bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrophysiological characterisation of tachykinin receptors in the rat nucleus of the solitary tract and dorsal motor nucleus of the vagus in vitro
Authors: Maubach Karen A. , Jones Roland S. G. 
Published: January 2005

Recent studies have shown antagonists at the NK1 subtype of receptor for tachykinins are anti‐emetics and suggested that this may result from blockade of tachykinin‐mediated synaptic transmission at a central site in the emetic reflex.
We have used intracellular recording in vitro to study the pharmacology of tachykinins in the nucleus of the solitary tract (NST) and dorsal motor nucleus of the vagus (DMNV).
Neurones in the NST were depolarized by substance P (SP), the presumed endogenous ligand for the NK1 receptor and these effects were mimicked by the NK1 agonists, SP‐O‐methylester (SPOMe), GR73632 and septide; however, SP was nearly an order of magnitude less potent than the latter two agonists.
In the DMNV, SP and NK1 receptor agonists evoked similar depolarising responses but SP appeared to be more potent than in the NST and was closer in potency to the other agonists.
NK1‐receptor antagonists blocked responses to septide and GR73632 in the NST but had little effect on responses to SP and SPOMe. In contrast, in the DMNV the NK1‐receptor antagonists blocked responses to septide and GR73632 but also reduced responses to SP and SPOMe.
Neurokinin A (NKA) was almost equipotent with septide and GR73632 in depolarizing both NST and DMNV neurones but these effects were not mimicked by a specific NK2‐receptor agonist. Responses to NKA were unaffected by an NK2‐receptor antagonist; however, the depolarizing effects of NKA were blocked by NK1‐receptor antagonists.
Neurones in both DMNV and NST were unaffected by the endogenous NK3‐receptor ligand, neurokinin B and by a specific agonist for this site, senktide.
The results with NK1 receptor agonists and antagonists suggest that the septide‐sensitive NK1 site is involved in the excitation of both NST and DMNV neurones. The ‘classical’ NK1 receptor may play more of a role in the DMNV and a third unknown site may be responsible for the depolarizing response to SP in the NST. The effects of NKA are best interpreted as an action at the septide‐sensitive NK1 site. This raises the possibility that anti‐emetic action of the NK1 antagonists may be due to blockade of NKA transmission at the septide‐sensitive site.

British Journal of Pharmacology (1997) 122, 1151–1159; doi:10.1038/sj.bjp.0701482
Ethanol inhibition of N‐methyl‐D‐aspartate‐activated current in mouse hippocampal neurones: whole‐cell patch‐clamp analysis
Authors: Peoples Robert W. , White Geoffrey , Lovinger David M. , Weight Forrest F. 
Published: January 2005

The action of ethanol on N‐methyl‐D‐aspartate (NMDA)‐activated ion current was studied in mouse hippocampal neurones in culture using whole‐cell patch‐clamp recording.
Ethanol inhibited NMDA‐activated current in a voltage‐independent manner, and did not alter the reversal potential of NMDA‐activated current.
Concentration–response analysis of NMDA‐ and glycine‐activated current revealed that ethanol decreased the maximal response to both agonists without affecting their EC50 values.
The polyamine spermine (1 μM) increased amplitude of NMDA‐activated current but did not alter the percentage inhibition of ethanol.
Compared to an extracellular pH of 7.0, pH 6.0 decreased and pH 8.0 increased the amplitude of NMDA‐activated current, but these changes in pH did not significantly alter the percentage inhibition by ethanol.
The sulphydryl reducing agent dithiothreitol (2 mM) increased the amplitude of NMDA‐activated current, but did not affect the percentage inhibition by ethanol.
Mg2+ (10, 100, 500 μM), Zn2+ (5, 20 μM) or ketamine (2, 10 μM) decreased the amplitude of NMDA‐activated current, but did not affect the percentage inhibition by ethanol.
The observations are consistent with ethanol inhibiting the function of NMDA receptors by a non‐competitive mechanism that does not involve several modulatory sites on the NMDA receptor–ionophore complex.

British Journal of Pharmacology (1997) 122, 1035–1042; doi:10.1038/sj.bjp.0701483
Release of 5‐hydroxytryptamine by hypoxia from epithelioid cells of chicken thoracic aorta
Authors: Ito Shigeo , Ohta Toshio , Nakazato Yoshikazu 
Published: January 2005

Epithelioid cells in the chicken thoracic aorta are shown to contain 5‐hydroxytryptamine (5‐HT) in immunocytochemical studies. To determine whether these cells act as chemoreceptors, as do type I cells of the carotid body, we examined the effects of hypoxia and acidosis on the release of 5‐HT from the chicken thoracic aorta. Hypoxia caused the output of 5‐HT in incubation medium. A reduction of pH to 6.8 failed to evoke 5‐HT release. The response to hypoxia was inhibited by the removal of extracellular Ca2+ and by nifedipine and ω‐conotoxin GVIA. These results suggest that epithelioid cells in the chicken thoracic aorta are chemoreceptors which sense a decrease in PO2 and then release 5‐HT by Ca2+ influx through voltage‐dependent L‐ and N‐type Ca2+ channels. The epithelioid cells in the chicken aorta may be a useful model for pharmacological and physiological studies of 5‐HT‐containing cells.British Journal of Pharmacology (1997) 122, 799–801; doi:10.1038/sj.bjp.0701489
Cardiovascular effects of the novel Ca2+‐sensitiser EMD 57033 in pigs at rest and during treadmill exercise
Authors: Stubenitsky René , Van Der Weerd Rick W. P. , Haitsma David B. , Verdouw Pieter D. , Duncker Dirk J. 
Published: January 2005

To date no study has described the cardiovascular effects of increased myofilament Ca2+ responsiveness in awake animals both under resting conditions and during treadmill exercise. In the present study we therefore investigated the systemic, pulmonary and coronary haemodynamic actions of the Ca2+ sensitizer EMD 57033 in 16 chronically instrumented awake pigs at rest and during treadmill exercise, and compared these to the haemodynamic actions of the Ca2+ sensitizer/phosphodiesterase inhibitor pimobendan.
Under resting conditions EMD 57033 (0.2, 0.4 and 0.8 mg kg−1 min−1, i.v.) produced dose‐dependent increases in LVdP/dtmax (up to 65±17% (mean ±s.e.mean), P0.05) and stroke volume (up to 20±3%, P0.05), with an increase in heart rate only after the highest dose (22±5%, P0.05), while mean aortic blood pressure and LVdP/dtmin were not altered. EMD 57033 had also no effect on pulmonary vascular resistance, but produced dose‐dependent decreases in systemic vascular resistance (32±4%, P0.05), and coronary vascular resistance (44±2%, P0.05). These effects were essentially unchanged when animals were pretreated with non‐selective β‐adrenoceptor blockade, indicating that phosphodiesterase inhibition did not contribute to the positive inotropic actions of EMD 57033.
During exercise at 2, 3, and 4 km h−1, the positive inotropic actions of EMD 57033 gradually waned at higher levels of exercise. This may have been caused by the exercise‐induced increase in β‐adrenergic activity, because after pretreatment with propranolol the positive inotropic actions of EMD 57033 were preserved at all levels of exercise. In contrast, the positive inotropic and chronotropic effects of pimobendan were amplified during exercise, but were abolished (at rest) or markedly attenuated (during exercise) after pretreatment with propranolol.
The responses to EMD 57033 during exercise after combined α‐ and β‐adrenergic receptor blockade were not different from those after β‐adrenergic receptor blockade alone, indicating that the positive inotropic actions of EMD 57033 were not mediated via or did not depend on intact α‐adrenergic receptor activity.
In conclusion, EMD 57033 increases left ventricular myocardial contractility in awake pigs. During exercise this effect is partially offset by the increased β‐adrenergic activity, with no effect of α‐adrenergic activity, suggesting that EMD 57033 may be most effective in patients with severe loss of β‐adrenergic responsiveness.
Cyclic GMP‐dependent protein kinase activation in the absence of negative inotropic effects in the rat ventricle
Authors: MacDonell Karen L. , Diamond Jack 
Published: January 2005

It has been suggested that activation of cyclic GMP‐dependent protein kinase (PKG) is a necessary step in the chain of events leading to the production of negative inotropy by muscarinic receptor agonists in mammalian ventricles, and that some cyclic GMP‐elevating agents, such as sodium nitroprusside (SNP), fail to exert a negative inotropic effect because they elevate cyclic GMP levels in a pool that does not activate the kinase. This hypothesis was tested in the present study by monitoring the effects of carbachol, SNP and atrial natriuretic peptide (ANP) on contractility, cyclic GMP content and PKG activity in rat intact ventricular preparations and freshly isolated ventricular cardiomyocytes.
The presence of PKG in both the intact vehicle and in isolated ventricular cardiomyocytes was confirmed by MonoQ anion exchange chromatography and Western blotting. The elution profile indicated that the conditions of the PKG assay were selective for measuring PKG activity.
Carbachol induced a marked negative inotropic effect in intact, perfused hearts and ventricular strips in the presence of isoproterenol. The negative inotropic effect of carbachol was not associated with significant changes in cyclic GMP content or PKG activity in intact ventricular tissue, or in PKG activity in isolated cardiomyocytes.
SNP and ANP significantly increased cyclic GMP levels and activated PKG in intact ventricular preparations. Both drugs also activated PKG in isolated cardiomyocytes. However, neither drug had any negative inotropic effect in isoprenaline‐stimulated perfused hearts and ANP did not change the contractility of isoprenaline‐stimulated isolated cardiomyocytes.
The results of this study demonstrate that the negative inotropic effects of muscarinic receptor agonists can occur in the absence of significant activation of PKG. Conversely, marked increases in ventricular cyclic GMP content and PKG activity caused by SNP or ANP were not accompanied by a negative inotropic effect.
These results suggest that increases in cyclic GMP levels and activation of PKG do not play important roles in the regulation of rat ventricular contractility by muscarinic receptor agonists.
Calcium mobilization in Jurkat cells via A2b adenosine receptors
Authors: Mirabet Maribel , Mallol Josefa , Lluis Carmen , Franco Rafael 
Published: January 2005

A functional study of cell surface A2b adenosine receptors was performed on the T cell leukaemia line, Jurkat.
A2b receptors were coupled both to the adenylate cyclase system and to intracellular calcium channels. In fact, the agonist of A2b receptors, 5′‐N‐ethylcarboxamidoadenosine (NECA), led to a transient accumulation of intracellular calcium by an inositol phosphate‐independent mechanism.
The NECA‐induced accumulation of cGMP was not responsible for the calcium mobilization via A2b receptors.
The calcium response elicited by activation of A2b receptors was independent of that evoked by activation of the T cell receptor.
These findings not only delineate a novel transduction mechanism for adenosine but also support a specific role for adenosine in modulating signals elicited via the T cell receptor.

British Journal of Pharmacology (1997) 122, 1075–1082; doi:10.1038/sj.bjp.0701495
Effect of peroxynitrite on plasma extravasation, microvascular blood flow and nociception in the rat
Authors: Ridger V. C. , Greenacre S. A. B. , Handy R. L. C. , Halliwell B. , Moore P. K. , Whiteman M. , Brain S. D. 
Published: January 2005

Peroxynitrite (ONOO−) is a cytotoxic species, formed by the reaction between nitric oxide and superoxide free radicals, that may be involved in inflammation. In this study we have investigated the effect of peroxynitrite on plasma extravasation and microvascular blood flow in the dorsal skin and on nociceptive responses in the hind paw of the rat.
Male Wistar rats were anaesthetized and their dorsal skin shaved. Plasma extravasation was measured by the extravascular accumulation of 125I‐labelled albumin over 0–45 min and 0–240 min. Blood flow was measured by laser‐Doppler flowmetry over 0–240 min. Studies in the hind paw were carried out in the conscious rat. Hind paw weight changes were determined by volume displacement and nociception by a mechanical hyperalgesia technique.
Intradermal (i.d.) peroxynitrite (100–200 nmol site−1) produced a significant (P<0.01) dose‐dependent increase in plasma extravasation in dorsal skin over 0–45 min which was not increased over 45–240 min. Plasma extravasation was significantly (P<0.001) decreased in rats pretreated with the anti‐inflammatory steroid dexamethasone (1 mg kg−1, i.v.; −180 min), but not modulated by treatment with the hydrogen peroxide deactivator catalase (2200 u site−1), or the superoxide scavenger superoxide dismutase (500 u site−1), effective doses of the tachykinin NK1 antagonist SR140333 (1 nmol site−1), the cyclo‐oxygenase inhibitor indomethacin (358 μmol site−1), or combined pretreatment with mepyramine (histamine H1‐receptor antagonist; 2.8 nmol site−1) and methysergide (5‐HT antagonist; 1.9 nmol site−1).
Microvascular blood flow was significantly (P<0.05) increased 30 and 120 min after i.d. peroxynitrite (100 nmol site−1) in dorsal skin and remained raised until the end of the recording period (240 min). The increase in blood flow was unaffected by dexamethasone (1 mg kg−1, i.v.; −180 min) or indomethacin (10 mg kg−1, s.c.; −30 min).
Hind paw volume was significantly (P<0.001) increased 30 min after intraplantar peroxynitrite (87.5 and 175 nmol paw−1) and remained raised for the duration of the experiment (360 min). By comparison, nociception was not altered by intraplantar peroxynitrite.
These data indicate that peroxynitrite can cause an increase in both plasma extravasation and blood flow, suggesting that peroxynitrite could be of biological relevance to microvascular responses. These findings may be of importance in the pathology of inflammatory diseases in which peroxynitrite formation occurs.

British Journal of Pharmacology (1997) 122, 1083–1088; doi:10.1038/sj.bjp.0701498
Lipopolysaccharide induces expression of tumour necrosis factor alpha in rat brain: inhibition by methylprednisolone and by rolipram
Authors: Buttini M. , Mir A. , Appel K. , Wiederhold K. H. , Limonta S. , Gebicke‐Haerter P. J. , Boddeke H. W. G. M. 
Published: January 2005

We have investigated the effects of the phosphodiesterase (PDE) type IV inhibitor rolipram and of the glucocorticoid methylprednisolone on the induction of tumour necrosis factor alpha (TNF‐α) mRNA and protein in brains of rats after peripheral administration of lipopolysaccharide (LPS).
After intravenous administration of LPS, a similar time‐dependent induction of both TNF‐α mRNA and protein was observed in rat brain. Peak mRNA and protein levels were found 7 h after administration of LPS.
In situ hybridization experiments with a specific antisense TNF‐α riboprobe suggested that the cells responsible for TNF‐α production in the brain were microglia.
Intraperitoneal administration of methylprednisolone inhibited the induction of TNF‐α protein in a dose‐dependent manner. A maximal inhibition of TNF‐α protein production by 42.9±10.2% was observed at a dose regimen consisting of two injections of each 30 mg kg−1 methylprednisolone.
Intraperitoneal administration of rolipram also inhibited the induction of TNF‐α protein in a dose‐dependent manner. The maximal inhibition of TNF‐α protein production was 96.1±12.2% and was observed at a dose regimen of three separate injections of each 3 mg kg−1 rolipram.
In situ hybridization experiments showed that the level of TNF‐α mRNA induced in rat brain by LPS challenge was reduced by intraperitoneal administration of methylprednisolone (2×15 mg kg−1) and of rolipram (3×3 mg kg−1).
We suggest that peripheral administration of LPS induces a time‐dependent expression of TNF‐α in rat brain, presumably in microglial cells, and that methylprednisolone and rolipram inhibit LPS‐induced expression of TNF‐α in these cells via a decrease of TNF‐α mRNA stability and/or TNF‐α gene transcription.
Evidence for a 5‐HT3 receptor involvement in the facilitation of peristalsis on mucosal application of 5‐HT in the guinea pig isolated ileum
Authors: Tuladhar B. R. , Kaisar M. , Naylor R. J. 
Published: January 2005

The 5‐HT receptor involved in the effect of mucosal application of 5‐HT to facilitate peristalsis was investigated in the isolated guinea pig ileum.
An application of 5‐HT (3–100 μM) to the mucosal surface (by inclusion of 5‐HT in the Krebs‐Henseleit solution passing through the lumen of the ileum) caused a concentration related facilitation of peristalsis characterized by a reduction in the peristaltic threshold.
Peristalsis was not modified by methiothepine (0.1 μM), ritanserin (0.1 μM), ondansetron (5 μM), granisetron (1 μM) or SB 204070 (0.1 μM) administered alone to the mucosal surface.
The concentration–response curve to mucosally applied 5‐HT was not altered by the mucosally applied 5‐HT1/2 receptor antagonist methiothepine (0.1 μM), the 5‐HT2 receptor antagonist ritanserin (0.1 μM) or the 5‐HT4 receptor antagonist SB 204070 (0.1 μM). However, the mucosally applied 5‐HT3 receptor antagonists ondansetron (5 μM) and granisetron (1 μM) shifted the response curves to mucosally applied 5‐HT to the right in a parallel and surmountable manner. The pD2 values in the absence and presence of ondansetron were 5.42±0.07 and 4.12±0.10, respectively, (n=6) and that of granisetron were 5.45±0.12 and 4.50±0.10 respectively, (n=5).
Serosally applied ondansetron (5 μM) or granisetron (1 μM) had no effect on the concentration–response curve to mucosally applied 5‐HT. However, the serosally applied ondansetron and granisetron antagonised the facilitatory effect of serosally applied 5‐HT (10 μM) when administered in the presence of serosally applied SB 204070 (0.1 μM).
It is concluded that the facilitatory effect of mucosally applied 5‐HT to reduce the peristaltic threshold in the guinea pig ileum is mediated via a 5‐HT3 receptor located on the mucosal and not the serosal side of the ileum.

British Journal of Pharmacology (1997) 122, 1174–1178; doi:10.1038/sj.bjp.0701503
ZM241385 is an antagonist of the facilitatory responses produced by the A2A adenosine receptor agonists CGS21680 and HENECA in the rat hippocampus
Authors: Cunha Rodrigo A. , Dolores Constantino M. , Alexandre Ribeiro J. 
Published: January 2005

In the present study, we investigated the ability of a recently introduced non‐xanthine A2A receptor antagonist, ZM241385 (4‐(2‐[7‐amino‐2‐(2‐furyl{1,2,4}‐triazolo{2,3‐a{1,3,5}triazin‐5‐yl‐aminoethyl)phenol) to displace binding of the prototypical A2A adenosine receptor agonist [3H]CGS21680 (2‐[4‐(2‐p‐carboxyethyl)phenylamino]‐5′‐N‐ethylcarboxamidoadenosine) and to modify the facilitatory responses caused by the A2A selective agonists, CGS21680 and HENECA (2‐hexynl‐5′‐N‐ethylcarboxamidoadenosine) in rat hippocampal preparations.
ZM241385 was nearly equipotent to displace [3H]CGS21680 (30 nM) binding to hippocampal (Ki of 0.52 nM) and to striatal membranes (Ki of 0.35 nM), whereas HENECA was a more potent displacer of [3H]CGS21680 binding to striatal (Ki of 4.5 nM) than to hippocampal membranes (Ki of 19 nM).
HENECA (3–30 nM) was equipotent with CGS21680 to facilitate veratridine‐evoked [3H]acetylcholine release from superfused hippocampal synaptosomes and ZM241385 (20 nM) inhibited the facilitatory effects of both HENECA (30 nM) and CGS21680 (30 nM); this antagonism was mimicked by CSC (250 nM).
In contrast, CGS21680 (10–30 nM) was more potent than HENECA (10–30 nM) to facilitate synaptic transmission in Schaffer fibres/CA1 pyramid synapses of hippocampal slices and the facilitatory effect of CGS21680 (10 nM) was blocked by ZM241385 (20 nM) whereas CSC (250 nM) caused a 40% attenuation of this CGS21680‐induced facilitation.
These results indicate that ZM241385 is the first A2A antagonist with equal potency to displace [3H]CGS21680 binding to striatal and limbic regions, and with general efficiency to antagonize HENECA‐ or CGS21680‐mediated facilitatory responses in the hippocampus.
Cardiovascular effects of CPU‐23, a novel L‐type calcium channel blocker with a unique molecular structure
Authors: Dong Hui , Earle Mary L. , Jiang Yanfen , Loutzenhiser Kathy A. , Triggle Christopher R. 
Published: January 2005

The cardiovascular effects of CPU‐23 (1‐{1‐[(6‐methoxy)‐naphth‐2‐yl]}‐ethyl‐2‐(1‐piperidinyl)‐acetyl‐6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline), a cleavage product of tetrandrine, were investigated using the whole cell perforated patch‐clamp technique, in vitro tension measurements and in vivo haemodynamic recordings.
CPU‐23 (1 and 10 μM) dose‐dependently reduced concentration–response curves for KCl and phenylephrine (PE) in the rat tail artery; inhibition of KCl‐induced contraction was much more potent than for PE. At the same concentrations, CPU‐23 inhibited the inward Ba2+ currents in single smooth muscle cells isolated from the rat tail artery, while CPU‐23 (10 μM) produced 95% vasorelaxation of the rat middle cerebral artery preconstricted with BayK 8644.
CPU‐23 (10 and 30 μM) inhibited the noradrenaline‐induced phasic contraction of the rat tail artery in the absence of extracellular Ca2+ from 40% of control to 23% and 14%, respectively (P<0.01) and tonic contraction of the artery after addition of Ca2+ (2 mM) from 100% of control to 83% and 75%, respectively (P<0.01). In the presence of extracellular Ca2+ the PE‐induced contraction was reduced by CPU‐23 (30 and 100 μM) to 27% and 37%, respectively.
The haemodynamic profile of CPU‐23 in the rat was very similar to diltiazem. At 5 mg kg−1 CPU‐23 induced a rapid onset and long‐lasting decrease in left ventricular systolic pressure (LVSP), maximal velocity of pressure increase (dP/dtmax), systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR). When haemodynamic actions of CPU‐23, verapamil, diltiazem and nifedipine were compared at equidepressor doses, the order of potency for reducing LVSP and dP/dtmax was verapamil > CPU‐23 = diltiazem > nifedipine and the order of potency for decreasing HR was verapamil = CPU‐23 = diltiazem > nifedipine.
These data indicate that CPU‐23 is a novel calcium channel blocker with unique molecular structure, which exerts antihypertensive and cardiac depressant effects due primarily to its action on L‐type voltage‐gated calcium channels.