bluuebunny/crossref_metadata_2025_split huggingface dataset:
Somatostatin potentiates NMDA receptor function via activation of InsP3 receptors and PKC leading to removal of the Mg2+ block without depolarization
Authors: Pittaluga Anna , Bonfanti Andrea , Raiteri Maurizio 
Published: January 2005

N‐methyl‐D‐aspartate (NMDA) receptors exist on noradrenergic axon terminals and mediate enhancement of noradrenaline (NA) release. We here investigated modulation by somatostatin (SRIF, somatotropin release inhibiting factor) of the NMDA‐induced release of NA using superfused hippocampal synaptosomes.
The NMDA response was increased by SRIF‐28 and SRIF‐14, but not SRIF‐28(1–14), whereas the release of [3H]‐NA elicited by α‐amino‐3‐hydroxy‐5‐methylisoxazide‐4‐propionic acid (AMPA) was unaffected. SRIF‐14 did not mimic glycine at the NMDA receptor but activated SRIF receptors sited on noradrenergic terminals.
The SRIF‐14 effect was blocked by pertussis toxin but mimicked by mastoparan, a G‐protein activator. BIM‐23056, but not Cyanamid 154806, antagonized the SRIF‐14 effect. This effect was mimicked by L362855, a partial agonist at the sst5 subtype, but not by the new selective sst1–sst4 receptor agonists L797591, L779976, L796778 and L803087.
Protein kinase C (PKC) inhibitors (H7, staurosporine, GF 209103X, cheleritrine and sphingosine) prevented the SRIF‐14 effect, while phorbol 12‐myristate 13‐acetate enhanced the NMDA response.
SRIF‐14 permitted NMDA receptor activation in the presence of 1.2 mM Mg2+ ions, both in hippocampal synaptosomes and slices. Blockade of inositol‐1,4,5‐trisphosphate (InsP3) receptors with heparin abolished the effect of SRIF‐14.
It is concluded that SRIF receptors, possibly of the sst5 subtype, can exert a permissive role on NMDA receptors colocalized on hippocampal noradrenergic terminals: activation of sst5 receptors is coupled to pertussis toxin‐sensitive G proteins enhancing phosphoinositide metabolism with activation of InsP3 receptors and PKC; NMDA receptor subunits might be phosphorylated with consequent removal of the Mg2+ block in absence of depolarization.

British Journal of Pharmacology (2000) 130, 557–566; doi:10.1038/sj.bjp.0703346
Endogenous nitric oxide decreases hippocampal levels of serotonin and dopamine in vivo
Authors: Wegener Gregers , Volke Vallo , Rosenberg Raben 
Published: January 2005

Nitric oxide (NO) modulates the levels of various neurotransmitters in the CNS. Here we determined whether the specific nitric oxide synthase (NOS) inhibitor 7‐nitroindazole (7‐NI), the non‐selective inhibitor of guanylate cyclase (GC) and NOS, methylene blue (MB), the NO‐precursor L‐arginine (L‐Arg), and the selective soluble GC inhibitor 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ) affect extracellular levels of serotonin (5‐HT), dopamine (DA), 5‐hydroxyindoleacetic acid (5‐HIAA), and homovanillic acid (HVA) in the rat ventral hippocampus by using microdialysis in freely moving animals.
Local perfusion of 7‐NI (1 mM) and MB (1 mM) significantly increased extracellular level of 5‐HT, whereas DA was increased by 7‐NI only. Systemic administration of 7‐NI (50 mg kg−1) and MB (30 mg kg−1) increased the extracellular levels of 5‐HT and DA. Extracellular levels of 5‐HIAA was not influenced by local or systemic MB or 7‐NI. In contrast, extracellular level of HVA was decreased by systemic MB and retrodialyzed MB, but was not influenced by 7‐NI.
Retrodialysis of L‐Arg (2 mM) decreased the levels of 5‐HT, DA, 5‐HIAA and HVA in the hippocampus. Systemic administration of L‐Arg (250 mg kg−1) decreased the level of 5‐HT, but failed to influence DA, 5‐HIAA and HVA.
Local perfusion of ODQ (400 μM) did not affect 5‐HT overflow in the hippocampus.
We conclude that NOS inhibitors increased extracellular levels of 5‐HT and DA in the rat ventral hippocampus after local or systemic administration, whereas the NO precursor L‐Arg had the opposite effect. Thus, endogenous NO may exert a negative control over the levels of 5‐HT and DA in the hippocampus. However, this effect is probably not mediated by cyclic GMP.

British Journal of Pharmacology (2000) 130, 575–580; doi:10.1038/sj.bjp.0703349
High affinity interaction of mibefradil with voltage‐gated calcium and sodium channels
Authors: Eller Philipp , Berjukov Stanislav , Wanner Siegmund , Huber Irene , Hering Steffen , Knaus Hans‐Günther , Toth Geza , Kimball S David , Striessnig Jörg 
Published: January 2005

Mibefradil is a novel Ca2+ antagonist which blocks both high‐voltage activated and low voltage‐activated Ca2+ channels. Although L‐type Ca2+ channel block was demonstrated in functional experiments its molecular interaction with the channel has not yet been studied. We therefore investigated the binding of [3H]‐mibefradil and a series of mibefradil analogues to L‐type Ca2+ channels in different tissues.
[3H]‐Mibefradil labelled a single class of high affinity sites on skeletal muscle L‐type Ca2+ channels (KD of 2.5±0.4 nM, Bmax=56.4±2.3 pmol mg−1 of protein).
Mibefradil (and a series of analogues) partially inhibited (+)‐[3H]‐isradipine binding to skeletal muscle membranes but stimulated binding to brain L‐type Ca2+ channels and α1C‐subunits expressed in tsA201 cells indicating a tissue‐specific, non‐competitive interaction between the dihydropyridine and mibefradil binding domain.
[3H]‐Mibefradil also labelled a heterogenous population of high affinity sites in rabbit brain which was inhibited by a series of nonspecific Ca2+ and Na+‐channel blockers.
Mibefradil and its analogue RO40‐6040 had high affinity for neuronal voltage‐gated Na+‐channels as confirmed in binding (apparent Ki values of 17 and 1.0 nM, respectively) and functional experiments (40% use‐dependent inhibition of Na+‐channel current by 1 μM mibefradil in GH3 cells).
Our data demonstrate that mibefradil binds to voltage‐gated L‐type Ca2+ channels with very high affinity and is also a potent blocker of voltage‐gated neuronal Na+‐channels. More lipophilic mibefradil analogues may possess neuroprotective properties like other nonselective Ca2+‐/Na+‐channel blockers.

British Journal of Pharmacology (2000) 130, 669–677; doi:10.1038/sj.bjp.0703352
Gadolinium inhibits Na+‐Ca2+ exchanger current in guinea‐pig isolated ventricular myocytes
Authors: Zhang Y H , Hancox J C 
Published: January 2005

The trivalent cation, gadolinium (Gd3+) is commonly used to inhibit stretch‐activated channels. In this report, we show that Gd3+ also inhibits ionic current (INaCa), carried by the Na+‐Ca2+ exchanger protein. Under selective recording conditions, Gd3+ inhibited both outward and inward INaCa from guinea‐pig isolated ventricular myocytes in a dose‐dependent manner, with half‐maximal inhibition concentrations (IC50) of 30.0±4.0 μM at +60 mV (Hill‐coefficient, h=1.04±0.13) and 20.0±2.7 μM at −100 mV (h=1.13±0.16), respectively (P>0.05, n=5–9). Thus, inhibition was not voltage‐dependent. The time from Gd3+ application to steady‐state effect was slow compared to the divalent blocker Ni2+. The slow time course appeared to reflect gradual Gd3+ accumulation at its binding site on the exchanger, rather than a use‐dependent blocking mechanism. This study indicates that for experiments in which Gd3+ is used, its inhibitory effect on INaCa should be taken into account.British Journal of Pharmacology (2000) 130, 485–488; doi:10.1038/sj.bjp.0703353
Xestospongin C, a selective and membrane‐permeable inhibitor of IP3 receptor, attenuates the positive inotropic effect of α‐adrenergic stimulation in guinea‐pig papillary muscle
Authors: Miyamoto Shigeki , Izumi Masanori , Hori Masatoshi , Kobayashi Motomasa , Ozaki Hiroshi , Karaki Hideaki 
Published: January 2005

We evaluated the role of the inositol 1,4,5‐triphosphate (IP3) receptor‐mediated Ca2+ release on the positive inotropic effects of α‐adrenergic stimulation using a novel, potent, selective membrane‐permeable blocker of IP3 receptor, xestospongin C.
Guinea‐pig papillary muscle permeabilized with saponin exhibited spontaneous oscillatory contractions in solution buffered with pCa2+ 6.5 by a low concentration of EGTA. The oscillatory activity was increased by adding 100 μM IP3 and abolished by 1 μM ryanodine or 30 μM cyclopiazonic acid. Xestospongin C (3 μM) inhibited the IP3‐induced increase in the oscillatory contractions without affecting basal oscillations.
In intact papillary muscle, xestospongin C (3 μM) inhibited the positive inotropic effects of phenylephrine, resulting in a rightward and downward shift of the concentration‐response curve for phenylephrine. On the contrary, xestospongin C did not affect the concentration‐response curve for phenylephrine obtained in the presence of ryanodine (1 μM).
On the other hand, xestospongin C affected neither basal contractions nor the positive inotropic effects of a high extracellular Ca2+ concentration (3.2 mM) or that of isoprenaline (1 and 10 nM).
These results suggest that the IP3‐mediated increase in Ca2+ release is involved in the positive inotropic effects of α‐adrenergic stimulation in the guinea‐pig cardiac muscle.

British Journal of Pharmacology (2000) 130, 650–654; doi:10.1038/sj.bjp.0703358
Adenosine receptor expression and function in rat striatal cholinergic interneurons
Authors: Preston Zoe , Lee Kevin , Widdowson Leon , Freeman Tom C , Dixon Alistair K , Richardson Peter J 
Published: January 2005

Cholinergic neurons were identified in rat striatal slices by their size, membrane properties, sensitivity to the NK1 receptor agonist (Sar9, Met(O2)11) Substance P, and expression of choline acetyltransferase mRNA. A1 receptor mRNA was detected in 60% of the neurons analysed, and A2A receptor mRNA in 67% (n=15).
The A1 receptor agonist R‐N6‐(2‐phenylisopropyl)adenosine (R‐PIA) hyperpolarized cholinergic neurons in a concentration dependent manner sensitive to the A1 antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX, 100 nM).
In dual stimulus experiments, the A2A receptor antagonist 8‐(3‐chlorostyryl)caffeine (CSC, 500 nM) decreased release of [3H]‐acetylcholine from striatal slices (S2/S1 0.78±0.07 versus 0.95±0.05 in control), as did adenosine deaminase (S2/S1 ratio 0.69±0.05), whereas the A1 receptor antagonist DPCPX (100 nM) had no effect (S2/S1 1.05±0.14).
In the presence of adenosine deaminase the adenosine A2A receptor agonist 2‐p‐((carboxyethyl)phenylethylamino)‐5′‐N‐ethylcarboxamidoadenosine (CGS21680, 10 nM) increased release (S2/S1 ratio 1.03±0.05 versus 0.88±0.05 in control), an effect blocked by the antagonist CSC (500 nM, S2/S1 0.68±0.05, versus 0.73±0.08 with CSC alone). The combined superfusion of bicuculline (10 μM), saclofen (1 μM) and naloxone (10 μM) had no effect on the stimulation by CGS21680 (S2/S1 ratio 0.99±0.04).
The A1 receptor agonist R‐PIA (100 nM) inhibited the release of [3H]‐acetylcholine (S2/S1 ratio 0.70±0.03), an effect blocked by DPCPX (S2/S1 ratio 1.06±0.07).
It is concluded that both A1 and A2A receptors are expressed on striatal cholinergic neurons where they are functionally active.

British Journal of Pharmacology (2000) 130, 886–890; doi:10.1038/sj.bjp.0703366
Increased defecation during stress or after 5‐hydroxytryptophan: selective inhibition by the 5‐HT4 receptor antagonist, SB‐207266
Authors: Sanger G J , Yoshida M , Yahyah M , Kitazumi K 
Published: January 2005

5‐HT4 receptor antagonism pr2events the ability of exogenous 5‐HT or 5‐HTP to sensitize the intestinal peristaltic reflex and increase the rate of defecation, generally without affecting non‐stimulated intestinal function. In this study we confirmed the ability of the selective 5‐HT4 receptor antagonist SB‐207266 1–1000 μg kg−1 p.o., to prevent the increase in defecation evoked over a 60 min period by 5‐HTP 10 mg kg−1 s.c. in conscious mice, in the absence of an apparent constipating action.
The role of endogenous 5‐HT in the mechanisms of increased defecation and/or diarrhoea was then investigated in conscious, fed rats. This was evoked by 180 min exposure to restraint stress, which increased both the number and mean weight of formed, faecal pellets excreted over the entire time period.
SB‐207266 1–1000 μg kg−1 p.o. (dosed 30 min before restraint) did not affect the increase in defecation evoked during the first 60 min of restraint stress, but significantly and dose‐dependently reduced or prevented the increased defecation during the remaining 120 min of the experiment; this action occurred in the absence of an apparent constipating action of SB‐207266.
In fasted rats exposed to restraint stress, watery diarrhoea developed and although there was a tendency for SB‐207266 1–1000 μg kg−1 p.o. (dosed 30 min before restraint) to reduce the incidence of diarrhoea, this inhibition was not complete.
We conclude that selective 5‐HT4 receptor antagonism prevents disruptions in defecation behaviours caused by exogenous or endogenous enteric 5‐HT and that this activity is not accompanied by a concomitant suppression of activity (constipation‐like) within the intestine itself.

British Journal of Pharmacology (2000) 130, 706–712; doi:10.1038/sj.bjp.0703367
Antagonist effects on human P2X7 receptor‐mediated cellular accumulation of YO‐PRO‐1
Authors: Michel A D , Kaur R , Chessell I P , Humphrey P P A 
Published: January 2005

We have examined the interaction of P2 antagonists with the human P2X7 receptor by studying their effect on 2′ and 3′‐O‐benzoyl‐benzoyl‐ATP (DbATP) stimulated cellular accumulation of the fluorescent, DNA binding dye, YO‐PRO‐1 (MW=375Da).
In suspensions of HEK293 cells expressing human recombinant P2X7 receptors, DbATP produced time and concentration‐dependent increases in YO‐PRO‐1 fluorescence. This response presumably reflects YO‐PRO‐1 entry through P2X7 receptor channels and binding to nucleic acids. When studies were performed in a NaCl‐free, sucrose‐containing buffer, full concentration‐effect curves to DbATP could be constructed.
The P2 antagonists, pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS) and periodate oxidized ATP (oATP), reduced the potency of DbATP and decreased its maximum response. 1‐[N,O‐bis(1,5‐isoquinolinesulphonyl)‐N‐methyl‐L‐tyrosyl]‐4‐phenylpiperazine (KN62) and its analogue, KN04, reduced the potency of DbATP. Schild slopes for KN62 and KN04 were shallow and exhibited a plateau at concentrations of compound greater than 1 μM, indicating that these compounds were not competitive antagonists.
Calmidazolium and a monoclonal antibody to human P2X7 receptors attenuated DbATP‐stimulated YO‐PRO‐1 accumulation but they were not competitive antagonists and only produced 2–3 fold decreases in the potency of DbATP.
The effects of PPADS and KN62 were partially reversible whereas those of oATP were not. PPADS protected cells against the irreversible antagonist effects of oATP suggesting a common site of action. In contrast KN62 was not effective suggesting that it may bind at a different site to oATP and PPADS.
This study has demonstrated that P2X7 receptor function can be quantified by measuring DbATP stimulated YO‐PRO‐1 accumulation and has provided additional information about the interaction of P2 receptor antagonists with the human P2X7 receptor.

British Journal of Pharmacology (2000) 130, 513–520; doi:10.1038/sj.bjp.0703368
Betaxolol, a β1‐adrenoceptor antagonist, reduces Na+ influx into cortical synaptosomes by direct interaction with Na+ channels: comparison with other β‐adrenoceptor antagonists
Authors: Chidlow Glyn , Melena José , Osborne Neville N 
Published: January 2005

Betaxolol, a β1‐adrenoceptor antagonist used for the treatment of glaucoma, is known to be neuroprotective in paradigms of ischaemia/excitotoxicity. In this study, we examined whether betaxolol and other β‐adrenoceptor antagonists interact directly with neurotoxin binding to sites 1 and 2 of the voltage‐sensitive sodium channel (Na+ channel) in rat cerebrocortical synaptosomes.
Betaxolol inhibited specific [3H]‐batrachotoxinin‐A 20‐α‐benzoate ([3H]‐BTX‐B) binding to neurotoxin site 2 in a concentration‐dependent manner with an IC50 value of 9.8 μM. Comparison of all the β‐adrenoceptor antagonists tested revealed a potency order of propranolol>betaxolol∼levobetaxolol>levobunolol∼carteololtimolol>atenolol.
None of the drugs caused a significant inhibition of [3H]‐saxitoxin binding to neurotoxin receptor site 1, even at concentrations as high as 250 μM.
Saturation experiments showed that betaxolol increased the KD of [3H]‐BTX‐B binding but had no effect on the Bmax. The association kinetics of [3H]‐BTX‐B were unaffected by betaxolol, but the drug significantly accelerated the dissociation rate of the radioligand. These findings argue for a competitive, indirect, allosteric mode of inhibition of [3H]‐BTX‐B binding by betaxolol.
Betaxolol inhibited veratridine‐stimulated Na+ influx in rat cortical synaptosomes with an IC50 value of 28.3 μM. Carteolol, levobunolol, timolol and atenolol were significantly less effective than betaxolol at reducing veratridine‐evoked Na+ influx.
The ability of betaxolol to interact with neurotoxin site 2 of the Na+ channel and inhibit Na+ influx may have a role in its neuroprotective action in paradigms of excitotoxicity/ischaemia and in its therapeutic effect in glaucoma.

British Journal of Pharmacology (2000) 130, 759–766; doi:10.1038/sj.bjp.0703369
Regulation of human D1, D2(long), D2(short), D3and D4dopamine receptors by amiloride and amiloride analogues
Authors: Hoare S R J , Coldwell M C , Armstrong D , Strange P G 
Published: January 2005

The modulatory effects of the allosteric effectors methylisobutylamiloride (MIA), benzamil and amiloride have been examined at human D1, D2, D3and D4dopamine receptors. The subtype selectivity and the mechanism of action of this allosteric regulation was examined.In radioligand dissociation experiments each modulator accelerated dissociation from all four receptor subtypes indicating allosteric regulation. MIA displayed selectivity for the D3subtype for acceleration of radioligand dissociation.In equilibrium binding (pseudo‐competition) experiments the three compounds inhibited radioligand binding at the four receptor subtypes. Inhibition curves for D1, D2(short), D2(long)and D3receptors were described by Hill coefficients exceeding unity and data were fitted best by a model that assumes binding of modulator to both the primary and allosteric binding sites of the receptor (the allosteric/competitive model).At the D4subtype, Hill coefficients of unity described the binding data for amiloride and benzamil, consistent with competitive inhibition. The Hill coefficient for MIA at the D4subtype was less than unity and data could be fitted well by the allosteric/competitive model, but it was not possible to define unambiguously the modulatory mechanism. For this effect a better definition of the mechanism could be obtained by simultaneous analysis of data obtained in the presence of a range of concentrations of a purely competitive ligand.MIA reduced the potency with which dopamine stimulated [35S]‐GTPγS binding at the D2receptor. The effects of MIA could be described by the allosteric/competitive model with effects of MIA to inhibit the binding of dopamine but not its ability to induce a response.British Journal of Pharmacology(2000)130, 1045–1059; doi:10.1038/sj.bjp.0703370
Citrulline does not relax isolated rat and rabbit vessels
Authors: Marx Stephen , Vedernikov Yuri , Saade George R , Garfield Robert E 
Published: January 2005

The study was prompted by the report of Ruiz E. & Tejerina T., 1998 describing endothelium‐independent relaxation by L‐citrulline via activation of particulate guanylate cyclase.
We compared the effects of L‐citrulline and L‐arginine in isolated aortic rings of rats and in isolated aortic, carotid and femoral artery rings of rabbits.
No significant relaxation to either L‐citrulline or L‐arginine was found in the concentration range of 10−12 to 10−3 M, while 3‐morpholinosydnonimine hydrochloride (SIN‐1, 10−6 M) relaxed vascular tissues.
This study does not support the conclusion that L‐citrulline has direct vasorelaxing action on vascular smooth muscle.

British Journal of Pharmacology (2000) 130, 713–716; doi:10.1038/sj.bjp.0703372
Endogenous calcitonin gene‐related peptide (CGRP) mediates adrenergic‐dependent vasodilation induced by nicotine in mesenteric resistance arteries of the rat
Authors: Shiraki Hinako , Kawasaki Hiromu , Tezuka Satoko , Nakatsuma Akira , Kurosaki Yuji 
Published: January 2005

The mechanisms underlying vasodilator effect of nicotine on mesenteric resistance blood vessels and the role of calcitonin gene‐related peptide (CGRP)‐containing (CGRPergic) vasodilator nerves were studied in the rat.
Mesenteric vascular beds isolated from Wistar rats were perfused with Krebs solution, and perfusion pressure was measured with a pressure transducer.
In preparations with intact endothelium and contracted by perfusion with Krebs solution containing methoxamine, perfusion of nicotine (1–100 μM) for 1 min caused a concentration‐dependent vasodilator response without vasoconstriction.
The nicotine‐induced vasodilation was markedly inhibited by hexamethonium (nicotinic cholinoceptor antagonist, 10 μM) and blocked by guanethidine (adrenergic neuron blocker, 5 μM).
Either denervation by cold storage (4°C for 72 h) or adrenergic denervation by 6‐hydroxydopamine (toxin for adrenergic neurons, 2 mM for 20 min incubation, twice) blocked the nicotine‐induced vasodilation.
Neither endothelium removal with perfusion of sodium deoxycholate (1.80 mg ml−1, for 30 s) nor treatment with Nω‐nitro‐L‐arginine (nitric oxide synthase inhibitor, 100 μM), atropine (muscarinic cholinoceptor antagonist, 10 nM) or propranolol (β‐adrenoceptor antagonist, 100 nM) affected the nicotine‐induced vasodilation.
In preparations without endothelium, treatment with capsaicin (depleting CGRP‐containing sensory nerves, 1 μM) or human CGRP[8–37] (CGRP receptor antagonist, 0.5 μM) markedly inhibited the nicotine‐induced vasodilation.
These results suggest that, in the mesenteric resistance artery of the rat, nicotine induces vasodilation, which is independent of the function of the endothelium and is involved in activation of CGRPergic nerves. It is also suggested that nicotine stimulates presynaptic nicotinic cholinoceptors on adrenergic nerves to release adrenergic neurotransmitters, which then act on CGRPergic nerves to release endogenous CGRP from the nerve.

British Journal of Pharmacology (2000) 130, 1083–1091; doi:10.1038/sj.bjp.0703376