on NMDA receptor activation
Authors: Kaminska Bozena , Figiel Izabela , Pyrzynska Beata , Czajkowski Rafal , Mosieniak Grazyna 
Published: January 2005

Calcineurin is a ubiquitous calcium/calmodulin dependent protein phosphatase that has been shown to regulate the activity of ion channels, glutamate release, and synaptic plasticity. In the present study we show that CsA, a specific inhibitor of calcineurin, affects the survival of cultures developed from hippocampal dentate gyrus. Mixed neuronal‐glial cultures exposed to 8–40 μM CsA undergo cell death characterized by apoptotic changes in cellular and nuclear morphology.
TUNEL‐positive staining was observed only in neurons that developed pyknotic morphology after treatment with 8 μM CsA for 24–72 h.
Immunocytochemical staining with an anti‐GFAP monoclonal antibody revealed that astrocytes from mixed neuronal/glial cultures were unaffected by exposure to CsA at doses toxic for neurons and all TUNEL‐positive cells were neurons.
MK‐801, a noncompetitive inhibitor of glutamate receptor, does not inhibit the appearance of TUNEL‐positive neurons and apoptotic changes in nuclear morphology.
Preincubation of cells with 8 μM CsA increased basal intracellular calcium level in time dependent manner and decreased relative calcium response to glutamate. Application of 1 μM MK‐801 had no effect on CsA‐induced changes in Ca2+ level.
Our findings suggest that the neuronal death after CsA treatment is not a result of glutamate excitotoxicity and the increase in intracellular calcium concentration in neurons is not dependent on calcium influx via NMDA channel.

British Journal of Pharmacology (2001) 133, 997–1004; doi:10.1038/sj.bjp.0704177
Neuroprotective and neurorescuing effects of isoform‐specific nitric oxide synthase inhibitors, nitric oxide scavenger, and antioxidant against beta‐amyloid toxicity
Authors: Law A , Gauthier S , Quirion R 
Published: January 2005

Beta amyloid (Aβ) is implicated in Alzheimer's disease (AD). Aβ1–42 (5, 10, or 20 μM) was able to increase NO release and decrease cellular viability in primary rat cortical mixed cultures.
L‐NOARG and SMTC (both at 10 or 100 μM) – type I NOS inhibitors – reduced cellular NO release in the absence of Aβ1–42. At 100 μM, both drugs decreased cell viability.
L‐NIL (10 or 100 μM), and 1400W (1 or 5 μM) – type II NOS inhibitors – reduced NO release and improved viability when either drug was administered up to 4 h post Aβ1–42 (10 μM) treatment. L‐NOARG and SMTC (both at 10 or 100 μM) were only able to decrease NO release. Carboxy‐PTIO or Trolox (both at 10 or 100 μM) – a NO scavenger and an antioxidant, respectively–increased viability when administered up to 1 h post Aβ1–42 treatment. Either L‐NIL (50 μM) or 1400W (3 μM) and Trolox (50 μM) showed synergistic actions.
Peroxynitrite (100 or 200 μM) reduced cell viability. Viabilities were improved by L‐NIL (100 μM), 1400W (5 μM), carboxy‐PTIO (10 or 100 μM), and Trolox (10 or 100 μM).
Hence, the data show that Aβ1–42 induced NO release in neurons and glial cells, and that Aβ neurotoxicity is, at least in part, mediated by NO. NO concentration modulating compounds and antioxidant may have therapeutic importance in neurological disorders where oxidative stress is likely involved such as in AD.

British Journal of Pharmacology (2001) 133, 1114–1124; doi:10.1038/sj.bjp.0704179
Voltage‐dependent acceleration of Cav1.2 channel current decay by (+)‐ and (−)‐isradipine
Authors: Berjukow S , Hering S 
Published: January 2005

Inhibition of Cav1.2 by antagonist 1,4 dihydropyridines (DHPs) is associated with a drug‐induced acceleration of the calcium (Ca2+) channel current decay. This feature is contradictorily interpreted as open channel block or as drug‐induced inactivation. To elucidate the underlying molecular mechanism we investigated the effects of (+)‐ and (−)‐isradipine on Cav1.2 inactivation gating at different membrane potentials.
α11.2 Constructs were expressed together with α2‐δ‐ and β1a‐ subunits in Xenopus oocytes and drug‐induced changes in barium current (IBa) kinetics analysed with the two microelectrode voltage clamp technique. To study isradipine effects on IBa decay without contamination by intrinsic inactivation we expressed a mutant (V1504A) lacking fast voltage‐dependent inactivation.
At a subthreshold potential of −30 mV a 200‐times higher concentration of (−)‐isradipine was required to induce a comparable amount of inactivation as by (+)‐isradipine. At +20 mV the two enantiomers were equally efficient in accelerating the IBa decay.
Faster recovery from (−)‐ than from (+)‐isradipine‐induced inactivation at −80 mV in a Cav1.2 construct (τ(−)‐isr.(Cav1.2)=0.74 s<τ(+)‐isr.(Cav1.2)=2.85 s) and even more rapid recovery of V1504A (τ(−)‐isr.(V1504A)=0.39 s<τ(+)‐isr.(V1504A)=1.98 s) indicated that drug‐induced determinants and determinants of intrinsic inactivation (V1504) stabilize the DHP‐induced channel conformation in an additive manner.
In the voltage range between −25 and 20 mV where the channels inactivate predominantly from the open state the (+)‐ and (−)‐isradipine‐induced acceleration of the IBa decay in V1504A displayed similar voltage‐dependence as intrinsic fast inactivation of Cav1.2.
Our data suggest that the isradipine‐induced acceleration of the Cav1.2 current decay reflects enhanced fast voltage‐dependent inactivation and not open channel block.

British Journal of Pharmacology (2001) 133, 959–966; doi:10.1038/sj.bjp.0704181
Inhibition of mechanical activation of guinea‐pig airway afferent neurons by amiloride analogues
Authors: Carr Michael J , Gover Tony D , Weinreich Daniel , Undem Bradley J 
Published: January 2005

The aim of this study was to investigate a role for Epithelial Sodium Channels (ENaCs) in the mechanical activation of low‐threshold vagal afferent nerve terminals in the guinea‐pig trachea/bronchus.
Using extracellular single‐unit recording techniques, we found that the ENaC blocker amiloride, and its analogues dimethylamiloride and benzamil caused a reduction in the mechanical activation of guinea‐pig airway afferent fibres.
Amiloride and it analogues also reduced the sensitivity of afferent fibres to electrical stimulation such that greater stimulation voltages were required to induce action potentials from their peripheral terminals within the trachea/bronchus.
The relative potencies of these compounds for inhibiting electrical excitability of afferent nerves were similar to that observed for inhibition of mechanical stimulation (dimethylamiloride∼#38;benzamil>amiloride). This rank order of potency is incompatible with the known rank order of potency for blockade of ENaCs (benzamil>amiloride>>dimethylamiloride).
As voltage‐gated sodium channels play an important role in determining the electrical excitability of neurons, we used whole‐cell patch recordings of nodose neuron cell bodies to investigate the possibility that amiloride analogues caused blockade of these channels. At the concentration required to inhibit mechanical activation of vagal nodose afferent fibres (100 μM), benzamil caused significant inhibition of voltage‐gated sodium currents in neuronal cell bodies acutely isolated from guinea‐pig nodose ganglia.
Combined, our findings suggest that amiloride and its analogues did not selectively block mechanotransduction in airway afferent neurons, but rather they reduced neuronal excitability, possibly by inhibiting voltage‐gated sodium currents.

British Journal of Pharmacology (2001) 133, 1255–1262; doi:10.1038/sj.bjp.0704197
Bradykinin increases Na+‐K+ pump activity in cultured guinea‐pig tracheal smooth muscle cells
Authors: Dodson Alicia M , Rhoden Kerry J 
Published: January 2005

The effect of bradykinin on the Na+‐K+ pump of airway smooth muscle was investigated by measuring ouabain‐sensitive 86Rb+ uptake in cultured guinea‐pig tracheal smooth muscle cells.
Bradykinin induced a concentration‐dependent increase in ouabain‐sensitive 86Rb+ uptake, with an EC50 of 3 nM (pD2=8.50±0.10). Stimulation was not affected by indomethacin (1 μM) suggesting that it is not mediated by cycloxygenase products of arachidonic acid.
The B1 receptor agonists Lys‐des‐Arg9‐bradykinin and des‐Arg9‐bradykinin had no effect on ouabain‐sensitive 86Rb+ uptake. In contrast, the B1 and B2 receptor agonist Lys‐bradykinin induced a concentration‐dependent increase in ouabain‐sensitive 86Rb+ uptake with an EC50 of 6 nM (pD2=8.21±0.20).
The B1 receptor antagonist des‐Arg10‐HOE 140 (1 μM) had no effect on bradykinin‐stimulated ouabain‐sensitive 86Rb+ uptake. The B2 receptor antagonists HOE 140 and WIN 64338 antagonized bradykinin‐stimulated ouabain‐sensitive 86Rb+ uptake with pKB values (−log M) of 8.20±0.08 and 8.11±0.20 respectively.
Reducing extracellular Na+ from 146 mM to 11 mM caused a 53.5% decrease in basal ouabain‐sensitive 86Rb+ uptake and abolished bradykinin‐induced uptake. Two inhibitors of the Na+‐H+ exchanger, methylisobutyl‐amiloride (MIA; 1–100 μM) and ethylisopropyl‐amiloride (EIPA; 0.1–10 μM), inhibited bradykinin‐stimulated ouabain‐sensitive 86Rb+ uptake without affecting basal uptake.
These results suggest that bradykinin increases Na+‐K+ pump activity of guinea‐pig tracheal smooth muscle via stimulation of B2 receptors and activation of the Na+‐H+ exchanger.

British Journal of Pharmacology (2001) 133, 1339–1345; doi:10.1038/sj.bjp.0704198
Activation of the p38 and p42/p44 mitogen‐activated protein kinase families by the histamine H1 receptor in DDT1MF‐2 cells
Authors: Robinson Alex J , Dickenson John M 
Published: January 2005

The mitogen‐activated protein kinases (MAPKs) consist of the p42/p44 MAPKs and the stress‐activated protein kinases, c‐Jun N‐terminal kinase (JNK) and p38 MAPK. In this study we have examined the effect of histamine H1 receptor activation on MAPK pathway activation in the smooth muscle cell line DDT1MF‐2.
Histamine stimulated time and concentration‐dependent increases in p42/p44 MAPK activation in DDT1MF‐2 cells. Responses to histamine were inhibited by the histamine H1 receptor antagonist mepyramine (KD 3.5 nM) and following pre‐treatment with pertussis toxin (PTX; 57% inhibition).
Histamine‐induced increases in p42/p44 MAPK activation were blocked by inhibitors of MAPK kinase 1 (PD 98059), tyrosine kinase (genistein and tyrphostin A47), phosphatidylinositol 3‐kinase (wortmannin and LY 294002) and protein kinase C (Ro 31‐8220; 10 μM; 41% inhibition). Inhibitors of Src tyrosine kinase (PP2) and the epidermal growth factor tyrosine kinase (AG1478) were without effect. Removal of extracellular Ca2+, chelation of intracellular Ca2+ with BAPTA and inhibition of focal adhesion assembly (cytochalasin D) had no significant effect on histamine‐induced p42/p44 MAPK activation.
Histamine stimulated time and concentration‐dependent increases in p38 MAPK activation in DDT1MF‐2 cells but had no effect on JNK activation. Histamine‐induced p38 MAPK activation was inhibited by pertussis toxin (74% inhibition) and the p38 MAPK inhibitor SB 203580 (95% inhibition).
In summary, we have shown the histamine H1 receptor activates p42/p44 MAPK and p38 MAPK signalling pathways in DDT1MF‐2 smooth muscle cells. Interestingly, signalling to both pathways appears to involve histamine H1 receptor coupling to Gi/Go‐proteins.

British Journal of Pharmacology (2001) 133, 1378–1386; doi:10.1038/sj.bjp.0704200