bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correolide, a nor‐triterpenoid blocker of Shaker‐type Kv1 channels elicits twitches in guinea‐pig ileum by stimulating the enteric nervous system and enhancing neurotransmitter release
Authors: Vianna‐Jorge Rosane , Oliveira Cyntia Ferreira , Garcia Maria L , Kaczorowski Gregory J , Suarez‐Kurtz Guilherme 
Published: January 2005

Correolide (1–10 μM), a nortriterpene purified from Spachea correae and a selective blocker of Kv1 potassium channels, elicits repetitive twitching in guinea‐pig ileum. This effect is not seen in guinea‐pig duodenum, portal vein, urinary bladder or uterine strips, nor in rat or mouse ileum.
The time course and amplitude of the correolide‐induced twitches in guinea‐pig ileum are similar to those elicited by electrical stimulation of the enteric nervous system.
The correolide‐induced twitching is not affected by pre‐treatment with capsaicin (1 μM), but is facilitated by the NO synthase inhibitor, NG‐nitro‐L‐arginine methyl esther (L‐NAME, 200 μM).
The correolide‐induced twitching is abolished by tetrodotoxin (1 μM) or hexamethonium (100 μM), and is markedly inhibited by nifedipine (0.3 μM) or atropine (0.2 μM). The atropine‐resistant component is inhibited by selective antagonists of NK1 and NK2 tachykinin receptors, namely GR 82334 and GR 94800 (1 μM each). The former compound is more effective in inhibiting the correolide‐induced, atropine‐resistant activity.
Correolide intensified the twitching of ileum segments exposed to saturating concentrations of margatoxin (MgTX), which suggests that Kv1 sub‐types other than Kv1.1 (Kv1.4 or Kv1.5) are involved in the relatively greater degree of stimulation of the enteric nervous system by correolide, as compared to MgTX.
We propose that blockade of Kv1 channels by correolide increases the excitability of intramural nerve plexuses promoting release of acetylcholine and tachykinins from excitatory motor neurons. This, in turn, leads to Ca2+‐dependent action potentials and twitching of the muscle fibres.

British Journal of Pharmacology (2000) 131, 772–778; doi:10.1038/sj.bjp.0703620
Short‐ and long‐term differential effects of neuroprotective drug NS‐7 on voltage‐dependent sodium channels in adrenal chromaffin cells
Authors: Yokoo Hiroki , Shiraishi Seiji , Kobayashi Hideyuki , Yanagita Toshihiko , Minami Shin‐ichi , Yamamoto Ryuichi , Wada Akihiko 
Published: January 2005

In cultured bovine adrenal chromaffin cells, NS‐7 [4‐(4‐fluorophenyl)‐2‐methyl‐6‐(5‐piperidinopentyloxy) pyrimidine hydrochloride], a newly‐synthesized neuroprotective drug, inhibited veratridine‐induced 22Na+ influx via voltage‐dependent Na+ channels (IC50=11.4 μM). The inhibition by NS‐7 occurred in the presence of ouabain, an inhibitor of Na+,K+ ATPase, but disappeared at higher concentration of veratridine, and upon the washout of NS‐7.
NS‐7 attenuated veratridine‐induced 45Ca2+ influx via voltage‐dependent Ca2+ channels (IC50=20.0 μM) and catecholamine secretion (IC50=25.8 μM).
Chronic (12 h) treatment of cells with NS‐7 increased cell surface [3H]‐STX binding by 86% (EC50=10.5 μM; t1/2=27 h), but did not alter the KD value; it was prevented by cycloheximide, an inhibitor of protein synthesis, or brefeldin A, an inhibitor of vesicular transport from the trans‐Golgi network, but was not associated with increased levels of Na+ channel α‐ and β1‐subunit mRNAs.
In cells subjected to chronic NS‐7 treatment, 22Na+ influx caused by veratridine (site 2 toxin), α‐scorpion venom (site 3 toxin) or β‐scorpion venom (site 4 toxin) was suppressed even after the extensive washout of NS‐7, and veratridine‐induced 22Na+ influx remained depressed even at higher concentration of veratridine; however, either α‐ or β‐scorpion venom, or Ptychodiscus brevis toxin‐3 (site 5 toxin) enhanced veratridine‐induced 22Na+ influx as in nontreated cells.
These results suggest that in the acute treatment, NS‐7 binds to the site 2 and reversibly inhibits Na+ channels, thereby reducing Ca2+ channel gating and catecholamine secretion. Chronic treatment with NS‐7 up‐regulates cell surface Na+ channels via translational and externalization events, but persistently inhibits Na+ channel gating without impairing the cooperative interaction between the functional domains of Na+ channels.

British Journal of Pharmacology (2000) 131, 779–787; doi:10.1038/sj.bjp.0703622
Alpha‐2 adrenoceptors are present in rat aorta smooth muscle cells, and their action is mediated by ATP‐sensitive K+ channels
Authors: Fauaz Grasiele , Feres Teresa , Borges Antonio C R , Paiva Therezinha B 
Published: January 2005

The role of α2‐adrenoceptors in the response of aorta smooth muscle rings to the α2‐adrenoceptors agonists UK 14,304 and clonidine was studied.
Stimulation by 1–10 nM UK 14,304 caused dose‐dependent relaxant responses in BaCl2‐contracted endothelium‐denuded aorta rings, and hyperpolarization in rings with or without endothelium, which were inhibited by yohimbine and glibenclamide, but not affected by prazosin, propranolol, apamin or iberiotoxin. At higher concentrations (10 nM–10 μM) UK 14,304 also induced a depolarizing effect which was potentiated by yohimbine and inhibited by prazosin. These results indicate that UK 14,304 acts on α2‐adrenoceptors at lower concentrations and on both α1‐ and α2‐adrenoceptors above 10 nM.
In rings, with or without endothelium, noradrenaline had a depolarizing effect which was inhibited by prazosin. Adrenaline did not affect the membrane potential but in the presence of prazosin caused hyperpolarization, which was inhibited by yohimbine and glibenclamide. These results indicate that noradrenaline is more selective for α1‐, whereas adrenaline has similar affinities for α1‐ and α2‐adrenoceptors.
In aortae with endothelium, L‐NNA caused a small depolarization but did not affect the hyperpolarization induced by UK 14,304, indicating that NO is not involved in that response.
Glibenclamide induced a small depolarization in aortae, with or without endothelium, indicating that ATP‐sensitive K+ channels may play a role in maintaining the smooth muscle's membrane potential.
Our results indicate that, in rat aorta, α2‐adrenoceptors are also present in the smooth muscle, and that these receptors act through small‐conductance ATP‐sensitive K+ channels.

British Journal of Pharmacology (2000) 131, 788–794; doi:10.1038/sj.bjp.0703630
Analysis of 3‐morpholinosydnonimine and sodium nitroprusside effects on dopamine release in the striatum of freely moving rats: role of nitric oxide, iron and ascorbic acid
Authors: Serra Pier Andrea , Esposito Giovanni , Delogu M Rosaria , Migheli Rossana , Rocchitta Gaia , Grella Giuseppe , Miele Egidio , Miele Maddalena , Desole Maria S 
Published: January 2005

The effects of intrastriatal infusion of 3‐morpholinosydnonimine (SIN‐1) or sodium nitroprusside (SNP) on dopamine (DA), 3‐methoxytyramine (3‐MT), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), L‐dihydroxyphenylalanine (L‐DOPA), ascorbic acid and uric acid concentrations in dialysates from the striatum of freely moving rats were evaluated using microdialysis.
SIN‐1 (1 mM) infusion for 180 min increased microdialysate DA and 3‐MT concentrations, while L‐DOPA, DOPCA+HVA, ascorbic acid and uric acid levels were unaffected. Co‐infusion with ascorbic acid (0.1 mM) inhibited SIN‐1‐induced increases in DA and 3‐MT dialysate concentration.
SNP (1 mM) infusion for 180 min increased greatly the dialysate DA concentration to a peak (2950% of baseline) at the end of the infusion, while increases in 3‐MT were negligible. In addition, SNP decreased ascorbic acid and L‐DOPA but increased uric acid concentration in the dialysate. Co‐infusion with deferoxamine (0.2 mM) inhibited the late SNP‐induced increase in DA dialysate concentration, but did not affect the decrease in ascorbic acid and increase uric acid dialysate concentrations.
SNP (1 mM) infusion for 20 min moderately increased uric acid, DA and 3‐MT, but decreased L‐DOPA levels in the dialysate. Ascorbic acid concentration increased at the end of SNP infusion. Co‐infusion with ascorbic acid (0.1 mM) inhibited the SNP‐induced increase in DA and 3‐MT, but did not affect the decrease in L‐DOPA and increase in uric acid dialysate concentrations.
These results suggest that NO released from SIN‐1 may account for the increase in the dialysate DA concentration. NO released following decomposition of SNP may account for the early increase in dialysate DA, while late changes in microdialysate composition following SNP may result from an interaction between NO and the ferrocyanide moiety of SNP. Exogenous ascorbic acid inhibits the effect of exogenous NO on DA release probably by scavenging NO, suggesting that endogenous ascorbic acid may modulate the NO control of DA release from 300 striatal dopaminergic terminals.

British Journal of Pharmacology (2000) 131, 836–842; doi:10.1038/sj.bjp.0703635
The antimalarial agent mefloquine inhibits ATP‐sensitive K‐channels
Authors: Gribble Fiona M , Davis Timothy M E , Higham Claire E , Clark Anne , Ashcroft Frances M 
Published: January 2005

The aim of this study was to determine whether antimalarial agents inhibit ATP‐sensitive potassium (KATP) channels and thereby contribute to the observed side‐effects of these drugs.
Mefloquine (10–100 μM), but not artenusate (100 μM), stimulated insulin release from pancreatic islets in vitro.
Macroscopic KATP currents were studied in inside‐out patches excised from Xenopus oocytes expressing cloned KATP channels.
Mefloquine (IC50 ∼3 μM), quinine (IC50 ∼3 μM), and chloroquine inhibited the pancreatic β‐cell type of KATP channel Kir6.2/SUR1. Artenusate (100 μM) was without effect.
Mefloquine and quinine also blocked a truncated form of Kir6.2 (Kir6.2ΔC36) when expressed in the absence of SUR1. The extent of block was similar to that observed for Kir6.2/SUR1 currents.
Our results suggest that inhibition of the β‐cell KATP channel accounts for the ability of quinoline‐based antimalarial drugs to stimulate insulin secretion, and thereby produce hypoglycaemia.
The results also indicate that quinoline‐based antimalarial agents inhibit KATP channels by interaction with the Kir6.2 subunit. This subunit is common to β‐cell, neuronal, cardiac, skeletal muscle, and some smooth muscle KATP channels suggesting that KATP channel inhibition may contribute to the other side effects of these drugs, which include cardiac conduction abnormalities and neuropsychiatric disturbances.

British Journal of Pharmacology (2000) 131, 756–760; doi:10.1038/sj.bjp.0703638
Pharmacological characterization of the human 5‐HT4(d) receptor splice variant stably expressed in Chinese hamster ovary cells
Authors: Mialet Jeanne , Berque‐Bestel Isabelle , Sicsic Sames , Langlois Michel , Fischmeister Rodolphe , Lezoualc'h Frank 
Published: January 2005

The recently identified C‐terminal splice variant of the human 5‐HT4 receptor, the h5‐HT4(d) receptor, was stably expressed in a CHO cell line at 493±25 fmol mg−1 protein. We analysed its pharmacological properties by measuring binding affinities and 5‐HT4 ligand‐induced cyclic AMP production.
The pharmacological binding profile determined in competition studies with the specific antagonist [3H]‐GR113808 revealed a rank order of affinity of 5‐HT4 ligands for the h5‐HT4(d) receptor that was consistent with those previously reported for other 5‐HT4 receptor isoforms.
In adenylyl cyclase functional assays, the h5‐HT4(d) receptor displayed equipotent coupling for all 5‐HT4 agonists tested (EC50 in the range of 1–6 nM). EC50 values were lower than those previously obtained with the 5‐HT4(e) receptor stably expressed in CHO cells indicating that the 5‐HT4(d) receptor was more efficiently coupled to its effector than the 5‐HT4(e) receptor isoform. Moreover, in terms of agonist efficacy (Emax), the benzamide derivative, renzapride displayed full agonist properties at the h5‐HT4(d) receptor (same Emax as 5‐HT) whereas it was previously shown to be a partial agonist at the h5‐HT4(e) receptor.
A constitutive activity of the h5‐HT4(d) receptor was observed in CHO cells in the absence of any 5‐HT4 ligand. Surprisingly, two 5‐HT4 ligands, SB204070 and RS39604 which are described as highly potent antagonists in various biological models, revealed partial agonist properties at the h5‐HT4(d) receptor.
We conclude that C‐terminal tails of 5‐HT4 receptor isoforms may directly influence their functional properties.

British Journal of Pharmacology (2000) 131, 827–835; doi:10.1038/sj.bjp.0703641
Cannabinoid receptor mediated inhibition of excitatory synaptic transmission in the rat hippocampal slice is developmentally regulated
Authors: Al‐Hayani Abdulmonem , Davies Stephen N 
Published: January 2005

The cannabinoid (CB) receptor agonist WIN55,212‐2 (500 nM) had no effect on the first of a pair of population spikes evoked in the CA1 region of hippocampal slices prepared from young adult (4–6 weeks old) rats, despite powerfully reducing paired‐pulse depression. In contrast WIN55,212‐2 caused a substantial depression of the single population spike (reduced to 43% control) and the field EPSP (reduced to 72% of control) recorded in slices prepared from neonatal (10–13 days old) rats. This effect was stereoselective and blocked by the CB1 receptor antagonist AM281 (500 nM). The results indicate that activation of CB1 receptors inhibits excitatory synaptic transmission in neonatal, but not adult rat hippocampus. This developmental regulation of CB1 receptor mediated control of excitatory transmission may help explain some, but not all, of the previous discrepancies in the literature.British Journal of Pharmacology (2000) 131, 663–665; doi:10.1038/sj.bjp.0703642
Neuroprotection against hypoxic/hypoglycaemic injury after the insult by the group III metabotropic glutamate receptor agonist (R,S)‐4‐phosphonophenylglycine
Authors: Sabelhaus Clemens F , Schröder Ulrich H , Breder Jörg , Henrich‐Noack Petra , Reymann Klaus G 
Published: January 2005

The role of group III metabotropic glutamate receptors (mGluR) in ischaemic neurodegeneration is still unsettled. In order to examine a possible modulatory effect of these receptors on ischaemia‐induced damage we tested the novel selective agonist (R,S)‐4‐phosphonophenylglycine [(R,S)‐PPG] after an hypoxic/hypoglycaemic insult in rat hippocampal slices. The recovery of population spike amplitudes in the CA1‐region was used as parameter for neuronal viability. (R,S)‐PPG significantly improved the recovery of synaptic transmission in the CA1‐region even when applied only during the recovery period. The results imply that presynaptic glutamate release after an insult contributes to neurodegeneration. Since agonists of group III mGluR reduce neurotransmitter release – probably via presynaptic autoreceptors – we interpret the results obtained in our in vitro model of hypoxia/hypoglycaemia as support of the hypothesis that group III mGluR agonists might be beneficial drugs against diseases where excitotoxicity is one of the dominant pathological mechanisms.British Journal of Pharmacology (2000) 131, 655–658; doi:10.1038/sj.bjp.0703646
Alteration of the [Ca2+]i‐force relationship during the vasorelaxation induced by a Ca2+ channel blocker SR33805 in the porcine coronary artery
Authors: Ieiri Satoshi , Hirano Katsuya , Nishimura Junji , Suita Sachiyo , Kanaide Hideo 
Published: January 2005

The mechanism of vasorelaxation induced by SR33805 was investigated by simultaneously monitoring the cytosolic Ca2+ concentration ([Ca2+]i) and force, and by determining level of myosin light chain (MLC) phosphorylation in the medial strip of the porcine coronary artery.
SR33805 inhibited the sustained increases in [Ca2+]i and force (IC50; 3.2±1.0 and 49.4±27.5 nM, respectively) induced by 118 mM K+‐depolarization. There was about a 10 fold difference in the inhibitory potency between [Ca2+]i and force.
SR33805 completely inhibited the [Ca2+]i elevation induced by a thromboxane A2 analogue, U46619 and histamine, at concentrations (1 μM) higher than those required for the complete inhibition of K+‐depolarization induced [Ca2+]i elevation.
SR33805 had no effect on the [Ca2+]i elevation induced by histamine or caffeine in the absence of extracellular Ca2+.
SR33805 caused a leftward shift of the [Ca2+]i‐force relationship of the contraction induced by cumulative application of extracellular Ca2+ during 118 mM K+‐depolarization. The relationship between [Ca2+]i and MLC phosphorylation also shifted to the left by SR33805, while the relationship between MLC phosphorylation and force remained unaffected.
In conclusion, SR33805 caused an apparent leftward shift of the [Ca2+]i‐force relationship, accompanied by a greater degree of MLC phosphorylation for a given level of [Ca2+]i. The mechanism of this leftward shift, however, still remains to be elucidated.

British Journal of Pharmacology (2000) 131, 1597–1606; doi:10.1038/sj.bjp.0703721
The effect of selective and non‐selective phosphodiesterase inhibitors on allergen‐ and leukotriene C4‐induced contractions in passively sensitized human airways
Authors: Schmidt Dunja T , Watson Nikki , Dent Gordon , Rühlmann Elke , Branscheid Detlev , Magnussen Helgo , Rabe Klaus F 
Published: January 2005

Non‐selective inhibitors of cyclic nucleotide phosphodiesterase (PDE) block allergen‐induced contraction of passively sensitized human airways in vitro by a dual mechanism involving a direct relaxant effect on smooth muscle and inhibition of histamine and cysteinyl leukotriene (LT) release from airways. We investigated the effects of non‐selective PDE inhibitors and selective inhibitors of PDE3 and PDE4 in order to determine the involvement of PDE isoenzymes in the suppression of allergic bronchoconstriction.
Macroscopically normal airways from 76 patients were sensitized with IgE‐rich sera (>250 u ml−1) containing specific antibodies against allergen (Dermatophagoides farinae). Contractile responses of bronchial rings were assessed using standard organ bath techniques.
Passive sensitization caused increased contractile responses to allergen, histamine and LTC4. Non‐selective PDE inhibitors (theophylline, 3‐isobutyl‐1‐methylxanthine [IBMX]), a PDE3‐selective inhibitor (motapizone), PDE4‐selective inhibitors (RP73401, rolipram, AWD 12‐281) and a mixed PDE3/4 inhibitor (zardaverine) all significantly relaxed inherent bronchial tone at resting tension and to a similar degree. Theophylline, IBMX, zardaverine and the combination of motapizone and RP73401 inhibited the contractile responses to allergen and LTC4. Pre‐treatment with motapizone, RP73401, rolipram or the methylxanthine adenosine receptor antagonist, 8‐phenyltheophylline, did not significantly decrease responses to either allergen or LTC4.
We conclude that combined inhibition of PDE3 and PDE4, but not selective inhibition of either isoenzyme or antagonism of adenosine receptors, is effective in suppressing allergen‐induced contractions of passively sensitized human airways. The relationship between allergen‐ and LTC4‐induced responses suggests that PDE inhibitors with PDE3 and PDE4 selectivity are likely to act in part through inhibition of mediator release and not simply through direct relaxant actions on airway smooth muscle.

British Journal of Pharmacology (2000) 131, 1607–1618; doi:10.1038/sj.bjp.0703725
Inhibitory action of brotizolam on circadian and light‐induced Per1 and Per2 expression in the hamster suprachiasmatic nucleus
Authors: Yokota Shin‐ichi , Horikawa Kazumasa , Akiyama Masashi , Moriya Takahiro , Ebihara Shizufumi , Komuro Goyo , Ohta Tatsuro , Shibata Shigenobu 
Published: January 2005

Triazolam reportedly causes phase advances in hamster wheel‐running rhythm after injection during subjective daytime. However, it is unclear whether benzodiazepine affects the Per gene expression accompanying a behavioural phase shift.
Brotizolam (0.5–10 mg kg−1) induced large phase advances in hamster rhythm when injected during mid‐subjective daytime (circadian time 6 or 9), but not at circadian time 0, 3 or 15.
Brotizolam (5 mg kg−1) significantly reduced the expression of Per1 and Per2 in the suprachiasmatic nucleus 1 and 2 h after injection at circadian time 6, and slightly reduced them at circadian time 20.
Injection of 8‐OH‐DPAT (5 mg kg−1) at subjective daytime induced similar phase advances with a reduction of Per1 and Per2 expression. Co‐administration of brotizolam with 8‐OH DPAT failed to potentiate the 8‐OH DPAT‐induced phase advances and reduced Per expression.
Both phase advance and rapid induction of Per1 and Per2 in the suprachiasmatic nucleus after light exposure (5 lux, 15 min) at circadian time 20 was strongly attenuated by co‐treatment with brotizolam 5 mg kg−1.
The present results strongly suggest that reduction of Per1 and/or Per2 expression during subjective daytime by brotizolam may be an important step in causing a behavioural phase advance. The co‐administration experiment suggests that common mechanism(s) are involved in brotizolam‐ or 8‐OH DPAT‐induced phase advances and the reduction of Per gene expression.
These results suggest that brotizolam is not only a good drug for insomnia but also a drug capable of facilitating re‐entrainment like melatonin.

British Journal of Pharmacology (2000) 131, 1739–1747; doi:10.1038/sj.bjp.0703735
Modification of adenosine modulation of synaptic transmission in the hippocampus of aged rats
Authors: Sebastião A M , Cunha R A , De Mendonça A , Ribeiro J A 
Published: January 2005

We compared the modulation of synaptic transmission by adenosine A1 receptors in the hippocampus of aged (24 months) and young adult rats (6 weeks).
The adenosine A1 receptor agonist, N6‐cyclopentyladenosine, was less potent (P<0.05) to inhibit synaptic transmission in aged (EC50=53 nM) than young adult (EC50=14 nM) hippocampal slices, these effects being prevented by the A1 receptor antagonist, 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX).
In contrast with the lower effect of the A1 receptor agonist, it was observed that blockade of A1 receptors with DPCPX (50 nM), or removal of endogenous extracellular adenosine with adenosine deaminase (2 u ml−1), caused a more pronounced disinhibition of synaptic transmission in aged rats. Also consistent with a more intense A1 receptor‐mediated inhibitory tonus by endogenous adenosine in aged rats was the finding that to fully prevent the depression of synaptic transmission induced by 3 min hypoxia, a higher concentration of DPCPX was required in slices from aged (100 nM) than from young (50 nM) rats.
It is concluded that in hippocampal slices of aged rats the efficiency of A1 receptors to modulate synaptic transmission is reduced, but this may be compensated by an enhanced inhibitory tonus by endogenous adenosine.

British Journal of Pharmacology (2000) 131, 1629–1634; doi:10.1038/sj.bjp.0703736