bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of the muscarinic receptor subtype mediating inhibition of the neurogenic contractions in rabbit isolated vas deferens by a series of polymethylene tetra‐amines
Authors: Budriesi R , Cacciaguerra S , Di Toro R , Bolognesi M L , Chiarini A , Minarini A , Rosini M , Spampinato S , Tumiatti V , Melchiorre C 
Published: January 2005

The pharmacological characteristics of the presynaptic muscarinic receptor subtype, which mediates inhibition of the neurogenic contractions in the prostatic portion of rabbit vas deferens, have been investigated by using a series of polymethylene tetra‐amines, which were selected for their ability to differentiate among muscarinic receptor subtypes.
It was found that all tetra‐amines antagonized McN‐A‐343‐induced inhibition in electrically stimulated rabbit vas deferens in a competitive manner and with affinity values (pA2) ranging between 6.27±0.09 (spirotramine) and 8.51±0.02 (AM170).
Competition radioligand binding studies, using native muscarinic receptors from rat tissues (M1, cortex; M2, heart; M3, submaxillary gland) or from NG 108‐15 cells (M4) and human cloned muscarinic M1‐M4 receptors expressed in CHO‐K1 cells, were undertaken with the same tetra‐amines employed in functional assays. All antagonists indicated a one‐site fit.
The affinity estimates (pKi) of tetra‐amines calculated in binding assays using native receptors were similar to those obtained using cloned receptors. Among these compounds some displayed selectivity between muscarinic receptor subtypes, indicating that they may be valuable tools in receptor characterization. Spirotramine was selective for M1 receptors versus all other subtypes (pKi native: M1, 7.32±0.10; M2, 6.50±0.11; M3, 6.02±0.13; M4, 6.28±0.16; pKi cloned: M1, 7.69±0.08; M2, 6.22±0.14; M3, 6.11±0.16; 6.35±0.11) whereas CC8 is highly selective for M2 receptors versus the other subtypes (pKi native: M1, 7.50±0.04; M2, 9.01±0.12; M3, 6.70±0.08; M4, 7.56±0.04; pKi cloned: M1, 7.90±0.20; M2, 9.04±0.08; M3, 6.40±0.07; M4, 7.40±0.04). Furthermore, particularly relevant for this investigation were tetra‐amines dipitramine and AM172 for their ability to significantly differentiate M1 and M4 receptors.
The apparent affinity values (pA2) obtained for tetra‐amines in functional studies using the prostatic portion of rabbit vas deferens correlated most closely with the values (pKi) obtained at either native or human recombinant muscarinic M4 receptors. This supports the view that the muscarinic receptor mediating inhibition of neurogenic contractions of rabbit vas deferens may not belong to the M1 type but rather appears to be of the M4 subtype.

British Journal of Pharmacology (2001) 132, 1009–1016; doi:10.1038/sj.bjp.0703891
Alterations in EDHF‐mediated hyperpolarization and relaxation in mesenteric arteries of female rats in long‐term deficiency of oestrogen and during oestrus cycle
Authors: Liu Ming‐Yue , Hattori Yuichi , Fukao Mistuhiro , Sato Atsushi , Sakuma Ichiro , Kanno Morio 
Published: January 2005

This study was undertaken to determine whether endothelium‐dependent relaxations are altered in mesenteric arteries from young female rats during oestrus cycle and after castration.
The contractile response to phenylephrine (Phe) was significantly enhanced in arteries from rats subjected to ovariectomy than in those from sham‐operated (control) rats. Treatment of ovariectomized rats with 17β‐oestradiol returned the Phe response to the control level. Arteries from rats at the diestrus stage also exhibited greater contraction in response to Phe. In the presence of 100 μM NG‐nitro‐L‐arginine (L‐NOARG), the enhancement of the Phe contractile response associated with oestrogen deficiency was not observed.
Endothelium‐dependent relaxations elicited by acetylcholine (ACh) in arteries precontracted with Phe were significantly reduced in ovariectomized and diestrus rats regardless of whether endothelium‐derived nitric oxide (NO) was blocked with L‐NOARG. Treatment with 17β‐oestradiol prevented the reduced vascular relaxant response to ACh in ovariectomized rats. The reduction in the ACh responses observed in ovariectomized and diestrus rats was eliminated when 500 nM apamin and 100 nM charybdotoxin were present.
ACh‐induced endothelium‐dependent hyperpolarizations were depressed in arteries from ovariectomized and diestrus rats. The hyperpolarizing response to ACh was significantly improved when ovariectomized rats were treated with 17β‐oestradiol. The resting membrane potentials and pinacidil‐induced hyperpolarizations were unaffected by ovariectomy or the diestrus stage.
These results suggest that oestrogen‐deficient states of both short and long duration reduce the basal release of NO from the endothelium and specifically attenuate endothelium‐dependent hyperpolarization and relaxation transduced by endothelium‐derived hyperpolarizing factor.

British Journal of Pharmacology (2001) 132, 1035–1046; doi:10.1038/sj.bjp.0703899
Involvement of cannabinoids in the cardioprotection induced by lipopolysaccharide
Authors: Lagneux Caroline , Lamontagne Daniel 
Published: January 2005

We have examined the involvement of the endocannabinoid system in the cardioprotection triggered by lipopolysaccharide (LPS). Rats were treated with saline or LPS (10 μg Kg−1). 24 h later, hearts were excised, retrogradely perfused, submitted to a low‐flow ischaemia (0.6 ml min−1) for 90 min and reperfused for 60 min. Some hearts were perfused with either SR 141716A (a cannabinoid CB1, receptor antagonist 1 μM), SR 144528 (a CB2 receptor anagonist μM), NNLA (3 μM) or sodium nitroprusside (1 μM) 5 min before ischaemia and during the ischaemic period. The cardioprotective effects of LPS treatment, in terms of infarction and functional recovery, were not altered by the perfusion of SR 141716A but abolished by both SR 144528 and NNLA. Finally, SR 144528 abolished the beneficial effects of SNP perfusion. Our results suggest an involvement of endocannabinoids, acting through the CB2 receptors, in the cardioprotection triggered by LPS against myocardial ischaemia. This could be attributed to a relationship between cannabinoids and NO.British Journal of Pharmacology (2001) 132, 793–796; doi:10.1038/sj.bjp.0703902
Protein phosphatase inhibitors facilitate DHPG‐induced LTD in the CA1 region of the hippocampus
Authors: Schnabel R , Kilpatrick I C , Collingridge G L 
Published: January 2005

We have shown earlier that activation of metabotropic glutamate (mGlu) receptors using a group I‐specific mGlu receptor agonist, (RS)‐3,5‐dihydroxyphenylglycine (DHPG), can induce long‐term depression (LTD) in the CA1 region of the hippocampus. In an attempt to determine the signal transduction mechanisms involved in this form of synaptic plasticity, we have tested the effects of a range of inhibitors on DHPG‐induced LTD.
In vitro grease‐gap electrophysiological recordings were performed in the rat hippocampal CA1 region.
We have found that DHPG‐induced LTD is resistant to the two potent protein kinase C (PKC) inhibitors, Gö 6976 (10 μM) and Gö 6983 (10 μM), the potent and selective protein kinase A (PKA) inhibitor, KT 5720 (10 μM), and the potent broad spectrum kinase inhibitor, staurosporine (10 μM).
In contrast, non‐selective inhibitors of protein phosphatases (PP1 and PP2A), okadaic acid (1 μM) or calyculin A (1 μM), facilitated DHPG‐induced LTD. However, an inhibitor of protein phosphatase 2B, FK 506 (1 μM), did not influence this process.
The PP1/PP2A protein phosphatase inhibitors, but none of the other agents tested, also inhibited (S)‐α‐methyl‐4‐carboxyphenylglycine (MCPG)‐induced reversal of DHPG‐induced LTD.
These data suggest that activation of neither PKC nor PKA is involved in DHPG‐induced LTD. They do, however, suggest that the process is under regulation by protein phosphorylation and dephosphorylation.

British Journal of Pharmacology (2001) 132, 1095–1101; doi:10.1038/sj.bjp.0703905
The endogenous cannabinoid agonist, anandamide stimulates sensory nerves in guinea‐pig airways
Authors: Tucker R C , Kagaya M , Page C P , Spina D 
Published: January 2005

The endogenous cannabinoid agonist, anandamide produced a modest contractile response in guinea‐pig isolated bronchus compared with the vanilloid receptor agonist capsaicin. The contractile response to both anandamide and capsaicin was inhibited by the vanilloid receptor antagonist, capsazepine. Furthermore, the NK2‐selective antagonist, SR48968 but not the NK1‐selective antagonist, SR140333 inhibited contractile responses to anandamide.
The contractile response to anandamide was abolished in tissues desensitized by capsaicin. However, anandamide failed to cross‐desensitize the contractile response to capsaicin.
The contractile response to anandamide was not significantly altered in the presence of the CB1 receptor antagonist, SR141716A, nor the amidase inhibitor, phenylmethylsulphonyl fluoride (PMSF) but was significantly increased in the presence of the neutral endopeptidase inhibitor, thiorphan.
The cannabinoid agonist, CP55,940 failed to significantly attenuate the excitatory non‐adrenergic non‐cholinergic (eNANC) response in guinea‐pig airways. In contrast, the ORL1 receptor agonist, nociceptin, significantly inhibited this response.
The results demonstrate that anandamide induces a modest contractile response in guinea‐pig isolated bronchus that is dependent upon the activation of vanilloid receptors on airway sensory nerves. However, cannabinoid receptors do not appear to play a role in this regard, nor in regulating the release of neuropeptides from airway sensory nerves under physiological conditions.

British Journal of Pharmacology (2001) 132, 1127–1135; doi:10.1038/sj.bjp.0703906
Effects of the endogenous opioid peptide, endomorphin 1, on supraoptic nucleus oxytocin and vasopressin neurones in vivo and in vitro
Authors: Doi Naomi , Brown Colin H , Cohen Helena Delgado , Leng Gareth , Russell John A 
Published: January 2005

We investigated the actions of the endogenous opioid tetra‐peptide endomorphin 1, a selective μ‐opioid receptor agonist, on oxytocin and vasopressin cell activity in vivo and in vitro.
The activity of antidromically‐identified supraoptic nucleus cells were recorded from urethane‐anaesthetized female rats. The firing rates of both oxytocin and vasopressin cells were reduced by intracerebroventricular endomorphin 1 (5–100 pmol); this inhibition was prevented by intravenous naloxone (5 mg kg−1).
A second group of rats was infused intracerebroventricularly with endomorphin 1 (27 pmol min−1) over 5 days. The firing rates of oxytocin and vasopressin cells in endomorphin 1 pre‐treated rats were similar to those of endomorphin 1 naïve rats, indicating tolerance to the inhibitory effects of endomorphin 1. Intravenous naloxone induced similar modest and transient increases in the firing rate of oxytocin cells in endomorphin 1 pre‐treated rats and endomorphin 1 naïve rats, indicating that endomorphin 1, unlike the μ‐opioid alkaloid agonist, morphine, does not induce μ‐opioid dependence in these cells.
In vitro, whole‐cell current clamp recordings were made from supraoptic nucleus cells in superfused coronal hypothalamic slices from young female rats. Endomorphin 1 (100 nM) inhibited the firing rate of oxytocin cells but had no significant effect on vasopressin cells at up to 10 μM. Inhibition of oxytocin cells was reversed by naloxone, and remained when synaptic transmission was blocked by superfusion with low Ca2+/Co2+‐containing medium.
Thus, endomorphin 1 directly inhibits oxytocin cells but inhibits vasopressin cells by indirect actions. Chronic endomorphin 1 administration induces μ‐opioid tolerance in oxytocin and vasopressin cells but not μ‐opioid dependence in oxytocin cells.

British Journal of Pharmacology (2001) 132, 1136–1144; doi:10.1038/sj.bjp.0703911
Comparative effects of frovatriptan and sumatriptan on coronary and internal carotid vascular haemodynamics in conscious dogs
Authors: Carel Ivan , Ghaleh Bijan , Edouard Alain , Dubois‐Rande Jean‐Luc , Parsons Andrew A , Giudicelli Jean‐François , Berdeaux Alain 
Published: January 2005

The effects of frovatriptan and sumatriptan on internal carotid and coronary vascular haemodynamics were investigated and compared in conscious dogs.
Frovatriptan and sumatriptan (0.1–100 μg kg−1) induced a transient increase in external coronary artery diameter (eCOD) of up to 2.9±1.2 and 1.8±0.6%, respectively (both P<0.05). This was followed by a prolonged and dose‐dependent decrease in eCOD of up to −5.2±1.2 and −5.3±0.9% (both P<0.05), with ED50 values of 86±21 and 489±113 μmol kg−1, respectively. In contrast, only a decrease in the external diameter of the internal carotid artery was observed (−6.0±0.6 and −6.2±1.4%, both P<0.05, and ED50 values of 86±41 and 493±162 μmol kg−1, respectively). Frovatriptan was thus 5.7 fold more potent than sumatriptan at the level of both large coronary and internal carotid arteries.
After endothelium removal by balloon angioplasty in coronary arteries, the initial dilatation induced by the triptans was abolished and delayed constriction enhanced.
The selective antagonist for the 5‐HT1B receptors SB224289 dose‐dependently blocked the effects of sumatriptan on large coronary and internal carotid arteries whereas the selective antagonist for the 5‐HT1D receptors BRL15572 did not affect any of these effects.
In conclusion, frovatriptan and sumatriptan initially dilate and subsequently constrict large coronary arteries in the conscious dog, whereas they directly constrict the internal carotid artery. The vascular endothelium modulates the effects of these triptans on large coronary arteries. Finally, 5‐HT1B but not 5‐HT1D receptors are primarily involved in canine coronary and internal carotid vasomotor responses to sumatriptan.

British Journal of Pharmacology (2001) 132, 1071–1083; doi:10.1038/sj.bjp.0703917
Cannabinoid inhibition of the capsaicin‐induced calcium response in rat dorsal root ganglion neurones
Authors: Millns Paul J , Chapman Victoria , Kendall David A 
Published: January 2005

Cannabinoids have marked inhibitory effects on somatosensory processing, which may arise from actions at both peripheral and central cannabinoid receptors. Here, the effect of a synthetic cannabinoid agonist HU210 on capsaicin‐evoked responses in adult rat dorsal root ganglion (DRG) neurones was studied. The vanilloid capsaicin produced a concentration‐related increase in intracellular calcium in DRG neurones, which was significantly inhibited by HU210 (1 μM). The cannabinoid CB1 receptor antagonist SR141716A (1 μM) had no effect alone and did not influence the response to capsaicin but significantly reversed the inhibitory effect of HU210. These data indicate that DRG CB1 receptors are functional and can inhibit nociceptive responses.British Journal of Pharmacology (2001) 132, 969–971; doi:10.1038/sj.bjp.0703919
Xenopus tropicalis oocytes as an advantageous model system for the study of intracellular Ca2+ signalling
Authors: Marchant Jonathan S , Parker Ian 
Published: January 2005

The purpose of this study was to compare oocytes from the pipid frogs Xenopus tropicalis and Xenopus laevis, with respect to their utility for studying Ca2+ signalling mechanisms and for expression of heterologous proteins.
We show that X. tropicalis oocytes possess an intracellular Ca2+ store that is mobilized by inositol (1,4,5) trisphosphate (IP3). Ca2+ signalling is activated by endogenous lysophosphatidic acid receptors and cytosolic Ca2+ activates a plasma membrane chloride conductance. The spatiotemporal organization of cytosolic Ca2+ signals, from the microscopic architecture of elementary Ca2+ ‘puffs’ to the macroscopic patterns of Ca2+ spiking are closely similar to the local and global patterns of Ca2+ release previously characterized in oocytes from X. laevis.
By injecting X. tropicalis oocytes with cDNA encoding an ER‐targeted fluorescent protein construct, we demonstrate the capacity of the X. tropicalis oocyte to readily express heterologous proteins. The organization of ER is polarized across the oocyte, with the IP3‐releaseable store targeted within an ∼8 μm wide band that circumscribes the cell.
We conclude that the X. tropicalis oocyte shares many of the characteristics that have made oocytes of X. laevis a favoured system for studying Ca2+ signalling mechanisms. Moreover, X. tropicalis oocytes display further practical advantages in terms of imaging depth, Ca2+ signal magnitude and electrical properties. These further enhance the appeal of X. tropicalis as an experimental system, in addition to its greater amenability to transgenic approaches.

British Journal of Pharmacology (2001) 132, 1396–1410; doi:10.1038/sj.bjp.0703922
Potential anxiolytic‐ and antidepressant‐like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist
Authors: Tatarczyńska Ewa , Kłodzińska Aleksandra , Chojnacka‐Wójcik Ewa , Pałucha Agnieszka , Gasparini Fabrizio , Kuhn Rainer , Pilc Andrzej 
Published: January 2005

Several lines of evidence suggest a crucial involvement of glutamate in the mechanism of action of anxiolytic and/or antidepressant drugs. The involvement of group I mGlu receptors in anxiety and depression has also been proposed. Given the recent discovery of a selective and brain penetrable mGlu5 receptor antagonists, the effect of 2‐methyl‐6‐(phenylethynyl)‐pyridine (MPEP), i.e. the most potent compound described, was evaluated in established models of anxiety and depression.
Experiments were performed on male Wistar rats or male Albino Swiss or C57BL/6J mice. The anxiolytic‐like effects of MPEP was tested in the conflict drinking test and the elevated plus‐maze test in rats as well as in the four‐plate test in mice. The antidepressant‐like effect was estimated using the tail suspension test in mice and the behavioural despair test in rats.
MPEP (1 – 30 mg kg−1) induced anxiolytic‐like effects in the conflict drinking test and the elevated plus‐maze test in rats as well as in the four‐plate test in mice. MPEP had no effect on locomotor activity or motor coordination. MPEP (1 – 20 mg kg−1) did shorten the immobility time in a tail suspension test in mice, however it was inactive in the behavioural despair test in rats.
These data suggest that selective mGlu5 receptor antagonists may play a role in the therapy of anxiety and/or depression, further studies are required to identify the sites and the mechanism of action of MPEP.

British Journal of Pharmacology (2001) 132, 1423–1430; doi:10.1038/sj.bjp.0703923
Effects of anti‐oestrogens and β‐estradiol on calcium uptake by cardiac sarcoplasmic reticulum
Authors: Dodds Marnie L , Kargacin Margaret E , Kargacin Gary J 
Published: January 2005

Tamoxifen and a group of structurally similar non‐steroidal, triphenolic compounds inhibit the oestrogen receptor. In addition to this action, these anti‐oestrogens are known to inhibit some types of plasma membrane ion channels and other proteins through mechanisms that do not appear to involve their interactions with the estrogen receptor but could be the result of their effect on membrane lipid structure or fluidity.
We studied the effects of β‐estradiol and three anti‐oestrogens (tamoxifen, 4‐hydroxytamoxifen and clomiphene) on Ca2+ uptake into sarcoplasmic reticulum (SR) vesicles isolated from canine cardiac ventricular tissue.
The antiestrogens all inhibit SR Ca2+ uptake in a concentration‐dependent manner (order of potency: tamoxifen > 4‐hydroxytamoxifen clomiphene). Although these compounds rapidly inhibit net Ca2+ uptake they do not have a similar rapid effect on the ATPase activity of the SR Ca pump. β‐estradiol has no effect on Ca2+ uptake nor does it alter the inhibitory action of tamoxifen on the SR.
The differences in the effects of β‐estradiol and the anti‐oestrogens on cardiac SR Ca2+ uptake do not correlate with differences in the ways in which these compounds have been reported to interact with membrane lipids. Our results are consistent, however, with direct effects on a membrane protein (possibly an SR Cl− or K+ channel).

British Journal of Pharmacology (2001) 132, 1374–1382; doi:10.1038/sj.bjp.0703924
Nerve evoked P2X receptor contractions of rat mesenteric arteries; dependence on vessel size and lack of role of L‐type calcium channels and calcium induced calcium release
Authors: Gitterman D P , Evans R J 
Published: January 2005

Contractile responses to short trains of nerve stimulation have been characterized in small, medium and large arteries from the rat mesenteric circulation (5th – 6th, 2nd – 3rd and 1st order, respectively). In addition, sources of calcium for smooth muscle contraction have been investigated.
Nerve stimulation (10 pulses at 10 Hz) evoked reproducible contractions. The P2 receptor antagonist suramin (100 μM) reduced constrictions by 65.3±7.4, 82.7±3.3 and 3.1±6.1% in small, medium and large arteries respectively. The α‐adrenoceptor antagonist prazosin (0.1 μM) reduced responses by 32.6±2.6, 27.0±1.5 and 97.0±1.9% respectively.
The L‐type calcium channel antagonist nifedipine (1 μM) reduced nerve‐evoked contractions by 2.8±3.3, 10.0±3.7 and 13.5±2.7% in small, medium and large arteries respectively. When the adrenergic component of contraction was blocked by prazosin (0.1 μM) nifedipine reduced responses by 4.6±7.9, 14.3±2.0 and 3.0±1.9% respectively.
Contractile responses to exogenous α,β‐meATP were unaffected by the depletion of calcium stores with cyclopiazonic acid (30 μM). This indicates that mobilization of calcium from internal stores is not required for P2X receptor mediated smooth muscle contraction.
We conclude that for neurogenic responses, the P2X receptor mediated component of constriction dominates in small mesenteric arteries (3rd  – 6th order) while in large arteries (1st order) noradrenaline mediates contraction. For P2X receptor mediated responses all the calcium required for smooth muscle contraction enters the cell directly through P2X receptor channels.

British Journal of Pharmacology (2001) 132, 1201–1208; doi:10.1038/sj.bjp.0703925
Pharmacokinetics of pefloxacin and its interaction with cyclosporin A, a P‐glycoprotein modulator, in rat blood, brain and bile, using simultaneous microdialysis
Authors: Tsai Tung‐Hu 
Published: January 2005

In vivo microdialysis with HPLC was used to investigate the pharmacokinetics of pefloxacin and its interaction with cyclosporin A. Microdialysis probes were inserted into the jugular vein/right atrium, the striatum and the bile duct of male Sprague‐Dawley rats. Biological fluid sampling thereby allowed the simultaneous determination of pefloxacin levels in blood, brain and bile.
Following pefloxacin administration, the brain‐to‐blood coefficient of distribution was 0.036. This was calculated by dividing the area under the concentration curve (AUC) of pefloxacin in brain by its AUC in blood (k=AUCbrain/AUCblood).
When the P‐glycoprotein cyclosporin A (10 mg kg−1) was co‐administered with pefloxacin (10 mg kg−1), the AUC and the mean residence time in rat blood did not differ significantly (P>0.05). Similarly, the pharmacokinetics of pefloxacin in rat brain was not affected by the presence of cyclosporin A.
The AUC of unbound pefloxacin in bile was significantly greater than that in blood. The disposition of pefloxacin in rat bile shows a slow elimination phase following a peak concentration 30 min after pefloxacin administration (10 mg kg−1, i.v.). The bile‐to‐blood coefficient of distribution (k=AUCbile/AUCblood) was 1.53.
The results indicated that pefloxacin was able to penetrate the blood‐brain barrier and that the concentration in bile was greater than that in the blood, suggesting active biliary excretion of pefloxacin. Current data obtained from rats show no significant impact of cyclosporin A on the pharmacokinetics of pefloxacin in rat blood and brain when administered by concomitant i.v. bolus.

British Journal of Pharmacology (2001) 132, 1310–1316; doi:10.1038/sj.bjp.0703927