bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extracellular protons differentially potentiate the responses of native AMPA receptor subtypes regulating neurotransmitter release
Authors: Pittaluga Anna , Segantini Daniela , Feligioni Marco , Raiteri Maurizio 
Published: January 2005

The effects of pH changes on the basal and evoked release of [3H]noradrenaline ([3H]NA) and [3H]5‐hydrohytryptamine ([3H]5‐HT) from hippocampal synaptosomes and of [3H]dopamine ([3H]DA) and [3H]acetylcholine ([3H]ACh) from striatal and cortical synaptosomes were investigated in rat brain.
Changing pH between 6.4 and 8.0 did not affect the spontaneous release of the four [3H]neurotransmitters; alkalinization to pH 8.8 significantly enhanced release. Acidification to pH 6.4 augmented the AMPA‐evoked overflows of [3H]NA, [3H]5‐HT and [3H]DA, but not that of [3H]ACh. In contrast, lowering pH to 6.4 decreased the K+‐evoked overflows of [3H]NA, [3H]5‐HT, [3H]DA and [3H]ACh.
AMPA released transmitters in a Ca2+‐dependent, exocytotic manner since its effects, at pH 7.4 or 6.4, were abolished by omitting external Ca2+ or by depleting vesicular transmitter stores with bafilomycin A1. AMPA did not evoke carrier‐mediated release because the uptake blockers nisoxetine, 6‐nitroquipazine, GBR12909 and hemicholinium‐3 could not inhibit the AMPA‐induced release of [3H]NA, [3H]5‐HT, [3H]DA and [3H]ACh.
Extraterminal acidification to pH 6.4 prevented the potentiating effect of cyclothiazide on the AMPA‐evoked release of [3H]NA, [3H]DA and [3H]5‐HT, whereas the proton‐insensitive AMPA‐evoked release of [3H]ACh, previously found to be cyclothiazide‐insensitive at pH 7.4 was cyclothiazide‐resistant also at pH 6.4.
To conclude, the cyclothiazide‐sensitive AMPA receptors mediating release of NA, 5‐HT and DA, but not the cyclothiazide‐insensitive AMPA receptors mediating the release of ACh, become more responsive when external pH is lowered to pathophysiologically relevant values. The results with cyclothiazide suggest that H+ ions may prevent desensitization of some AMPA receptor subtypes.

British Journal of Pharmacology (2005) 144, 293–299. doi:10.1038/sj.bjp.0705960
Functional implications of modifying RyR‐activating peptides for membrane permeability
Authors: Dulhunty Angela F , Cengia Louise , Young Jacqui , Pace Suzy M , Harvey Peta J , Lamb Graham D , Chan Yiu‐Ngok , Wimmer Norbert , Toth Istvan , Casarotto Marco G 
Published: January 2005

Our aim was to determine whether lipoamino acid conjugation of peptides that are high‐affinity activators of ryanodine receptor (RyR) channels would (a) render the peptides membrane permeable, (b) alter their structure or (a) reduce their activity. The peptides correspond to theAregion of the II–III loop of the skeletal dihydropyridine receptor.The lipoamino acid conjugation increased the apparent permeability of the peptide across the Caco‐2 cell monolayer by up to ∼20‐fold.Nuclear magnetic resonance showed that theα‐helical structure of critical basic residues, required for optimal activation of RyRs, was retained after conjugation.The conjugated peptides were more effective in enhancing resting Ca2+release, Ca2+‐induced Ca2+release and caffeine‐induced Ca2+release from isolated sarcoplasmic reticulum (SR) than their unconjugated counterparts, and significantly enhanced caffeine‐induced Ca2+release from mechanically skinned extensor digitorum longus (EDL) fibres.The effect of both conjugated and unconjugated peptides on Ca2+release from skeletal SR was 30‐fold greater than their effect on either cardiac Ca2+release or on the Ca2+Mg2+ATPase.A small and very low affinity effect of the peptide in slowing Ca2+uptake by the Ca2+, Mg2+ATPase was exacerbated by lipoamino acid conjugation in both isolated SR and in skinned EDL fibres.The results show that lipoamino acid conjugation ofAregion peptides increases their membrane permeability without impairing their structure or efficacy in activating skeletal and cardiac RyRs.British Journal of Pharmacology(2005)144, 743–754. doi:10.1038/sj.bjp.0705981
Transition from placental to air breathing stimulates haem‐oxygenase‐1 expression without functional consequence for pulmonary vascular adaptation in pigs and mice
Authors: Stanford Salome J , Hislop Alison A , Oltmanns Ute , Nabel Elizabeth G , Sang Hong , Haworth Shelia G , Mitchell Jane A 
Published: January 2005

In systemic vessels, haem‐oxygenase (HO) is induced during oxidative stress and known to modulate vasodilatation and vascular remodelling. At birth, with the transition from placental to air breathing, the pulmonary vessels are exposed to oxidative stress and undergo well‐documented remodelling processes. Thus, we investigated the role of HO in the lung during adaptation to extra‐uterine life using a pig and mouse model. In addition to the novel data presented with regard to one isoform, HO‐1, this study is among the first to describe the pulmonary vascular remodelling in the mouse after birth.
We show, for the first time, that another isoform, HO‐2, is present constitutively at birth and HO‐1 protein is induced in the porcine and murine lung after birth in vascular and airway structures, peaking at 14 days in the pig and at about 4 days in the mouse. Furthermore, we show that HO‐1 mRNA declines after birth in the mouse lung.
Inhibitors of HO did not modify vasodilator responses in vessels from 14‐day‐old pigs.
Moreover, lungs from HO‐1‐deficient mice developed normally after birth.
HO‐1 is induced at birth but plays no role in the development of vasodilator responses or remodelling that occurs at this time. These data suggest that HO‐1 expression at birth is a redundant response to oxidative stress in the lungs of healthy mammals. However, it remains possible that this pathway protects if complications occur during or after birth.

British Journal of Pharmacology (2005) 144, 467–476. doi:10.1038/sj.bjp.0705988
Captopril improves cerebrovascular structure and function in old hypertensive rats
Authors: Dupuis François , Atkinson Jeffrey , Limiñana Patrick , Chillon Jean‐Marc 
Published: January 2005

We examined the effects of an angiotensin‐converting enzyme inhibitor (ACEI), captopril, on cerebral arterioles in young and old spontaneously hypertensive rats (SHR).
Animals were anesthetized with sodium pentobarbitone (60 mg kg−1 day−1). We measured cerebral blood flow (CBF, arbitrary units) and cerebral arteriolar internal diameter (ID, μm) prior to and during stepwise hypotension (SH) in 6‐ (WKY‐6) and 15‐month‐old (WKY‐15) Wistar Kyoto rats and in age‐matched SHR that were untreated (SHR‐6 and SHR‐15) or treated for 3 months with captopril (SHR‐6C, 105±2 mg kg−1 day−1 and SHR‐15C, 94±1 mg kg−1 day−1). ID and cross‐sectional area of the vessel wall (CSA) were measured in deactivated (EDTA) cerebral arterioles during a second SH.
Captopril decreased the lower limit of CBF autoregulation (61±6 in SHR‐6C and 51±2 in SHR‐15C versus 52±6 in WKY‐6 and 62±7 in WKY‐15 and 83±14 mmHg in SHR‐6 and 120±19 mmHg in SHR‐15; P<0.05) and CSA (510±21 in SHR‐6C and 585±25 in SHR‐15C versus 529±12 in WKY‐6 and 549±20 in WKY‐15 and 644±38 mmHg in SHR‐6 and 704±38 mmHg in SHR‐15; P<0.05).
Captopril increased cerebral arteriolar external diameter of SHR (105±5 in SHR‐6C and 94±4 in SHR‐15C vs 125±8 in WKY‐6 and 108±3 in WKY‐15 and 83±2 mmHg in SHR‐6 and 80±2 mmHg in SHR‐15 for a pial arteriolar pressure step of 35–39 mmHg; P<0.05). Captopril attenuated increases in cerebral arteriolar distensibility in young SHR.
Thus, ACEIs attenuate eutrophic and hypertrophic inward remodeling of cerebral arterioles in young and old SHR, thus decreasing the lower limit of CBF autoregulation.

British Journal of Pharmacology (2005) 144, 349–356. doi:10.1038/sj.bjp.0706001
Role of SKCa and IKCa in endothelium‐dependent hyperpolarizations of the guinea‐pig isolated carotid artery
Authors: Gluais Pascale , Edwards Gillian , Weston Arthur H , Falck John R , Vanhoutte Paul M , Félétou Michel 
Published: January 2005

This study was designed to determine whether the endothelium‐dependent hyperpolarizations evoked by acetylcholine in guinea‐pig carotid artery involve a cytochrome P450 metabolite and whether they are linked to the activation of two distinct populations of endothelial KCa channels, SKCa and IKCa.
The membrane potential was recorded in the vascular smooth muscle cells of the guinea‐pig isolated carotid artery. All the experiments were performed in the presence of Nω‐L‐nitro arginine (100 μM) and indomethacin (5 μM).
Under control conditions (Ca2+: 2.5 mM), acetylcholine (10 nM to 10 μM) induced a concentration‐ and endothelium‐dependent hyperpolarization of the vascular smooth muscle cells. Two structurally different specific blockers of SKCa, apamin (0.5 μM) or UCL 1684 (10 μM), produced a partial but significant inhibition of the hyperpolarization evoked by acetylcholine whereas charybdotoxin (0.1 μM) and TRAM‐34 (10 μM), a nonpeptidic and specific blocker of IKCa, were ineffective. In contrast, the combinations of apamin plus charybdotoxin, apamin plus TRAM‐34 (10 μM) or UCL 1684 (10 μM) plus TRAM‐34 (10 μM) virtually abolished the acetylcholine‐induced hyperpolarization.
In the presence of a combination of apamin and a subeffective dose of TRAM‐34 (5 μM), the residual hyperpolarization produced by acetylcholine was not inhibited further by the addition of either an epoxyeicosatrienoic acid antagonist, 14,15‐EEZE (10 μM) or the specific blocker of BKCa, iberiotoxin (0.1 μM).
In presence of 0.5 mM Ca2+, the hyperpolarization in response to acetylcholine (1 μM) was significantly lower than in 2.5 mM Ca2+. The EDHF‐mediated responses became predominantly sensitive to charybdotoxin or TRAM‐34 but resistant to apamin.
This investigation shows that the production of a cytochrome P450 metabolite, and the subsequent activation of BKCa, is unlikely to contribute to the EDHF‐mediated responses in the guinea‐pig carotid artery. Furthermore, the EDHF‐mediated response involves the activation of both endothelial IKCa and SKCa channels, the activation of either one being able to produce a true hyperpolarization.

British Journal of Pharmacology (2005) 144, 477–485. doi:10.1038/sj.bjp.0706003
Protein kinase Cγ mediates ethanol withdrawal hyper‐responsiveness of NMDA receptor currents in spinal cord motor neurons
Authors: Li Hui‐Fang , Mochly‐Rosen Daria , Kendig Joan J 
Published: January 2005

The present studies were designed to test the hypothesis that neuronal‐specific protein kinase Cγ (PKCγ) plays a critical role in acute ethanol withdrawal hyper‐responsiveness in spinal cord.
Patch‐clamp studies were carried out in motor neurons in neonatal rat spinal cord slices. Postsynaptic currents were evoked by brief pulses of 2 mM N‐methyl‐D‐aspartic acid (NMDA) in the presence of bicuculline methiodide 10 μM; strychnine 5 μM and tetrodotoxin 0.5 μM.
Both ethanol depression and withdrawal hyper‐responsiveness of NMDA‐evoked currents are dependent on increases in intracellular Ca2+. Blocking intracellular increase in Ca2+ by 30 mM 1,2‐bis(2‐aminophenoxy)‐ethane‐N,N,N′,N′‐tetraacetic acid (BAPTA) not only decreased the ethanol‐induced depression of NMDA‐evoked currents (33±5% in control vs 20±3% in BAPTA, P<0.05) but also eliminated acute ethanol withdrawal hyper‐responsiveness.
Immunohistochemistry studies revealed that neonatal spinal cord motor neurons contain an abundance of nuclear PKCγ.
Exposure to ethanol (100 mM) induced PKCγ translocation from the nucleus to cytoplasm in motor neurons. Pretreatment with the γ‐isozyme‐specific peptide PKC inhibitor, γV5‐3, blocked ethanol‐induced translocation and also blocked withdrawal hyper‐responsiveness.
The results show that PKCγ mediates ethanol withdrawal hyper‐responsiveness in spinal motor neurons; the results may be relevant to some symptoms of ethanol withdrawal in vivo.

British Journal of Pharmacology (2005) 144, 301–307. doi:10.1038/sj.bjp.0706033
Effects of synaptotagmin reveal two distinct mechanisms of agonist‐stimulated internalization of the M4 muscarinic acetylcholine receptor
Authors: Madziva Michael T , Bai Jihong , Bhalla Akhil , Chapman Edwin R , Edwardson J Michael 
Published: January 2005

Synaptotagmin has been reported to function in clathrin‐mediated endocytosis. Here, we investigated its involvement in agonist‐stimulated internalization of M4 muscarinic acetylcholine receptors exogenously expressed in human embryonic kidney (HEK‐293 tsA201) cells.
Synaptotagmin I was present at low levels in these cells, and when overexpressed resided at the plasma membrane.
Synaptotagmin overexpression alone did not affect receptor internalization, but ‘rescued’ internalization that had been inhibited by either dominant‐negative dynamin‐1 or dominant‐negative arrestin‐2. Both normal and ‘rescued’ internalization were sensitive to inhibitors of clathrin‐mediated endocytosis, but not to inhibitors of the function of caveolae.
There was no increase in AP‐2 recruitment to the plasma membrane in cells overexpressing synaptotagmin. However, a mutant form of the receptor lacking a potential AP‐2 recruitment motif, while being internalized normally in response to agonist stimulation, was not rescued by synaptotagmin in cells expressing dominant‐negative dynamin or arrestin.
A mutant form of synaptotagmin (K326,327A), which binds phosphatidylinositol‐4,5‐bisphosphate (PIP2) much more weakly than the wild‐type protein, did not rescue internalization. Furthermore, internalization was inhibited by the PH domain of phospholipase C‐δ1, which sequesters PIP2, and synaptotagmin was now unable to rescue.
We propose that AP‐2 binding to the C‐terminal tail of the receptor is not normally required for its endocytosis, but that the synaptotagmin‐mediated rescue involves the formation of a ternary complex with the receptor and AP‐2. PIP2 might play a role as an intermediary in the formation of this complex.

British Journal of Pharmacology (2005) 144, 761–771. doi:10.1038/sj.bjp.0706035
Endothelium‐dependent contractions in hypertension
Authors: Vanhoutte Paul M , Feletou Michel , Taddei Stefano 
Published: January 2005

Endothelial cells, under given circumstances, can initiate contraction (constriction) of the vascular smooth muscle cells that surround them. Such endothelium‐dependent, acute increases in contractile tone can be due to the withdrawal of the production of nitric oxide, to the production of vasoconstrictor peptides (angiotensin II, endothelin‐1), to the formation of oxygen‐derived free radicals (superoxide anions) and/or the release of vasoconstrictor metabolites of arachidonic acid. The latter have been termed endothelium‐derived contracting factor (EDCF) as they can contribute to moment‐to‐moment changes in contractile activity of the underlying vascular smooth muscle cells.
To judge from animal experiments, EDCF‐mediated responses are exacerbated by aging, spontaneous hypertension and diabetes.
To judge from human studies, they contribute to the blunting of endothelium‐dependent vasodilatations in aged subjects and essential hypertensive patients.
Since EDCF causes vasoconstriction by activation of the TP‐receptors on the vascular smooth muscle cells, selective antagonists at these receptors prevent endothelium‐dependent contractions, and curtail the endothelial dysfunction in hypertension and diabetes.

British Journal of Pharmacology (2005) 144, 449–458. doi:10.1038/sj.bjp.0706042
Synergistic and additive interactions of the cannabinoid agonist CP55,940 with μ opioid receptor and α2‐adrenoceptor agonists in acute pain models in mice
Authors: Tham Shao M , Angus James A , Tudor Elizabeth M , Wright Christine E 
Published: January 2005

Cannabinoid receptor agonists elicit analgesic effects in acute and chronic pain states via spinal and supraspinal pathways. We investigated whether the combination of a cannabinoid agonist with other classes of antinociceptive drugs exerted supra‐additive (synergistic) or additive effects in acute pain models in mice.
The interactions between the cannabinoid agonist CP55,940, α2‐adrenoceptor agonist dexmedetomidine and μ‐opioid receptor agonist morphine were evaluated by isobolographic analysis of antinociception in hot plate (55°C) and tail flick assays in conscious male Swiss mice. Drug interactions were examined by administering fixed‐ratio combinations of agonists (s.c.) in 1 : 1, 3 : 1 and 1 : 3 ratios of their respective ED50 fractions.
CP55,940, dexmedetomidine and morphine all caused dose‐dependent antinociception. In the hot plate and tail flick assays, ED50 values (mg kg−1) were CP55,940 1.13 and 0.51, dexmedetomidine 0.066 and 0.023, and morphine 29.4 and 11.3, respectively. Synergistic interactions existed between CP55,940 and dexmedetomidine in the hot plate assay, and CP55,940 and morphine in both assays. Additive interactions were found for CP55,940 and dexmedetomidine in the tail flick assay, and dexmedetomidine and morphine in both assays.
Thus, an α2‐adrenoceptor agonist or μ opioid receptor agonist when combined with a cannabinoid receptor agonist showed significant synergy in antinociception in the hot plate test. However, for the tail flick nociceptive response to heat, only cannabinoid and μ opioid receptor antinociceptive synergy was demonstrated. If these results translate to humans, then prudent selection of dose and receptor‐specific agonists may allow an improved therapeutic separation from unwanted side effects.

British Journal of Pharmacology (2005) 144, 875–884. doi:10.1038/sj.bjp.0706045
The selectivity of β‐adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors
Authors: Baker Jillian G 
Published: January 2005

β‐Adrenoceptor antagonists (‘β‐blockers’) are one of the most widely used classes of drugs in cardiovascular medicine (hypertension, ischaemic heart disease and increasingly in heart failure) as well as in the management of anxiety, migraine and glaucoma. Where known, the mode of action in cardiovascular disease is from antagonism of endogenous catecholamine responses in the heart (mainly at β1‐adrenoceptors), while the worrisome side effects of bronchospasm result from airway β2‐adrenoceptor blockade. The aim of this study was to determine the selectivity of β‐antagonists for the human β‐adrenoceptor subtypes.
3H‐CGP 12177 whole cell‐binding studies were undertaken in CHO cell lines stably expressing either the human β1‐, β2‐ or the β3‐adrenoceptor in order to determine the affinity of ligands for each receptor subtype in the same cell background.
In this study, the selectivity of well‐known subtype‐selective ligands was clearly demonstrated: thus, the selective β1 antagonist CGP 20712A was 501‐fold selective over β2 and 4169‐fold selective over β3; the β2‐selective antagonist ICI 118551 was 550‐ and 661‐fold selective over β1 and β3, respectively, and the selective β3 compound CL 316243 was 10‐fold selective over β2 and more than 129‐fold selective over β1.
Those β2‐adrenoceptor agonists used clinically for the treatment of asthma and COPD were β2 selective: 29‐, 61‐ and 2818‐fold for salbutamol, terbutaline and salmeterol over β1, respectively. There was little difference in the affinity of these ligands between β1 and β3 adrenoceptors.
The clinically used β‐antagonists studied ranged from bisoprolol (14‐fold β1‐selective) to timolol (26‐fold β2‐selective). However, the majority showed little selectivity for the β1‐ over the β2‐adrenoceptor, with many actually being more β2‐selective.
This study shows that the β1/β2 selectivity of most clinically used β‐blockers is poor in intact cells, and that some compounds that are traditionally classed as ‘β1‐selective’ actually have higher affinity for the β2‐adrenoceptor. There is therefore considerable potential for developing more selective β‐antagonists for clinical use and thereby reducing the side‐effect profile of β‐blockers.

British Journal of Pharmacology (2005) 144, 317–322. doi:10.1038/sj.bjp.0706048
Endothelin‐1 exerts a preconditioning‐like cardioprotective effect against ischaemia/reperfusion injury via the ETA receptor and the mitochondrial KATP channel in the rat in vivo
Authors: Gourine Audrey V , Molosh Audrey I , Poputnikov Dmitry , Bulhak Aliaksandr , Sjöquist Per‐Ove , Pernow John 
Published: January 2005

In vitro studies have demonstrated that endothelin‐1 (ET‐1) given before myocardial ischaemia may evoke a preconditioning (PC)‐like cardioprotective effect. The first aim of this study was to investigate whether administration of ET‐1 before ischaemia exerts cardioprotection against ischaemia/reperfusion injury in vivo and to determine involvement of the ET‐1 receptor subtype. The second aim was to examine the role of mitochondrial ATP‐sensitive K+ channels (mitoKATP) as a mediator of this cardioprotection.
Anaesthetised open‐chest Wistar rats were subjected to 30 min of coronary artery occlusion followed by 2 h reperfusion (I/R). In protocol I, the first group was subjected to I/R only (control, n=10). In the second (n=10) group, PC was elicited by three 5 min cycles of coronary artery occlusion, separated by 5 min reperfusion before I/R. The third (n=6) and fourth (n=7) groups were given ET‐1 intravenous (i.v.) during three 5 min infusion periods separated by 5 min before I/R. The fourth group was in addition given the ETA receptor antagonist LU 135252 5 min before the infusions of ET‐1. In protocol II, the first group was I/R control as in protocol I (n=8). The second (n=6), third (n=7) and fourth (n=7) groups were given ET‐1 as in protocol I. The third group was in addition given the nonselective KATP channel antagonist glibenclamide (Glib) 30 min before the ET‐1 infusions and the fourth group the selective mitoKATP channel antagonist 5‐hydroxydecanoic acid (5‐HD) 5 min before I/R.
There were no significant differences in MAP or heart rate between the groups during I/R. In protocol I, PC reduced IS compared to the control group (10±3 vs 35±5%, P<0.01). Infusion of ET‐1 also reduced IS (to 14±3%, P<0.05 vs control). The ETA receptor antagonist blocked the reduction in IS induced by ET‐1 (IS 47±8% after LU+ET‐1; P< 0.05 vs ET‐1). In protocol II, Glib and 5‐HD abolished the cardioprotective effect induced by ET‐1 (IS 48±7% after Glib+ET‐1 and 42±5% after ET‐1+5‐HD vs 18±4% after ET‐1 alone; P<0.05).
In conclusion, administration of ET‐1 before ischaemia resulted in a PC‐like cardioprotective effect. This effect is mediated via the ETA receptor and activation of mitoKATP channels.

British Journal of Pharmacology (2005) 144, 331–337. doi:10.1038/sj.bjp.0706050