bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of the potassium channels involved in EDHF‐mediated relaxation in cerebral arteries
Authors: Petersson Jesper , Zygmunt Peter M. , Högestätt Edward D. 
Published: August 2006

In the presence of NG‐nitro‐l‐arginine (l‐NOARG, 0.3 mm) and indomethacin (10 μm), the relaxations induced by acetylcholine and the calcium (Ca) ionophore A23187 are considered to be mediated by endothelium‐derived hyperpolarizing factor (EDHF) in the guinea‐pig basilar artery.
Inhibitors of adenosine 5′‐triphosphate (ATP)‐sensitive potassium (K)‐channels (KATP; glibenclamide, 10 μm), voltage‐sensitive K‐channels (KV; dendrotoxin‐I, 0.1 μm or 4‐aminopyridine, 1 mm), small (SKCa; apamin, 0.1 μm) and large (BKCa; iberiotoxin, 0.1 μm) conductance Ca‐sensitive K‐channels did not affect the l‐NOARG/indomethacin‐resistant relaxation induced by acetylcholine.
Synthetic charybdotoxin (0.1 μm), an inhibitor of BKCa and KV, caused a rightward shift of the concentration‐response curve for acetylcholine and reduced the maximal relaxation in the presence of l‐NOARG and indomethacin, whereas the relaxation induced by A23187 was not significantly inhibited.
A combination of charybdotoxin (0.1 μm) and apamin (0.1 μm) abolished the l‐NOARG/indomethacin‐resistant relaxations induced by acetylcholine and A23187. However, the acetylcholine‐induced relaxation was not affected by a combination of iberiotoxin (0.1 μm) and apamin (0.1 μm).
Ciclazindol (10 μm), an inhibitor of KV in rat portal vein smooth muscle, inhibited the l‐NOARG/indomethacin‐resistant relaxations induced by acetylcholine and A23187, and the relaxations were abolished when ciclazindol (10 μm) was combined with apamin (0.1 μm).
Human pial arteries from two out of four patients displayed an l‐NOARG/indomethacin‐resistant relaxation in response to substance P. This relaxation was abolished in both cases by pretreatment with the combination of charybdotoxin (0.1 μm) and apamin (0.1 μm), whereas each toxin had little effect alone.
The results suggest that KV, but not KATP and BKCa, is involved in the EDHF‐mediated relaxation in the guinea‐pig basilar artery. The synergistic action of apamin and charybdotoxin (or ciclazindol) could indicate that both KV and SKCa are activated by EDHF. However, a single type of K‐channel, which may be structurally related to KV and allosterically regulated by apamin, could also be the target for EDHF.

British Journal of Pharmacology (1997) 120, 1344–1350; doi:10.1038/sj.bjp.0701032
Effect of short‐term and long‐term treatments with σ ligands on the N‐methyl‐d‐aspartate response in the CA3 region of the rat dorsal hippocampus
Authors: Bergeron Richard , De Montigny Claude , Debonnel Guy 
Published: August 2006

Long‐term treatments with the σ ligand haloperidol decrease the density of σ receptors in mammalian CNS. We have shown that σ ligands, such as di(2‐tolyl)guanidin (DTG), potentiate dose‐dependently, with bell‐shaped dose‐response curves, the neuronal response of pyramidal neurones to N‐methyl‐d‐aspartate (NMDA) in the CA3 region of the rat dorsal hippocampus. σ Ligands producing such a potentiation were denoted ‘agonists’. This potentiation was suppressed by low doses of other σ ligands denoted ‘antagonists’. High doses of DTG and JO‐1784 did not modify the NMDA response but acted as ‘antagonists’ by suppressing the potentiation induced by σ ‘agonists’.
Following a 21‐day treatment with haloperidol as well as with high doses of DTG or JO‐1784, after a 48 h washout, the acute administration of σ ‘agonists’ failed to induce any potentiation of the NMDA response. Following a 21 day treatment with a low dose of DTG or JO‐1784, after a 48 h washout, the neuronal response to microiontophoretic applications of NMDA was markedly increased. A 21 day treatment with low or high doses of (+)‐pentazocine, after a 48 h washout, did not produce any change.
Following a two day treatment with a high dose of haloperidol, DTG, JO‐1784 and (+)‐pentazocine, after a 24 h washout, the potentiation of the NMDA response induced by the acute administration of the σ ‘agonists’ was unchanged.
With the minipumps on board, with DTG and JO‐1784, a dose‐dependent enhancement of the NMDA response was seen but no effect was observed in the groups of rats treated at the same doses with haloperidol or (+)‐pentazocine.
The present data suggest that long‐term treatments with σ ‘antagonists’ induce a desensitization of the σ receptors, whereas long‐term treatments with σ ‘agonists’ induce a supersensitivity of the σ receptors.

British Journal of Pharmacology (1997) 120, 1351–1359; doi:10.1038/sj.bjp.0701042
An autoradiographic study of dextromethorphan high‐affinity binding sites in rat brain: sodium‐dependency and colocalization with paroxetine
Authors: Meoni P. , Tortella F. C. , Bowery N. G. 
Published: August 2006

The distribution and some pharmacological properties of centrally located dextromethorphan high‐affinity binding sites were investigated by in vitro autoradiography.
Sodium chloride (50 mm) induced a 7 to 12 fold increase in dextromethorphan binding to rat brain in all areas tested. The effect of sodium was concentration‐dependent with a higher dose (120 mm) exerting a smaller effect on binding.
[3H]‐dextromethorphan binding in the presence of sodium was inhibited in the presence of the anticonvulsant phenytoin at a concentration of 100 μm, while the σ ligand (+)‐3‐(‐3‐hydroxyphenyl)‐N‐(1‐propyl)pipendine ((+)‐PPP) had no effect on the binding, suggesting an interaction with the DM2 site.
The distribution of the sodium‐dependent binding identified in this study correlated significantly with the distribution of the selective 5‐HT uptake inhibitor [3H]‐paroxetine, and paroxetine and dextromethorphan mutually displaced their binding at concentrations in the low nanomolar range.
These data show that dextromethorphan and paroxetine share a sodium‐dependent high affinity binding site in rat brain, and suggest that dextromethorphan might interact, in the presence of sodium, with the 5‐HT uptake mechanism in rat brain.

British Journal of Pharmacology (1997) 120, 1255–1262; doi:10.1038/sj.bjp.0701043
β‐Adrenoceptor‐mediated effects in rat cultured thymic epithelial cells
Authors: Kurz Bodo , Feindt Janka , Von Gaudecker Brita , Kranz Andrea , Loppnow Harald , Mentlein Rolf 
Published: August 2006

Sympathetic nerves were visualized in sections from rat thymus by immunostaining of tyrosine hydroxylase, the rate‐limiting enzyme of catecholamine biosynthesis, and by glyoxylic acid‐induced fluorescence of catecholamines. Catecholaminergic nerve fibres were detected in close connection to thymic epithelial cells which therefore might be preferred target cells. To evaluate this, rat immunocytochemically defined, cultured thymic epithelial cells were investigated for adrenoceptors and adrenergic effects.
In rat cultured thymic epithelial cells mRNA for β1‐ and β2‐adrenoceptors was detected by reverse transcription‐polymerase chain reaction by use of sequence‐specific primers. Specific, saturable binding to the cultivated cells was observed with the β‐adrenoceptor agonist CGP 12177.
Adrenaline, noradrenaline or the β‐adrenoceptor agonist, isoprenaline, increased intracellular adenosine 3′: 5′‐cyclic monophosphate (cyclic AMP) levels in cultivated thymic epithelial cells dose‐dependently about 25 fold. The pharmacological properties revealed that this response was mediated by receptors of the β1‐ and the β2‐subtypes. The selective β3‐adrenoceptor agonist BRL 37344 had no effect on cyclic AMP levels. The increase in cyclic AMP was downregulated by preincubation with glucocorticoids like dexamethasone or cortisol which also changed the relative importance of β1‐/β2‐adrenoceptors to the response.
Incubation with isoprenaline or the adenylate cyclase activator forskolin decreased basal and serum‐stimulated proliferation of thymic epithelial cells. However, adrenergic stimulation of thymic epithelial cells did not induce interleukin 1 production. Since thymic epithelial cells create a microenvironment which influences the maturation and differentiation of thymocytes to T‐lymphocytes, their observed capacity to respond to catecholamines provides novel evidence for the suggestion that adrenergic stimulation may interfere with the regulation of immune functions.

British Journal of Pharmacology (1997) 120, 1401–1408; doi:10.1038/sj.bjp.0701045
Evidence for a dilator function of 8‐iso prostaglandin F2α in rat pulmonary artery
Authors: Jourdan Karen B. , Evans Timothy W. , Curzen Nicholas P. , Mitchell Jane A. 
Published: August 2006

8‐Iso prostaglandin F2α (8‐iso PGF2α) is one of a series of prostanoids formed independently of the cyclo‐oxygenase pathway. It has been shown to be upregulated in many conditions of oxidant stress where its formation is induced by free radical‐catalysed actions on arachidonic acid. As 8‐iso PGF2α is formed in vivo in diseases in which oxidant stress is high such as septic shock, we have assessed the relative potency and efficacy of this compound in pulmonary arteries from control and lipopolysaccharide (LPS)‐treated rats.
Several studies have characterized the contractile actions of 8‐iso PGF2α on various smooth muscle preparations, but its potential dilator actions have not been addressed. Thus these studies examined both the contractile and dilator actions of 8‐iso PGF2α in rat pulmonary artery rings. The thromboxane mimetic U46619, PGE2 sodium nitroprusside (SNP) and acetyl choline (ACh) were used for comparison. Each prostanoid had to be dissolved in ethanol to a maximum concentration of 1×10−2 m. At high concentrations, ethanol directly contracted pulmonary vessels. We were therefore limited by the actions of the vehicle such that we were unable to add prostanoids at concentrations higher than 1×10−4 m. In some cases this meant that maximum responses were not achieved and in these cases the Emax and pD2 values are apparent estimates.
The following rank order of potency was obtained from contractile studies; U46619>8‐iso PGF2α>PGE2, each prostanoid producing concentration‐dependent contractions (10−103×10−4 m, 10−910−4 m, 10−810−4 m, respectively). As has been shown previously for other smooth muscle preparations, the thromboxane receptor (TP) antagonist ICI 192605, (1×10−6, 1×10−5 and 1×10−4 m), inhibited the contractions of 8‐iso PGF2α in a concentration‐dependent fashion.
The nitric oxide synthase inhibitor, NG‐nitro‐l‐arginine methyl ester (l‐NAME; 1×10−4 m), enhanced the contractile function of both 8‐iso PGF2α and PGE2, but had no effect on that caused by U46619. Similarly, l‐NAME inhibited the dilator function of all agents tested except the exogenous nitric oxide (NO) donor SNP, indicating that PGE2 and 8‐iso PGF2α like ACh, act through the release of NO. The specificity of the effects of l‐NAME were confirmed in studies with the inactive enantiomer d‐NAME (1×10−4 m), which did not affect the contractile or the dilator actions of 8‐iso PGF2α. Furthermore, ICI 192605 enhanced the dilator actions of 8‐iso PGF2α, suggesting that the dilator component of 8‐iso PGF2α was achieved via activation of a non‐TP receptor.
Isoprostanes may modulate vascular tone by a direct action on TP receptors to cause contraction and via a distinct receptor leading to the release of NO to cause dilatation.

British Journal of Pharmacology (1997) 120, 1280–1285; doi:10.1038/sj.bjp.0701052
[Ca2+]i oscillations induced by muscarinic stimulation in airway smooth muscle cells: receptor subtypes and correlation with the mechanical activity
Authors: Roux Etienne , Guibert Christelle , Savineau Jean‐Pierre , Marthan Roger 
Published: August 2006

Cytosolic calcium concentration ([Ca2+]i) by indo 1 microspectrofluorimetry in freshly isolated cells and isometric contraction of isolated rings were measured in response to muscarinic cholinoceptor stimulation in rat tracheal smooth muscle.
In isolated myocytes, acetylcholine (ACh, 0.031 μm) caused a rapid and graded increase in [Ca2+]i up to a net amplitude of 492±26 nm (n=19) which gradually declined. The EC50 for ACh was 0.13 μm. This first [Ca2+]i peak was followed, when the ACh concentration increased, in approximately 5060% of the cells, by successive peaks of decreased amplitude ([Ca2+]i oscillations) superimposed on the plateau phase. Whereas the percentage of cells exhibiting [Ca2+]i oscillations remained consistent, the frequency of these oscillations increased to up to 10 min−1 with an ACh concentration of 100 μm.
Removal of extracellular calcium (in the presence of EGTA, 0.4 mm) or addition of the voltage‐dependent Ca2+‐channel blocker verapamil (10 μm) did not alter the first [Ca2+]i peak, the plateau or the oscillations induced by ACh or carbachol. In contrast, the specific inhibitor of the sarcoplasmic Ca2+‐ATPase, thapsigargin (1 μm), completely abolished the [Ca2+]i response. Thapsigargin (1 μm) also blocked the caffeine (5 mm)‐induced transient rise in [Ca2+]i.
Atropine (a non‐selective muscarinic cholinoceptor antagonist) and 4‐diphenyl acetoxy N‐methyl piperidine (4‐DAMP, a selective M3 antagonist) inhibited the [Ca2+]i response to muscarinic cholinoceptor activation with an IC50 of 13 and 20 nm, respectively. Pirenzepine (a selective M1 antagonist) also totally inhibited the [Ca2+]i response to ACh but with a higher IC50 of 2 μm. Methoctramine (a selective M2 antagonist) up to a concentration of 10 μm caused only a 40% inhibition. The effect of muscarinic antagonists on cumulative concentration‐response curves (CCRC) for carbachol was assessed at the following concentrations: atropine and 4‐DAMP at 3, 10 and 30 nm; pirenzepine 0.3, 1 and 3 μm, and methoctramine at 1, 3 and 10 μm. For these concentrations, all of the antagonists produced a rightward shift of the CCRC for carbachol and pA2 values were 9.2, 8.8, 6.7 and 6.3, respectively.
In conclusion, the present study indicates that muscarinic stimulation of rat isolated tracheal smooth muscle cells induces [Ca2+]i oscillations. The occurrence of these oscillations depends on the graded amplitude of the first [Ca2+]i rise and their frequency may play a role in the amplitude of the mechanical activity in response to muscarinic cholinoceptor activation. Both the [Ca2+]i and the contractile responses are primarily dependent on activation of the M3 receptor subtype.

British Journal of Pharmacology (1997) 120, 1294–1301; doi:10.1038/sj.bjp.0701061
Investigation of role for oxidant stress in vascular tolerance development to glyceryl trinitrate in vitro
Authors: Laight David W. , Carrier Martin J. , Änggård Erik E. 
Published: August 2006

The role of reactive oxygen species (ROS) during the development of vascular cellular tolerance to glyceryl trinitrate (GTN), was studied in the rat isolated aorta.
Nitrate tolerance induced by a 30 min incubation with GTN (30 or 100 μm) in vitro, was not affected by pretreatment with the intracellular superoxide anion scavenger, tiron (10 mm), or the intracellular scavenger of peroxynitrite anion and hydroxyl radical, dimethylsulphoxide (DMSO, 0.2% v v−1). In contrast, pretreatment with the intracellular sulphydryl donor, N‐acetyl‐l‐cysteine (NAC, 1 mm), significantly attenuated GTN‐induced tolerance.
Pretreatment with a putative inhibitor of oxidant stress‐mediated, transcription factor NF‐κ B activation, pyrrolidine dithiocarbamate (PDTC, 50 μm), an inhibitor of gene activation by NF‐κB, dexamethasone (1 μm) or an inhibitor of protein synthesis, cycloheximide (10 μm), failed to affect tolerance development to GTN.
Pretreatment with DMSO (0.2% v v−1) or PDTC (50 μm) depressed non‐tolerant vasorelaxation to GTN (1 nm1 μm) per se.
Tiron (10 mm) abolished the reduction of ferricytochrome c by a superoxide anion generating system, assessed photometrically in vitro. In contrast, DMSO (0.2% v v−1), NAC (1 mm) and PDTC (50 μm) were without effect.
Our data suggests that neither oxidant stress nor nuclear activation, is important in the development of cellular tolerance to GTN in rat isolated aortic smooth muscle.

British Journal of Pharmacology (1997) 120, 1477–1482; doi:10.1038/sj.bjp.0701078
Synergistic interaction between endothelium‐derived NO and prostacyclin in pulmonary artery: potential role for K+ATP channels
Authors: Gambone Linda M , Murray Paul A , Flavahan Nicholas A 
Published: August 2006

The aim of the present study was to assess interactions between nitric oxide (NO) and prostacyclin (PGI2) during endothelium‐dependent relaxations evoked by bradykinin, calcium ionophore (A23187) and acetylcholine in canine isolated pulmonary artery.
Relaxations to low concentrations of bradykinin and A23187 were abolished by combined inhibition of NO‐synthase (by NΩ‐nitro‐L‐arginine methyl ester L‐NAME, 30 μM) and cyclo‐oxygenase (indomethacin, 10 μM), suggesting mediation by NO and PGI2. The individual contributions of NO and PGI2 to the dilator responses were quantified by use of areas above the separate indomethacin‐insensitive and L‐NAME‐insensitive components of the concentration‐effect curves, respectively. Individually, NO and PGI2 accounted for only 53±5% and 16±9% of total bradykinin‐induced relaxation, and 46±10% and 20±9% of total A23187‐induced relaxation, suggesting that NO and PGI2 acted synergistically to cause endothelium‐dependent relaxation.
Relaxation to low concentrations of acetylcholine was abolished by L‐NAME but not affected by indomethacin, suggesting the response was mediated solely by NO with no interaction from PGI2.
Glibenclamide (1 μM), an inhibitor of ATP‐sensitive potassium (K+ATP) channels, inhibited responses to bradykinin or A23187 but did not affect relaxations evoked by acetylcholine. Glibenclamide did not affect endothelium‐independent relaxations to PGI2 or the NO‐donor, 3‐morpholinosydnonimine (SIN‐1).
With bradykinin, glibenclamide attenuated total relaxation by 49±8%, but did not alter the individual NO and PGI2‐mediated components of the response. Glibenclamide abolished the synergistic interaction between endothelium‐derived NO and PGI2.
At high concentrations, bradykinin, A23187 or acetylcholine caused endothelium‐dependent relaxation that was insensitive to L‐NAME + indomethacin. With bradykinin or A23187, this component of relaxation was inhibited by glibenclamide, whereas with acetylcholine, glibenclamide had no effect.
The synergistic interaction between endothelium‐derived NO and PGI2 in canine pulmonary artery is mediated by activation of K+ATP channels, presumably by an endothelium‐derived hyperpolarizing factor (EDHF). The pattern of endothelial dilator mediators and the presence of this synergistic interaction is dependent on the nature of the endothelial stimulus.

British Journal of Pharmacology (1997) 121, 271–279; doi:10.1038/sj.bjp.0701082
Reduced responsiveness of rat mesenteric resistance artery smooth muscle to phenylephrine and calcium following myocardial infarction
Authors: Stassen Frank R. M. , Willemsen Maurice J. J. M. F. , Janssen Ger M. J. , Fazzi Gregorio E. , Schiffers Paul M. H. , Smits Jos F. M. , De Mey Jo G. R. 
Published: August 2006

We evaluated responses of peripheral resistance arterial smooth muscle to α1‐adrenoceptor stimulation in a rat model of heart failure in relation to neurohumoral changes, wall structure, receptor density and cellular calcium handling.
Plasma samples and third order mesenteric artery side‐branches were obtained from Wistar rats after induction of left ventricular infarction (MI) or sham surgery. Vessels were denuded of endothelium, sympathectomized, depleted of neuropeptides, and mounted in a myograph for recording of isometric force development in response to calcium, agonist and high potassium. Also, the morphology of these preparations was determined. Separate vessel segments were used in radioligand binding assays with [3H]‐prazosin.
At 1 week after MI, circulating plasma levels of adrenaline, angiotensin II, atrial natriuretic factor (ANF) and vasopressin were significantly elevated. At 5 weeks only a significant elevation of ANF persisted.
At 5 weeks after MI, the structure of the vessels and responsiveness to high potassium or Bay K 8466 (10−6 mol l−1) were not modified. Yet, at this stage, sensitivity to phenylephrine was increased (pD2: 6.24±0.04 vs 5.98±0.04 for controls) while maximal contractile responses to phenylephrine in the presence of 2.5 mmol l−1 calcium (2.26±0.28 vs 3.53±0.34 N m−1) and the sensitivity to calcium in the presence of phenylephrine (pD2: 2.81±0.22 vs 3.74±0.16) were reduced. Responses to the agonist in calcium‐free solution and the calcium sensitivity in the presence of 125 mmol l−1 potassium or of phorbol myristate acetate (PMA, 10−6 mol l−1) were not altered.
At 5 weeks after MI, the density of prazosin binding sites was not reduced (4.04±1.40 vs 2.29±0.21 fmol μg−1 DNA in controls).
In conclusion, myocardial infarction leads in the rat to a reduction of contractile responses of mesenteric resistance arterial smooth muscle to α1‐adrenoceptor stimulation. This seems to involve impaired agonist‐stimulated calcium influx.

British Journal of Pharmacology (1997) 120, 1505–1512; doi:10.1038/sj.bjp.0701089
Effects of hypomagnesia on histamine H1 receptor‐mediated facilitation of NMDA responses
Authors: Payne Geoffrey W , Neuman Richard S 
Published: August 2006

The ability of histamine to facilitate the N‐methyl‐D‐aspartate (NMDA) induced depolarization of cortical projection neurones was examined by use of grease‐gap recording.
Histamine (1 to 15 μM) reversibly facilitated the NMDA‐induced depolarization yielding a bell‐shaped concentration‐response relationship. The peak enhancement was 167% above the control at 10 μM histamine. Desensitization was present in 4 out of 5 slices on second exposure 40 min following the first exposure.
Histamine did not alter the depolarization induced by 10 μM kainate.
The histamine‐induced facilitation persisted in the presence of tetrodotoxin, but was reduced in a concentration‐dependent manner by diphenhydramine (IC50=7.6 nM). Cyproheptadine (10 nM) also reduced the facilitation, whereas ranitidine (200 nM) and thioperamide (10 nM) were ineffective in this regard.
Histamine (10 μM) facilitated the NMDA (25 μM)‐induced depolarization in nominally Mg2+‐free medium. The magnitude of the facilitation was smaller than that observed in Mg2+‐containing medium (17% above the control) and desensitization was not observed. This facilitation was not reduced by cyproheptadine (10 nM) or diphenhydramine (1 μM).
We conclude that histamine facilitates the NMDA depolarization at cortical neurones via two distinct mechanisms. One mechanism involves activation of the histamine H1 receptor and is sensitive to Mg2+. The second mechanism is independent of histamine cell surface receptor activation and may reflect a direct action of histamine at the NMDA receptor.

British Journal of Pharmacology (1997) 121, 199–204; doi:10.1038/sj.bjp.0701123