bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of the gap junction uncoupler palmitoleic acid on the activation and repolarization wavefronts in isolated rabbit hearts
Authors: Dhein S , Krüsemann K , Schaefer T 
Published: January 2005

The heart normally acts as an electrical syncytium coupled via gap junctional channels. Since closure of these channels has been considered arrhythmogenic, we wanted to elucidate, how activation and repolarization wavefronts are altered during progressive pharmacological gap junctional uncoupling.
We used the well known gap junction uncoupler palmitoleic acid (PA). The specificity of PA was tested in rabbit papillary muscles, which exhibited slowed conduction without affecting action potential morphology. We submitted isolated rabbit hearts (Langendorff‐technique) to increasing concentrations of palmitoleic acid (0.2, 1, 2, 5, 10, 20 μM), while 256 channel epicardial potential mapping was carried out.
In presence of PA activation recovery intervals (ARI) at the 256 electrodes became highly inhomogeneous with a dramatic increase in the dispersion of activation recovery intervals (from 6 to 35 ms, P>0.01; EC50=7 μM), while the mean ARI‐duration at 256 sites remained stable. PA led to marked alterations of the activation pattern, expressed as percentage of unchanged activation vectors (reduction from 32 to 10%, P<0.01, EC50=3.3 μM), to prolongation of atrioventricular conduction time (from 58 to 107 ms, P<0.01; EC50=8 μM) of total activation time (from 7 to 14 ms, P<0.05, EC50=11 μM) and of QRS‐complex‐duration.
In additional experiments the ventricle was paced via a bipolar electrode during the mapping procedure. From the isochrones longitudinal and transversal velocities were assessed showing that PA reduced transversal conduction velocity more distinctly than longitudinal.
With regard to maximum effects and EC50 values we conclude that gap junction uncoupling by PA mainly affects atrioventricular conduction, ARI‐dispersion and ventricular activation pattern. As important arrhythmogenic effects of uncoupling enhancement of dispersion with concomitant disturbation of the normal activation pattern and slowing of conduction might be considered.

British Journal of Pharmacology (1999) 128, 1375–1384; doi:10.1038/sj.bjp.0702902
Inhibition by genistein of the hyperpolarization‐activated cation current in porcine sino‐atrial node cells
Authors: Shibata Shigehiro , Ono Kyoichi , Iijima Toshihiko 
Published: January 2005

The hyperpolarization‐activated cation current (If) was recorded in single pacemaker cells of the porcine sino‐atrial node, and the effects of genistein, an isoflavone inhibitor of tyrosine‐specific protein kinases was investigated by the whole‐cell patch clamp technique.
Genistein (20–500 μM) decreased If in a dose‐dependent manner with an IC50 value of 62.3 μM and a maximum inhibition of 45.3%.
The effect on If appeared without altering the half‐activation potential (control, −88.3±2.8 mV; genistein, −87.0±1.8 mV) and the slope factor (control, 8.0±0.3 mV; genistein, 8.6±0.7 mV) of the steady‐state activation curve. No significant voltage‐dependency was detected in the fully‐activated current‐voltage relation measured by the double‐pulse protocols.
The inactive form of genistein analogue, daidzein (500 μM) or genistin (200 μM), were without effect. If was not affected by another tyrosine kinase inhibitor, tryphostin‐47 (100 μM), but tyrphostin‐25 (100–200 μM) suppressed If in an irreversible manner.
Neither bath nor intracellular application of the tyrosine phosphatase inhibitor, orthovanadate, affected If, and subsequent application of genistein inhibited If significantly.
These data indicate that the inhibition of If by genistein is not mediated through tyrosine kinase inhibition but through nonselective block of the If channels.

British Journal of Pharmacology (1999) 128, 1284–1290; doi:10.1038/sj.bjp.0702903
Functional pharmacology of cloned heterodimeric GABAB receptors expressed in mammalian cells
Authors: Bräuner‐Osborne Hans , Krogsgaard‐Larsen Povl 
Published: January 2005

In this study we report a new assay of heterodimeric γ‐amino‐butanoic acid subtype B (GABAB) receptors where either GABABR1a or GABABR1b are co‐expressed with GABABR2 and the chimeric G‐protein Gαq‐z5 in tsA cells. In this manner we obtained a robust response to GABAB agonists measured as increase in phosphoinositide hydrolysis.
We used this assay to characterize a number of commonly used GABAB receptor ligands. Both splice variants displayed the same rank order of agonist potency; 3‐aminopropyl(methyl)phosphinic acid (SKF‐97541)>GABA>(R)‐4‐amino‐3‐(4‐chlorophenyl)butanoic acid ((R)‐baclofen)>(RS)‐4‐amino‐3‐(5‐chloro‐2‐thienyl)butanoic acid (BCTG)>3‐aminopropylphosphonic acid (3‐APPA) and furthermore, the absolute agonist potency values were very close to each other.
3‐APPA was a partial agonist displaying maximal responses of 41 and 61% compared to GABA at GABABR1a and GABABR1b, respectively. The antagonist (RS)‐3‐amino‐2‐(4‐chlorophenyl)‐2‐hydroxypropylsulphonic acid (2‐OH‐saclofen) displayed KB values of 15 and 7.8 μM at GABABR1a and GABABR1b, respectively.
The rank order of agonist potency as well as the absolute ligand potencies correspond very well with those previously reported in different tissues, and this study thus provides a functional assay of cloned GABAB receptors which should be a valuable tool for further characterization of GABAB ligands. Finally, we can conclude that the functional pharmacological profiles of the two GABABR1 splice variants are very similar.

British Journal of Pharmacology (1999) 128, 1370–1374; doi:10.1038/sj.bjp.0702914
Further investigation of endothelium‐derived hyperpolarizing factor (EDHF) in rat hepatic artery: studies using 1‐EBIO and ouabain
Authors: Edwards G , Gardener M J , Félétou M , Brady G , Vanhoutte P M , Weston A H 
Published: January 2005

The characteristics of endothelium‐dependent hyperpolarization in rat hepatic artery have been further investigated in the presence of inhibitors of cyclo‐oxygenase and nitric oxide synthase.
Using sharp micro‐electrodes, the smooth muscle hyperpolarization induced by acetylcholine, KCl or 1‐ethyl‐2‐benzimidazolinone (1‐EBIO) in intact hepatic arteries was abolished by 30 μM barium plus 500 nM ouabain.
In vessels without endothelium, the smooth muscle hyperpolarization induced by KCl was not reduced by 30 μM barium alone. However, in the presence of barium the effects of KCl were partially inhibited by 100 nM ouabain and essentially abolished by 500 nM ouabain.
Using sharp micro‐electrodes, the hyperpolarization of both the smooth muscle and the endothelium induced by 1‐EBIO or by acetylcholine was unaffected by 100 nM iberiotoxin. However, in the presence of 100 nM charybdotoxin, the effects of 1‐EBIO were abolished whereas those of acetylcholine were only partially reduced. The hyperpolarization induced by levcromakalim was unaffected by either charybdotoxin or iberiotoxin.
Under whole‐cell patch‐clamp recording conditions, 1‐EBIO induced a voltage‐insensitive, charybdotoxin‐sensitive K+ current in cultured endothelial cells but was without effect on K+ currents in smooth muscle cells isolated from hepatic arteries.
It is concluded that the endothelium‐dependent hyperpolarization of smooth muscle induced by either acetylcholine or by 1‐EBIO in rat hepatic artery is initially associated with the opening of endothelial calcium‐sensitive K+‐channels insensitive to iberiotoxin. The resulting accumulation of K+ in the myoendothelial space activates an isoform of Na+/K+‐ATPase which is sensitive to low concentrations of ouabain.

British Journal of Pharmacology (1999) 128, 1064–1070; doi:10.1038/sj.bjp.0702916
Histamine H1‐receptor‐mediated modulation of the delayed rectifier K+ current in guinea‐pig atrial cells: opposite effects on IKs and IKr
Authors: Matsumoto Yasunori , Ogura Takehiko , Uemura Hiroko , Saito Toshihiro , Masuda Yoshiaki , Nakaya Haruaki 
Published: January 2005

Histamine receptor‐mediated modulation of the rapid and slow components of the delayed rectifier K+ current (IK) was investigated in enzymatically‐dissociated atrial cells of guinea‐pigs using the whole cell configuration of the patch clamp technique.
Histamine at a concentration of 10 μM enhanced IK recorded during strong depolarization to potentials ranging from +20 to +40 mV and inhibited IK recorded during mild depolarization to potentials ranging from −20 to −10 mV. The increase of IK was more prominent with longer depolarizing pulses, whereas the inhibition of IK was more marked with shorter depolarizing pulses, suggesting that histamine enhances IKs (the slow component of IK) and inhibits IKr (the rapid component of IK).
The histamine‐induced enhancement of IKs and inhibition of IKr were abolished by 3 μM chlorpheniramine but not by 10 μM cimetidine, suggesting that these opposite effects of histamine on IKr and IKs are mediated by H1‐receptors.
In the presence of 5 μM E‐4031, an IKr blocker, histamine hardly affected IK during mild depolarization although it enhanced IK during strong depolarization in a concentration‐dependent manner. Histamine increased IKs with EC50 value of 0.7 μM. In the presence of 300 μM indapamide, an IKs blocker, histamine hardly affected IKs but inhibited IKr in a concentration‐dependent manner. Histamine decreased IKr with IC50 value of 0.3 μM.
Pretreatment with 100 nM calphostin C or 30 nM staurosporine, protein kinase C inhibitors, abolished the histamine‐induced enhancement of IKs, but failed to affect the histamine‐induced inhibition of IKr.
We conclude that in guinea‐pig atrial cells H1‐receptor stimulation enhances IKs and inhibits IKr through different intracellular mechanisms.

British Journal of Pharmacology (1999) 128, 1545–1553; doi:10.1038/sj.bjp.0702918
The anticonvulsant effects of the enantiomers of losigamone
Authors: Jones Francis A , Davies John A 
Published: January 2005

Losigamone is a novel anticonvulsant undergoing phase III clinical trials in patients with partial and secondary generalized seizures. This study investigated the effects of the S(+)‐ and R(−)‐ enantiomers of losigamone on endogenous amino acid release from BALB/c mouse cortical slices, spontaneous depolarizations in the cortical wedge preparation of the DBA/2 mouse and audiogenic seizures in DBA/2 mice.
S(+)‐losigamone (100 and 200 μM) significantly reduced both potassium‐ and veratridine‐elicited release of glutamate and aspartate from cortical slices. R(−)‐losigamone had no effect on release at concentrations up to 400 μM.
Cortical wedges exhibit spontaneous depolarizations when perfused with magnesium‐free artificial cerebrospinal fluid. S(+)‐losigamone significantly reduced these depolarizations at 50–200 μM whilst R(−)‐losigamone had a significant effect at 200–800 μM.
DBA/2 mice are susceptible to audiogenic seizures and S(+)‐losigamone dose‐dependently (5, 10 and 20 mg kg−1, i.p.) significantly inhibited clonic/tonic convulsions with 91% of the mice protected at 20 mg kg−1. There was no protection at 20 mg kg−1 with R(−)‐losigamone.
These results, from both in vitro and in vivo experiments, confirm that the pharmacological activity profiles of the two losigamone enantiomers are not identical and suggest further that excitatory amino acid‐mediated processes are involved in the mode of action of S(+)‐losigamone whereas R(−)‐losigamone does not possess such properties. For the treatment of neurological conditions involving exaggerated excitatory amino acid function the use of S(+)‐losigamone might therefore be more effective clinically than losigamone or its R(−)‐enantiomer.

British Journal of Pharmacology (1999) 128, 1223–1228; doi:10.1038/sj.bjp.0702919
Functional and electrophysiological effects of a novel imidazoline‐based KATP channel blocker, IMID‐4F
Authors: McPherson Grant A , Bell Karen L , Favaloro Joanne L , Kubo Masahiro , Standen Nicholas B 
Published: January 2005

The functional and electrophysiological effects of IMID‐4F (2‐[N‐(2,6‐dichlorophenyl)‐N‐(4‐flurorobenzyl)amino]imidazoline), a fluoro‐benzyl derivative of clonidine, on vascular KATP channels were investigated. In pig coronary artery, IMID‐4F inhibited the vasorelaxation response to the KATP channel opener levcromakalim with a pKB value of approximately 7.1. IMID‐4F (30 μM) did not affect the vasorelaxation response to sodium nitroprusside (SNP).
In rat mesenteric artery smooth muscle cells IMID‐4F (1–10 μM) caused a concentration‐dependent depolarization of membrane potential. IMID‐4F (10 μM) abolished the hyperpolarizing effects of levcromakalim (10 μM).
In patch clamp experiments using rat mesenteric artery smooth muscle cells, KATP channel currents induced by levcromakalim (10 μM) were inhibited by IMID‐4F (0.3–3 μM) in a concentration‐dependent manner. The calculated IC50 for IMID‐4F inhibiting KATP channel current was approximately 0.8 μM.
Radioligand binding studies using bovine aortic smooth muscle cell membranes showed that IMID‐4F (30 μM) did not displace binding to the KATP channel opener [3H]‐P1075. However, both levcromakalim (10 μM) and glibenclamide (10 μM) caused significant displacement of [3H]‐P1075.
These studies show that the imidazoline compound IMID‐4F is one of the most potent antagonists of arterial KATP channels identified. Vasorelaxation, hyperpolarization and K+ currents through KATP channels were all inhibited by IMID‐4F at micromolar concentrations. Radioligand binding studies indicate that IMID‐4F does not bind to the same site as levcromakalim or as glibenclamide. Considering other evidence, it is likely that IMID‐4F acts by interacting directly with the pore of the KIR channel, rather than through the sulphonylurea subunit of the KATP channel complex.

British Journal of Pharmacology (1999) 128, 1636–1642; doi:10.1038/sj.bjp.0702925
Antiplatelet effect of the anaesthetic drug propofol: influence of red blood cells and leucocytes
Authors: De La Cruz J P , Páez M V , Carmona J A , Sánchez De La Cuesta F 
Published: January 2005

The present study was designed to investigate the mechanism of the antiplatelet action of the anaesthetic propofol in vitro.
Human whole blood was incubated with different concentrations of propofol and its solvent Intralipid®. We determined, platelet aggregometry in whole blood, platelet‐enriched plasma (PRP), PRP plus red blood cells (RBC), and PRP plus leucocytes (LC); platelet production of thromboxane B2 (TxB2), ATP release by platelet dense granules, adenosine uptake by RBC, intraplatelet levels of cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), and LC production of nitric oxide (NO).
Propofol‐induced inhibition of platelet aggregation was greater in whole blood (IC50 80–136 μM) than in PRP (IC50>600 μM), except when aggregation was induced by arachidonic acid, in which case the antiaggregatory effect of the anaesthetic was similar in both media (IC50 72–85 μM). Inhibition of platelet aggregation correlated significantly with inhibition of TxB2 synthesis (r2=0.83). Propofol also inhibited granular ATP release; this effect was greatest in whole blood.
The presence of RBC or LC increased the antiaggregatory effect of propofol, mainly when collagen was used as aggregating agent. Intralipid inhibited the uptake of adenosine by RBC, however this effect probably does not contribute significantly to its antiaggregatory effect.
The anaesthetic potentiated the NO‐cyclic GMP pathway, mainly by increasing the synthesis of NO by LC. Intralipid had no effect on the NO‐cyclic GMP pathway in the LC‐platelet interaction.
Propofol inhibited platelet aggregation in human whole blood, possibly through the sum of the effects of Intralipid on the platelet‐RBC interaction and the increased synthesis of NO by LC in the platelet‐LC interaction.

British Journal of Pharmacology (1999) 128, 1538–1544; doi:10.1038/sj.bjp.0702927
Evidence that somatostatin sst2 receptors mediate striatal dopamine release
Authors: Hathway G J , Humphrey P P A , Kendrick K M 
Published: January 2005

Somatostatin (SRIF) is a cyclic tetradecapeptide present in medium‐sized aspiny interneurones in the rat striatum. We have previously shown that exogenous SRIF potently stimulates striatal dopamine (DA) release via a glutamate‐dependent mechanism. We now report the ability of the selective sst2 receptor agonist, BIM‐23027, to mimic this effect of SRIF.
In vivo microdialysis studies were performed in anaesthetized male Wistar rats. In most experiments, compounds were administered by retrodialysis into the striatum for 15 min periods, 90 min and 225 min after sampling commenced, with levels of neurotransmitters being measured by HPLC with electrochemical and fluorescence detection.
BIM‐23027 (50 and 100 nM) stimulated DA release with extracellular levels increasing by up to 18 fold.
Prior retrodialysis of BIM‐23027 (50 nM) abolished the effects of subsequent administration of SRIF (100 nM).
The agonist effects of both BIM‐23027 and SRIF were abolished by the selective sst2 receptor antagonist, L‐Tyr8‐CYN‐154806 (100 nM).
The AMPA/kainate receptor antagonist, DNQX (100 μM), abolished the agonist effects of BIM‐23027 as previously shown for SRIF.
This study provides evidence that the sst2 receptor mediates the potent dopamine‐releasing actions observed with SRIF in the rat striatum. Dopamine release evoked by both peptides appears to be mediated indirectly via a glutamatergic pathway. Other subtype‐specific somatostatin receptor ligands were unable to elicit any effects and therefore we conclude that no other somatostatin receptor types are involved in mediating the dopamine‐releasing actions of SRIF in the striatum.

British Journal of Pharmacology (1999) 128, 1346–1352; doi:10.1038/sj.bjp.0702934
Platelet‐activating factor increases mucosal permeability in rat intestine via tyrosine phosphorylation of E‐cadherin
Authors: Tan Xiao‐Di , Chang Hong , Qu Xiao‐Wu , Caplan Michael , Gonzalez‐Crussi Frank , Hsueh Wei 
Published: January 2005

Platelet‐activating factor (PAF), an inflammatory mediator, plays an important role in mediating intestinal injury. However, it remains unclear whether PAF has a function in the intestine. The production of PAF by normal intestine and by unstimulated intestinal epithelial cell lines suggests that PAF may have a regulatory function in the normal bowel.
In this study we investigated the role of PAF in modulating intestinal mucosal permeability in rats. Lumen‐to‐blood transit of FD‐4 (dextran 4400), (an index of intestinal permeability), was assessed in sham‐operated rats and rats injected with PAF (1.25 μg kg−1, i.v., a dose insufficient to induce intestinal injury).
PAF‐induced villus cytoskeletal changes were examined by staining the intestine for F‐actin. The effect of PAF on tyrosine phosphorylation of the junctional protein E‐cadherin was examined by immunoprecipitation. Some rats were pretreated with AG1288 (a tyrosine kinase inhibitor) before PAF injection, and mucosal permeability change was assessed.
To investigate the role of endogenous PAF upon mucosal permeability, we studied the effect of PAF antagonists on (intraluminal) glucose‐induced increase in mucosal permeability.
We found that low dose PAF: (a) alters the cytoskeletal structure of intestinal epithelium, (b) causes the influx of FD4 from intestinal lumen to systemic circulation, (c) induces tyrosine phosphorylation of E‐cadherin and cadherin‐associated proteins. Glucose‐induced mucosal permeability increase is abolished by using two structurally different PAF antagonists.
These results suggest that endogenous PAF modulates macromolecular movement across the intestinal mucosal barrier, probably via tyrosine phosphorylation of E‐cadherin and cytoskeletal alteration of enterocytes.

British Journal of Pharmacology (2000) 129, 1522–1529; doi:10.1038/sj.bjp.0702939
Oxidative stress as a mechanism for quinolinic acid‐induced hippocampal damage: protection by melatonin and deprenyl
Authors: Behan W M H , McDonald M , Darlington L G , Stone T W 
Published: January 2005

There are differences between the excitotoxic actions of quinolinic acid and N‐methyl‐D‐aspartate (NMDA) which suggest that quinolinic acid may act by mechanisms additional to the activation of NMDA receptors. The present study was designed to examine the effect of a potent antioxidant, melatonin, and the potential neuroprotectant, deprenyl, as inhibitors of quinolinic acid‐induced brain damage. Injections were made into the hippocampus of anaesthetized rats, which were allowed to recover before the brains were taken for histology and the counting of surviving neurones.
Quinolinic acid (120 nmols) induced damage to the pyramidal cell layer, which was prevented by the co‐administration of melatonin (5 nmols locally plus 2×20 mg kg−1 i.p.). This protective effect was not prevented by the melatonin receptor blocker luzindole. Neuronal damage produced by NMDA (120 nmols) was not prevented by melatonin.
Quinolinic acid increased the formation of lipid peroxidation products from hippocampal tissue and this effect was prevented by melatonin.
Deprenyl also prevented quinolinic acid‐induced damage at a dose of 50 nmols but not 10 nmols plus 2×1.0 mg kg−1 i.p. The non‐selective monoamine oxidase inhibitor nialamide (10 and 50 nmols plus 2×25 mg kg−1) did not afford protection.
The results suggest that quinolinic acid‐induced neuronal damage can be prevented by a receptor‐independent action of melatonin and deprenyl, agents which can act as a potent free radical scavenger and can increase the activity of endogenous antioxidant enzymes respectively. This suggests that free radical formation contributes significantly to quinolinic acid‐induced damage in vivo.

British Journal of Pharmacology (1999) 128, 1754–1760; doi:10.1038/sj.bjp.0702940
Effect of vasoactive intestinal peptide (VIP)‐related peptides on cholinergic neurogenic and direct mucus secretion in ferret trachea in vitro
Authors: Liu Yu‐Chih , Khawaja Aamir M , Rogers Duncan F 
Published: January 2005

We investigated whether vasoactive intestinal peptide (VIP) and its related peptides, pituitary adenylate cyclase activating peptide (PACAP) and secretin, regulate cholinergic neural mucus secretion in ferret trachea in vitro, using 35SO4 as a mucus marker. We also studied the interaction between VIP and secretin on cholinergic mucus output.
VIP (1 and 10 μM) increased secretion, whereas neither PACAP1–27, PACAP1–38 nor secretin (up to 10 μM) increased mucus output. In contrast, VIP, PACAP1–27 and PACAP1–38 concentration‐dependently inhibited cholinergic neural secretion, with an order of potency of VIP>PACAP 1–38>PACAP1–27. Neither PACAP1–27 nor PACAP1–38 altered the secretion induced by acetylcholine (ACh).
Secretin increased cholinergic neural secretion with a maximal increase of 190% at 1 μM. This potentiation was blocked by VIP or atropine. Similarly, secretin (1 μM) potentiated VIP (1 μM)‐induced mucus output by 160%. Secretin did not alter exogenous ACh‐induced secretion. VIP vs secretin competition curves suggested these two peptides were competing reversibly for the same receptor.
We conclude that, in ferret trachea in vitro, VIP and PACAPs inhibit cholinergic neural secretion via pre‐junctional modulation of cholinergic neurotransmission. VIP and secretin compete for the same receptor, possibly a VIP1 receptor, at which secretin may be a receptor antagonist.

British Journal of Pharmacology (1999) 128, 1353–1359; doi:10.1038/sj.bjp.0702942