bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diurnal variation in 5‐HT1B autoreceptor function in the anterior hypothalamus in vivo: effect of chronic antidepressant drug treatment
Authors: Sayer Tamsin J O , Hannon Serina D , Redfern Peter H , Martin Keith F 
Published: January 2005

Intracerebral microdialysis was used to examine the function of the terminal 5‐hydroxytryptamine (5‐HT) autoreceptor in the anterior hypothalamus of anaesthetized rats at two points in the light phase of the light–dark cycle.
Infusion of the 5‐HT1A/1B agonist 5‐methoxy‐3‐(1,2,3,6‐tetrahydro‐4‐pyridyl)‐1H‐indole (RU24969) 0.1, 1.0 and 10 μM through the microdialysis probe led to a concentration‐dependent decrease (49, 56 and 65% respectively) in 5‐HT output. The effect of RU24969 (1 and 5 μM) was prevented by concurrent infusion of methiothepin (1 and 10 μM) into the anterior hypothalamus via the microdialysis probe. Infusion of methiothepin alone (1.0 and 10 μM) increased (15 and 142% respectively) 5‐HT output.
Infusion of RU24969 (5 μM) through the probe at mid‐light and end‐light resulted in a quantitatively greater decrease in 5‐HT output at end‐light compared with mid‐light.
Following treatment with either paroxetine hydrochloride (10 mg kg−1 i.p.) or desipramine hydrochloride (10 mg kg−1 i.p.) for 21 days the function of the terminal 5‐HT1B autoreceptor was more markedly attenuated at end‐light.
The data show that, as defined by the response to RU24969, the function of the 5‐HT1B receptors that control 5‐HT output in the anterior hypothalamus is attenuated following chronic desipramine or paroxetine treatment in a time‐of‐day‐dependent manner.

British Journal of Pharmacology (1999) 126, 1777–1784; doi:10.1038/sj.bjp.0702535
Comparison of the redox forms of nitrogen monoxide with the nitrergic transmitter in the rat anococcygeus muscle
Authors: Li Chun Guang , Karagiannis Joanna , Rand Michael J 
Published: January 2005

A sustained tone was produced in rat isolated anococcygeus muscles with guanethidine and clonidine and relaxant responses were elicited by electrical stimulation of its nitrergic nerves and by the three redox forms of nitrogen monoxide.
The nitroxyl anion (NO−) was donated by dissociation of Angeli's salt; the free radical (NO•) was from an aqueous solution of nitric oxide gas; the nitrosonium cation (NO+) was donated by dissociation of nitrosonium tetrafluoroborate.
The concentrations producing approximately 50% relaxations of the anococcygeus muscle were 0.3 μM for Angeli's salt (nitroxyl), 0.5 μM for NO• and 100 μM for nitrosonium tetrafluoroborate. Nitrergic nerve stimulation at 1 Hz for 10 s produced equivalent relaxant responses.
The superoxide generator pyrogallol (100 μM) had no effect on responses to nitrergic nerve stimulation or Angeli's salt but significantly reduced responses to NO• and nitrosonium tetrafluoroborate.
The NO• scavenger carboxy‐PTIO (100 μM) had no effect on responses to nitrergic nerve stimulation or Angeli's salt but significantly reduced responses to NO• and nitrosonium tetrafluoroborate.
Hydroxocobalamin (30 μM) had no significant effect on responses to the nitrergic transmitter, enhanced the response to Angeli's salt, and significantly reduced responses to NO• and nitrosonium tetrafluoroborate.
The findings suggest that the nitroxyl anion donated by Angeli's salt is a better candidate than NO• to serve as the nitrergic transmitter in the rat anococcygeus muscle, although it still does not behave exactly like the transmitter.

British Journal of Pharmacology (1999) 127, 826–834; doi:10.1038/sj.bjp.0702540
Effects of (−)‐tertatolol, (−)‐penbutolol and (±)‐pindolol in combination with paroxetine on presynaptic 5‐HT function: anin vivomicrodialysis and electrophysiological study
Authors: Gartside S E , Clifford E M , Cowen P J , Sharp T 
Published: January 2005

The antidepressant efficacy of selective serotonin reuptake inhibitors (SSRIs) might be enhanced by co‐administration of 5‐HT1Areceptor antagonists. Thus, we have recently shown that the selective 5‐HT1Areceptor antagonist, WAY 100635, blocks the inhibitory effect of an SSRI on 5‐HT cell firing, and enhances its ability to elevate extracellular 5‐HT in the forebrain. Here we determined whether the β‐adrenoceptor/5‐HT1Areceptor ligands (±)‐pindolol, (−)‐tertatolol and (−)‐penbutolol, interact with paroxetine in a similar manner.Both (−)‐tertatolol (2.4 mg kg−1i.v.) and (−)‐penbutolol (2.4 mg kg−1i.v.) enhanced the effect of paroxetine (0.8 mg kg−1i.v.) on extracellular 5‐HT in the frontal cortex, whilst (±)‐pindolol (4 mg kg−1i.v.) did not. (−)‐Tertatolol (2.4 mg kg−1i.v.) alone caused a slight increase in 5‐HT however, (−)‐penbutolol (2.4 mg kg−1i.v.) alone had no effect.In electrophysiological studies (−)‐tertatolol (2.4 mg kg−1i.v.) alone had no effect on 5‐HT cell firing but blocked the inhibitory effect of paroxetine. In contrast, (−)‐penbutolol (0.1–0.8 mg kg−1i.v.) itself inhibited 5‐HT cell firing, and this effect was reversed by WAY 100635 (0.1 mg kg−1i.v.). We have recently shown that (±)‐pindolol inhibits 5‐HT cell firingviaa WAY 100635‐sensitive mechanism.Our data suggest that (−)‐tertatolol enhances the effect of paroxetine on forebrain 5‐HTviablockade of 5‐HT1Aautoreceptors which mediate paroxetine‐induced inhibition of 5‐HT cell firing. In comparison, the mechanisms by which (−)‐penbutolol enhances the effect of paroxetine on extracellular 5‐HT is unclear, since (−)‐penbutolol itself appears to have agonist properties at the 5‐HT1Aautoreceptor. Indeed, the agonist action of (±)‐pindolol at 5‐HT1Aautoreceptors probably explains its inability to enhance the effect of paroxetine on 5‐HT in the frontal cortex.Overall, our data suggest that both (−)‐tertatolol and (−)‐penbutolol are superior to (±)‐pindolol in terms of enhancing the effect of an SSRI on extracellular 5‐HT. Both (−)‐tertatolol and (−)‐penbutolol are worthy of investigation for use as adjuncts to SSRIs in the treatment of major depression.British Journal of Pharmacology(1999)127, 145–152; doi:10.1038/sj.bjp.0702546
Synergistic effect with Phe‐Gly‐Leu‐Met‐NH2 of the C‐terminal of substance P and insulin‐like growth factor‐1 on epithelial wound healing of rabbit cornea
Authors: Nakamura Masatsugu , Chikama Tai‐ichiro , Nishida Teruo 
Published: January 2005

We previously reported that substance P and insulin‐like growth factor‐1 (IGF‐1) synergistically stimulate corneal epithelial wound healing in vitro and in vivo. We wished to identify which portion of the amino acid sequence of substance P might be responsible for this synergism.
Corneal epithelial migration was not affected by the addition of any one of the following factors: substance P; Phe‐Gly‐Leu‐Met‐NH2 (C‐terminal of substance P); Val‐Gly‐Leu‐Met‐NH2 (C‐terminal of neurokinin A, neurokinin B, and kassinin); Tyr‐Gly‐Leu‐Met‐NH2 (C‐terminal of physalaemin); Ile‐Gly‐Leu‐Met‐NH2 (C‐terminal of eledoisin); or Gly‐Leu‐Met‐NH2 (common C‐terminal of tachykinins).
In the presence of IGF‐1, only substance P and Phe‐Gly‐Leu‐Met‐NH2 were synergistic in stimulating corneal epithelial migration in a dose‐dependent fashion.
The combination of Phe‐Gly‐Leu‐Met‐NH2 and IGF‐1 did not affect the incorporation of [3H]‐thymidine into corneal epithelial cells.
Treatment with Phe‐Gly‐Leu‐Met‐NH2 and IGF‐1, but not with Phe‐Gly‐Leu‐Met‐NH2 or IGF‐1 alone, increased attachment of corneal epithelial cells to a fibronectin matrix.
The levels of α5 and β1 integrin were not affected by Phe‐Gly‐Leu‐Met‐NH2 or IGF‐1 alone, but they were significantly increased by the combination of Phe‐Gly‐Leu‐Met‐NH2 and IGF‐1.
Topical application of the same combination facilitated corneal epithelial wound closure in vivo.
These results demonstrated that Phe‐Gly‐Leu‐Met‐NH2, a sequence of 4 amino‐acids of the C‐terminal of substance P, is the minimum sequence necessary to produce the synergistic effects of substance P and IGF‐1 on corneal epithelial wound healing.

British Journal of Pharmacology (1999) 127, 489–497; doi:10.1038/sj.bjp.0702550
Characterization of [3H]‐heparin binding in human vascular smooth muscle cells and its relationship to the inhibition of DNA synthesis
Authors: Patel Mahendra K , Refson Jonathan S , Schachter Michael , Hughes Alun D 
Published: January 2005

The glycosaminoglycan heparin inhibits vascular smooth muscle cell (VSMC) proliferation and migration, but the mechanism of its antiproliferative action remains unclear. Heparin has been reported to bind to high affinity cell surface sites on animal VSMC before undergoing receptor mediated endocytosis resulting in signal transduction into the cytoplasm and modulation of genes involved in proliferation. In this study, we have characterized the binding of [3H]‐heparin to human saphenous vein‐derived VSMC and examined whether there is any relationship between the affinity of [3H]‐heparin binding and the inhibitory effect of heparin and its structural analogues on DNA synthesis.
At 4°C [3H]‐heparin binding to human VSMC occurred in a specific, time and concentration‐dependent manner and was not influenced by the removal of calcium ions. Binding of the ligand appeared to occur to the cell surface and was both saturable and reversible. Kinetic and steady state data indicated a single class of binding sites.
The pharmacology of [3H]‐heparin binding was examined in displacement studies using unlabelled heparin and structural analogues. A comparison of the rank potencies of heparin, heparan sulphate fraction II, low molecular weight heparin and trehalose octasulphate showed that there was a marked discrepancy between their estimated affinities in the binding assays and their effect on DNA synthesis.
In summary, we have characterized the heparin binding site on human saphenous vein‐derived VSMC. Our findings suggest that the action of heparin and its analogues on DNA synthesis does not simply reflect an interaction with the cell‐associated heparin binding site defined in these studies, but may also be determined by the internalization and metabolism of the glycosaminoglycan(s).

British Journal of Pharmacology (1999) 127, 361–368; doi:10.1038/sj.bjp.0702559
Capsaicin‐insensitive sensory‐efferent meningeal vasodilatation evoked by electrical stimulation of trigeminal nerve fibres in the rat
Authors: Peitl Barna , Pethô Gábor , Pórszász Róbert , Németh József , Szolcsányi János 
Published: January 2005

Antidromic vasodilatation and plasma extravasation to stimulation of the trigeminal ganglion or its perivascular meningeal fibres was investigated by laser‐Doppler flowmetry and 125I‐labelled bovin serum albumin in the dura mater and in exteroceptive areas (nasal mucosa, upper eyelid) of anaesthetized rats pretreated with guanethidine and pipecuronium.
Trigeminal stimulation at 5 Hz for 20 s elicited unilateral phasic vasodilatation in the dura and lasting response in the nasal mucosa. Resiniferatoxin (1–3 μg kg−1 i.v.), topical (1%) or systemic capsaicin pretreatment (300 mg kg−1 s.c. plus 1 mg kg−1 i.v.) did not inhibit the meningeal responses but abolished or strongly inhibited the nasal responses. Administration of vinpocetine (3 mg kg−1 i.v.) increased both basal blood flow and the dural vasodilatation to perivascular nerve stimulation.
Dural vasodilatation to trigeminal stimulation was not inhibited by the calcitonin gene‐related peptide‐1 receptor (CGRP‐1) antagonist hCGRP8–37 (15 or 50 μg kg−1 i.v). or the neurokinin‐1 receptor antagonist RP 67580 (0.1 mg kg−1 i.v.) although both antagonists inhibited the nasal response. Neither mucosal nor meningeal responses were inhibited by atropine (5 mg kg−1 i.v.), hexamethonium (10 mg kg−1 i.v.) or the vasoactive intestinal polypeptide (VIP) antagonist (p‐chloro‐D‐Phe6‐Leu17)VIP (20 μg kg−1 i.v.).
Plasma extravasation in the dura and upper eyelid elicited by electrical stimulation of the trigeminal ganglion was almost completely abolished in rats pretreated with resiniferatoxin (3 μg kg−1 i.v.).
It is concluded that in the rat meningeal vasodilatation evoked by stimulation of trigeminal fibres is mediated by capsaicin‐insensitive primary afferents, while plasma extravasation in the dura and upper eyelid and the vasodilatation in the nasal mucosa are mediated by capsaicin‐sensitive trigeminal fibres.

British Journal of Pharmacology (1999) 127, 457–467; doi:10.1038/sj.bjp.0702561
Subunit mutations affect ethanol actions on GABAA receptors expressed in Xenopus oocytes
Authors: Ueno Susumu , Wick Marilee J , Ye Qing , Harrison Neil L , Harris R Adron 
Published: January 2005

Mutations of specific amino acids were introduced in transmembrane domains (TM) of GABAA receptor α2, β1 and γ2L subunits. The effects of these mutations on the action of ethanol were studied using the Xenopus oocyte expression system and two‐electrode voltage‐clamp recording techniques.
Mutant α2 subunits containing S270I (TM2) or A291W (TM3) made the receptor more sensitive to GABA, as compared to wild‐type α2β1γ2L receptor. The mutation S265I (TM2) of β1 and S280I (TM2) or S301W (TM3) in γ2L subunits did not alter apparent affinity of the receptor for GABA. M286W (TM3) in the β1 subunit resulted in a receptor that was tonically open.
Using an EC5 concentration of GABA, the function of the wild‐type receptor with α2β1γ2L subunits was potentiated by ethanol (50–200 mM). The mutations in TM2 or TM3 of the α2 subunit diminished the potentiation by ethanol. The action of ethanol was also eliminated with a mutation in the TM2 site of the β1 subunit. Ethanol produced significant inhibition of GABA responses in receptors containing the combination of α2 and β1 TM2 mutants with a wild‐type γ2L subunit. A small but significant reduction in the potentiation by ethanol was observed with γ2L TM2 and/or TM3 mutants.
From these results, we suggest that in heteromeric GABAA receptors composed of the α, β and γ subunits, ethanol may bind in a cavity formed by TM2 and TM3, and that binding to the α or β subunit may be more critical than the γ subunit.

British Journal of Pharmacology (1999) 127, 377–382; doi:10.1038/sj.bjp.0702563
Effects and interaction, of cariporide and preconditioning on cardiac arrhythmias and infarction in rat in vivo
Authors: Aye Nu Nu , Komori Sadayoshi , Hashimoto Keitaro 
Published: January 2005

Although Na+‐H+ exchange (NHE) inhibitors are reported to protect the myocardium against ischaemic injury, NHE activation has also been proposed as a potential mechanism of ischaemic preconditioning‐induced protection. This study was performed to test any modifiable effect of cariporide, an NHE inhibitor, on cardioprotective effects of preconditioning.
Anaesthetized rats were subjected to 30 min of coronary artery occlusion and 150 min of reperfusion. The preconditioning (PC) was induced by 3 min of ischaemia and 10 min of reperfusion (1PC) or three episodes of 3 min ischaemia and 5 min reperfusion (3PC). Cariporide (0.3 mg kg−1) an NHE inhibitor, was administered 30 min (cari(30)) or 45 min (cari(45)) before coronary ligation (n=8–11 for each group).
Ventricular arrhythmias during 30 min ischaemia and infarct size (measured by triphenyltetrazolium (TTC) and expressed as a per cent area at risk (%AAR)) were determined. Cari(30) reduced ventricular fibrillation (VF) incidence and infarct size (from 45 to 0% and 34±4 to 9±2%; each P<0.05), whereas cari(45) did not. Likewise, 3PC reduced these variables (to 0% and 10±2%; P<0.05 in each case) whereas 1PC did not. Moreover, subthreshold preconditioning (1PC) and cariporide (cari(45)), when combined, reduced VF incidence and infarct size (to 0% and 15+3%; each P<0.05).
In conclusion, changes in NHE activity do not seem to be responsible for the cardioprotective action of ischaemic preconditioning. Protective effects of NHE inhibition and subthreshold preconditioning appear to act additively.

British Journal of Pharmacology (1999) 127, 1048–155; doi:10.1038/sj.bjp.0702566
Serotonin reuptake inhibitor, fluoxetine, dilates isolated skeletal muscle arterioles. Possible role of altered Ca2+ sensitivity
Authors: Pacher Pal , Ungvari Zoltan , Kecskemeti Valéria , Koller Akos 
Published: January 2005

Inhibitors of serotonin reuptake in the central nervous system, such as fluoxetine, may also affect the function of vascular tissues. Thus, we investigated the effect of fluoxetine on the vasomotor responses of isolated, pressurized arterioles of rat gracilis muscle (98±4 μm in diameter at 80 mmHg perfusion pressure).
We have found that increasing concentrations of fluoxetine dilated arterioles up to 155±5 μm with an EC50 of 2.5±0.5×10−6 M.
Removal of the endothelium, application of 4‐aminopyridine (4‐AP, an inhibitor of aminopyridine sensitive K+ channels), or use of glibenclamide (an inhibitor of ATP‐sensitive K+ channels) did not affect the vasodilator response to fluoxetine.
In the presence of 10−6, 2×10−6 or 10−5 M fluoxetine noradrenaline (NA, 10−9–10−5 M) and 5‐hydroxytryptamine (5‐HT, 10−9–10−5 M)‐induced constrictions were significantly attenuated resulting in concentration‐dependent parallel rightward shifts of their dose‐response curves (pA2=6.1±0.1 and 6.9±0.1, respectively).
Increasing concentrations of Ca2+ (10−4–3×10−2 M) elicited arteriolar constrictions (up to ∼30%), which were markedly reduced by 2×10−6 M fluoxetine, whereas 10−5 M fluoxetine practically abolished these responses.
In conclusion, fluoxetine elicits substantial dilations of isolated skeletal muscle arterioles, a response which is not mediated by 4‐AP‐ and ATP‐sensitive K+ channels or endothelium‐derived dilator factors. The findings that fluoxetine had a greater inhibitory effect on Ca2+ elicited constrictions than on responses to NA and 5‐HT suggest that fluoxetine may inhibit Ca2+ channel(s) or interfere with the signal transduction by Ca2+ in the vascular smooth muscle cells.

British Journal of Pharmacology (1999) 127, 740–746; doi:10.1038/sj.bjp.0702571
Antiarrhythmic effect and its underlying ionic mechanism of 17β‐estradiol in cardiac myocytes
Authors: Nakajima Toshiaki , Iwasawa Kuniaki , Oonuma Hitoshi , Morita Toshihiro , Goto Atsuro , Wang Yuepeng , Hazama Hisanori 
Published: January 2005

The effects of oestrogens on action potential and membrane currents were examined in single guinea‐pig atrial myocytes.
17β‐estradiol (3–10 μM) shortened the action potential duration without significant changes in the resting membrane potential. E‐4031 (1 μM) markedly prolonged the action potential duration and induced early afterdepolarization, and 17β‐estradiol (10 μM) abolished it.
When cells were perfused in isoproterenol‐containing solution, action potentials due to abnormal automaticity caused by membrane depolarization developed, and were also inhibited by 17β‐estradiol.
Under voltage clamp conditions, the voltage‐dependent Ca2+ currents consisted of both T‐(ICa.T) and L‐type (ICa.L). 17β‐estradiol reduced ICa.L concentration‐dependently, while it (10 μM) suppressed ICa.T only by approximately 10%. 17β‐estradiol did not affect time courses of ICa.L inactivation, but it shifted the steady‐state inactivation curve to more negative potentials.
17β‐estradiol (10 μM) did not affect the time‐dependent K+ current (IK), referred to as IKr and IKs, and inwardly rectifying K+ current. However, 17β‐estradiol (30 μM) or diethylstilbestrol (10 μM) inhibited K+ currents.
DES and ethinylestradiol (EES) also suppressed ICa.L, but testosterone and progesterone failed to inhibit ICa.L. The potency of the inhibitory effect on ICa.L was DES>EES>17β‐estradiol.
17β‐estradiol and DES also inhibited the cyclic AMP‐enhanced ICa.L, but cyclic GMP in the pipette or pretreatment of L‐NAME could not block the effects of oestrogen on ICa.L.
These results suggest that oestrogen specifically has antiarrhythmic effects, possibly by acting the L‐type Ca2+ channels. The antiarrhythmic effects of oestrogens may contribute to the cardioprotective actions of oestrogens.

British Journal of Pharmacology (1999) 127, 429–440; doi:10.1038/sj.bjp.0702576
Augmented acetylcholine‐induced, Rho‐mediated Ca2+ sensitization of bronchial smooth muscle contraction in antigen‐induced airway hyperresponsive rats
Authors: Chiba Yoshihiko , Takada Yuka , Miyamoto Shigeki , Mitsui‐Saito Minori , Karaki Hideaki , Misawa Miwa 
Published: January 2005

Treatment with acetylcholine (ACh) of a β‐escin‐permeabilized intrapulmonary bronchial smooth muscle of the rat induced force when the Ca2+ concentration was clamped at 1 μM. The ACh‐induced Ca2+ sensitization of myofilaments was significantly greater in antigen‐induced airway hyperresponsive rats than in control rats. The ACh‐induced Ca2+ sensitization was completely blocked by treatment with Clostridium botulinum C3 exoenzyme, an inactivator of Rho family of proteins. Moreover, the protein level of RhoA in the intrapulmonary bronchi was significantly increased in the airway hyperresponsive rats. Thus, increased airway smooth muscle contractility observed in asthmatics may be related to augmented agonist‐induced, Rho‐mediated Ca2+ sensitization of myofilaments.British Journal of Pharmacology (1999) 127, 597–600; doi:10.1038/sj.bjp.0702585
Modulation of haemostatic function and prevention of experimental thrombosis by red wine in rats: a role for increased nitric oxide production
Authors: Wollny Tomasz , Aiello Luca , Di Tommaso Donata , Bellavia Vincenzo , Rotilio Domenico , Donati Maria Benedetta , De Gaetano Giovanni , Iacoviello Licia 
Published: January 2005

The effects of ethyl alcohol and wine (red and white) on haemostatic parameters and experimental thrombosis were studied in rats; NO was evaluated as a possible mediator of these effects.
We found that red wine (12% alcohol) supplementation (8.4±0.4 ml d−1 in drinking water, for 10 days) induced a marked prolongation of ‘template’ bleeding time (BT) (258±13 vs 132±13 s in controls; P<0.001), a decrease in platelet adhesion to fibrillar collagen (11.6±1.0 vs 32.2±1.3%; P<0.01) and a reduction in thrombus weight (1.45±0.33 vs 3.27±0.39 mg; P<0.01).
Alcohol‐free red wine showed an effect similar to red wine. In contrast, neither ethyl alcohol (12%) nor white wine (12% alcohol) affected these systems.
All these effects were also observed after red wine i.v. injection (1 ml kg−1 of 1 : 4 dilution) 15 min before the experiments.
The effects of red wine were prevented by the NO inhibitor, Nωnitro‐L‐arginine‐methyl ester (L‐NAME). L‐arginine, not D‐arginine, reversed the effect of L‐NAME on red wine infusion.
Red wine injection induced a 3 fold increase in total radical‐trapping antioxidant parameter values of rat plasma with respect to controls, while white wine and alcohol did not show any effect.
Our study provides evidence that red wine modulates primary haemostasis and prevents experimental thrombosis in rats, independently of its alcohol content, by a NO‐mediated mechanism.

British Journal of Pharmacology (1999) 127, 747–755; doi:10.1038/sj.bjp.0702586