bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibitory effects of aprindine on the delayed rectifier K+ current and the muscarinic acetylcholine receptor‐operated K+ current in guinea‐pig atrial cells
Authors: Ohmoto‐Sekine Yuki , Uemura Hiroko , Tamagawa Masaji , Nakaya Haruaki 
Published: January 2005

In order to clarify the mechanisms by which the class Ib antiarrhythmic drug aprindine shows efficacy against atrial fibrillation (AF), we examined the effects of the drug on the repolarizing K+ currents in guinea‐pig atrial cells by use of patch‐clamp techniques. We also evaluated the effects of aprindine on experimental AF in isolated guinea‐pig hearts.
Aprindine (3 μM) inhibited the delayed rectifier K+ current (IK) with little influence on the inward rectifier K+ current (IK1) or the Ca2+ current. Electrophysiological analyses including the envelope of tails test revealed that aprindine preferentially inhibits IKr (rapidly activating component) but not IKs (slowly activating component).
The muscarinic acetylcholine receptor‐operated K+ current (IK.ACh) was activated by the extracellular application of carbachol (1 μM) or by the intracellular loading of GTPγS. Aprindine inhibited the carbachol‐ and GTPγS‐induced IK.ACh with the IC50 values of 0.4 and 2.5 μM, respectively.
In atrial cells stimulated at 0.2 Hz, aprindine (3 μM) per se prolonged the action potential duration (APD) by 50±4%. The drug also reversed the carbachol‐induced action potential shortening in a concentration‐dependent manner.
In isolated hearts, perfusion of carbachol (1 μM) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered atrial fibrillation threshold. Addition of aprindine (3 μM) inhibited the induction of AF by prolonging MAP and ERP.
We conclude the efficacy of aprindine against AF may be at least in part explained by its inhibitory effects on IKr and IK.ACh.

British Journal of Pharmacology (1999) 126, 751–761; doi:10.1038/sj.bjp.0702334
Vasorelaxation and inhibition of the voltage‐operated Ca2+ channels by FK506 in the porcine coronary artery
Authors: Yasutsune Toru , Kawakami Nozomi , Hirano Katsuya , Nishimura Junji , Yasui Hisataka , Kitamura Kenji , Kanaide Hideo 
Published: January 2005

Using fura‐2 fluorometry, the effects of FK506, an immunosuppressant, on changes in cytosolic Ca2+ concentrations ([Ca2+]i) and tension were investigated in porcine coronary arterial strips. The effects of FK506 on the activity of voltage‐operated Ca2+ channels were examined by applying a whole cell patch clamp to the isolated smooth muscle cells of porcine coronary artery.
FK506 inhibited the sustained increases in both [Ca2+]i and tension induced by 118 mM K+ depolarization and 100 nM U46619 in a concentration‐dependent manner (1–30 μM). The extent of inhibition of the K+‐induced contraction was greater than that of the U46619‐induced contraction. The increases in [Ca2+]i and tension induced by histamine and endothelin‐1 in the presence of extracellular Ca2+ were also inhibited by 10 μM FK506.
FK506 (10 μM) had no effect on Ca2+ release induced by caffeine or by histamine in the Ca2+‐free solution.
FK506 (10 μM) had no effect on the [Ca2+]i‐tension relationships of the contractions induced by cumulative increases of extracellular Ca2+ during K+ depolarization or stimulation with U46619.
In the patch clamp experiments, FK506 (30 μM) partially inhibited the inward current induced by depolarization pulse from −80 mV to 0 mV.
In conclusion, FK506 induces arterial relaxation by decreasing [Ca2+]i mainly due to the inhibition of the L‐type Ca2+ channels, with no effect on the Ca2+ sensitivity of the contractile apparatus.

British Journal of Pharmacology (1999) 126, 717–729; doi:10.1038/sj.bjp.0702339
Effect of prolonged administration of a urinary kininase inhibitor, ebelactone B on the development of deoxycorticosterone acetate‐salt hypertension in rats
Authors: Ito Hiroshi , Majima Masataka , Nakajima Shin‐ichi , Hayashi Izumi , Katori Makoto , Izumi Tohru 
Published: January 2005

The effect of prolonged administration of a carboxypeptidase Y‐like kininase inhibitor, ebelactone B (EB) (2‐ethyl‐3, 11‐dihydroxy‐4, 6, 8, 10, 12‐pentamethyl‐9‐oxo‐6‐tetradecenoic 1, 3‐lactone), on the development of deoxycorticosterone acetate (DOCA)‐salt hypertension was tested.
The systolic blood pressure (SBP) of non‐treated 6‐week‐old Sprague‐Dawley strain rats was gradually increased by DOCA‐salt treatment from 137±2 mmHg (n=11) to 195±7 mmHg at 10 weeks of age.
With daily oral administration of lisinopril (5 mg kg−1, twice a day), which is an inhibitor of angiotensin converting enzyme, a major kininase in plasma, the development of hypertension was not suppressed.
By contrast, administration of EB (5 mg kg−1, twice a day), completely inhibited the development of hypertension (SBP: 146±1 mmHg, n=5, 10 weeks old). The reduced SBP at 10 weeks of age was equal to the SBP before any treatment (142±1 mmHg, n=5).
Direct determination of mean blood pressure (MBP) in conscious, unrestrained rats confirmed that MBP elevation was completely inhibited by EB.
Continuous subcutaneous infusion (5 mg kg−1 day−1) of HOE140, a bradykinin B2 receptor antagonist, restored the elevation of SBP, which was suppressed by EB.
The weights of left ventricle of DOCA‐salt treated rats 10‐weeks‐old (0.36±0.02 g 100 g body weight−1, n=11) was significantly reduced by EB (0.27±0.01, n=5), as were the sodium levels in serum, cerebrospinal fluid and erythrocyte.
These findings suggested that EB is effective in preventing salt‐related hypertension presumably by eliminating sodium retention.

British Journal of Pharmacology (1999) 126, 613–620; doi:10.1038/sj.bjp.0702340
Modulation of noradrenergic neuronal firing by selective serotonin reuptake blockers
Authors: Szabo Steven T , De Montigny Claude , Blier Pierre 
Published: January 2005

Using in vivo extracellular unitary recording, the effect of short term (2‐day) and long‐term (21‐day) administration of the selective 5‐HT reuptake inhibitor (SSRI) paroxetine (10 mg kg−1 day−1, s.c. using osmotic minipumps) was examined on the spontaneous firing activity of locus coeruleus noradrenergic neurons. Long‐term but not short‐term treatment significantly decreased firing activity. Thus, it appears that enhancing 5‐HT neurotransmission by sustained SSRI administration leads to a reduction of the firing rate of noradrenergic neurons. The SSRI paroxetine therefore alters the activity of noradrenergic neurons with a delay that is consistent with its therapeutic action in depression and panic disorder.British Journal of Pharmacology (1999) 126, 568–571; doi:10.1038/sj.bjp.0702343
Electrophysiological examination of the effects of sustained flibanserin administration on serotonin receptors in rat brain
Authors: Rueter Lynne E , Blier Pierre 
Published: January 2005

5‐HT1A receptor agonists have proven to be effective antidepressant medications, however they suffer from a significant therapeutic lag before depressive symptoms abate. Flibanserin is a 5‐HT1A receptor agonist and 5‐HT2A receptor antagonist developed to possibly induce a more rapid onset of antidepressant action through its preferential postsynaptic 5‐HT1A receptor agonism.
Flibanserin antagonized the effect of microiontophoretically‐applied DOI in the medial prefrontal cortex (mPFC) following 2 days of administration, indicating antagonism of postsynaptic 5‐HT2A receptors. This reduction in the effect of locally‐applied DOI was no longer present following 7‐day flibanserin administration.
Two‐day flibanserin administration only marginally reduced the firing activity of dorsal raphe (DRN) 5‐HT neurons. Following 7 days of administration, 5‐HT neuronal firing activity had returned to normal and the somatodendritic 5‐HT1A autoreceptors were desensitized.
The responsiveness of postsynaptic 5‐HT1A receptors located on CA3 hippocampus pyramidal neurons and mPFC neurons, examined using microiontophoretically‐applied 5‐HT and gepirone, was unchanged following a 7‐day flibanserin treatment.
As demonstrated by the ability of the 5‐HT1A receptor antagonist WAY 100635 to selectively increase the firing of hippocampal neurons in 2‐ and 7‐day treated rats, flibanserin enhanced the tonic activation of postsynaptic 5‐HT1A receptors in this brain region.
The results suggest that flibanserin could be a therapeutically useful compound putatively endowed with a more rapid onset of antidepressant action.

British Journal of Pharmacology (1999) 126, 627–638; doi:10.1038/sj.bjp.0702344
Effects of vasopressin on the sympathetic contraction of rabbit ear artery during cooling
Authors: García‐Villalón A L , Padilla J , Monge L , Fernández N , Sánchez M A , Gómez B , Diéguez G 
Published: January 2005

In order to analyse the effects of arginine‐vasopressin on the vascular contraction to sympathetic nerve stimulation during cooling, the isometric response of isolated, 2‐mm segments of the rabbit central ear (cutaneous) artery to electrical field stimulation (1–8 Hz) was recorded at 37 and 30°C.
Electrical stimulation (37°C) produced frequency‐dependent arterial contraction, which was reduced at 30°C and potentiated by vasopressin (10 pM, 100 pM and 1 nM). This potentiation was greater at 30 than at 37°C and was abolished at both temperatures by the antagonist of vasopressin V1 receptors d(CH2)5 Tyr(Me)AVP (100 nM). Desmopressin (1 μM) did not affect the response to electrical stimulation.
At 37°C, the vasopressin‐induced potentiation was abolished by the purinoceptor antagonist PPADS (30 μM), increased by phentolamine (1 μM) or prazosin (1 μM) and not modified by yohimbine (1 μM), whilst at 30°C, the potentiation was reduced by phentolamine, yohimbine or PPADS, and was not modified by prazosin.
The Ca2+‐channel blockers, verapamil (10 μM) and NiCl2 (1 mM), abolished the potentiating effects of vasopressin at 37°C whilst verapamil reduced and NiCl2 abolished this potentiation at 30°C. The inhibitor of nitric oxide synthesis, L‐NOARG (100 μM), or endothelium removal did not modify the potentiation by vasopressin at 37 and 30°C.
Vasopressin also increased the arterial contraction to the α2‐adrenoceptor agonist BHT‐920 (10 μM) and to ATP (2 mM) at 30 and 37°C, but it did not modify the contraction to noradrenaline (1 μM) at either temperature.
These results suggest that in cutaneous (ear) arteries, vasopressin potentiaties sympathetic vasoconstriction to a greater extent at 30 than at 37°C by activating vasopressin V1 receptors and Ca2+ channels at both temperatures. At 37°C, the potentiation appears related to activation of the purinoceptor component and, at 30°C, to activation of both purinoceptor and α2‐adrenoceptor components of the sympathetic response.

British Journal of Pharmacology (1999) 126, 785–793; doi:10.1038/sj.bjp.0702345
N‐substituted analogues of S‐nitroso‐N‐acetyl‐D,L‐penicillamine: chemical stability and prolonged nitric oxide mediated vasodilatation in isolated rat femoral arteries
Authors: Megson I L , Morton S , Greig I R , Mazzei F A , Field R A , Butler A R , Caron G , Gasco A , Fruttero R , Webb D J 
Published: January 2005

Previous studies show that linking acetylated glucosamine to S‐nitroso‐N‐acetyl‐D,L‐penicillamine (SNAP) stabilizes the molecule and causes it to elicit unusually prolonged vasodilator effects in endothelium‐denuded, isolated rat femoral arteries. Here we studied the propanoyl (SNPP; 3 carbon side‐chain), valeryl (SNVP; 5C) and heptanoyl (SNHP; 7C) N‐substituted analogues of SNAP (2C), to further investigate other molecular characteristics that might influence chemical stability and duration of vascular action of S‐nitrosothiols.
Spectrophotometric analysis revealed that SNVP was the most stable analogue in solution. Decomposition of all four compounds was accelerated by Cu(II) and cysteine, and neocuproine, a specific Cu(I) chelator, slowed decomposition of SNHP. Generation of NO from the compounds was confirmed by electrochemical detection at 37°C.
Bolus injections of SNAP (10 μl; 10−8–10−3 M) into the perfusate of precontracted, isolated rat femoral arteries taken from adult male Wistar rats (400–500 g), caused concentration‐dependent, transient vasodilatations irrespective of endothelial integrity. Equivalent vasodilatations induced by SNVP and SNHP were transient in endothelium‐intact vessels but failed to recover to pre‐injection pressures at moderate and high concentrations (10−6–10−3 M) in those denuded of endothelium. This sustained effect (>1 h) was most prevalent with SNHP and was largely reversed by the NO scavenger, haemoglobin.
We suggest that increased lipophilicity of SNAP analogues with longer sidechains facilitates their retention by endothelium‐denuded vessels; subsequent slow decomposition within the tissue generates sufficient NO to cause prolonged vasodilatation. This is a potentially useful characteristic for targeting NO delivery to areas of endothelial damage.

British Journal of Pharmacology (1999) 126, 639–648; doi:10.1038/sj.bjp.0702346
Effects of the prostanoid EP3‐receptor agonists M&B 28767 and GR 63799X on infarct size caused by regional myocardial ischaemia in the anaesthetized rat
Authors: Zacharowski Kai , Olbrich Antje , Otto Mike , Hafner Gerd , Thiemermann Christoph 
Published: January 2005

This study investigates the effects of two agonists of the prostanoid EP3‐receptor (M&B 28767 and GR 63799X) on the infarct size caused by regional myocardial ischaemia and reperfusion in the anaesthetized rat.
One hundred and sixty‐seven, male Wistar rats were anaesthetized (thiopentone, 120 mg kg−1, i.p.), ventilated (8–10 ml kg−1, 70 strokes min−1, inspiratory oxygen concentration: 30%; PEEP: 1–2 mmHg) and subjected to occlusion of the left anterior descending coronary artery (LAD, for 7.5, 15, 25, 35, 45 or 60 min) followed by reperfusion (2 h). Infarct size was determined by staining of viable myocardium with a tetrazolium stain (NBT), histological evaluation by light and electron microscopy and determination of the plasma levels of cardiac troponin T.
M&B 28767 (0.5 μg kg−1 min−1, i.v., n=7) or GR 63799X (3 μg kg−1 min−1, i.v., n=7) caused significant reductions in infarct size from 60±3% (25 min ischaemia and 2 h reperfusion; saline‐control, n=8) to 39±6 and 38±4% of the area at risk, without causing a significant fall in blood pressure. Pretreatment of rats with 5‐hydroxydecanoate (5‐HD), an inhibitor of ATP‐sensitive potassium channels, attenuated the cardioprotective effects of both EP3‐receptor agonists. The reduction in infarct size afforded by M&B 28767 was also abolished by glibenclamide and the protein kinase C (PKC) inhibitors staurosporine and chelerythrine.
Thus, M&B 28767 and GR 63799X reduce myocardial infarct size in the rat by a mechanism(s) which involves the activation of PKC and the opening of ATP‐sensitive potassium channels.

British Journal of Pharmacology (1999) 126, 849–858; doi:10.1038/sj.bjp.0702348
Antagonism by acetyl‐RYYRIK‐NH2 of G protein activation in rat brain preparations and of chronotropic effect on rat cardiomyocytes evoked by nociceptin/orphanin FQ
Authors: Berger H , Albrecht E , Wallukat G , Bienert M 
Published: January 2005

For the further elucidation of the central functions of nociceptin/orphanin FQ (noc/OFQ), the endogenous ligand of the G protein‐coupled opioid receptor‐like receptor ORL1, centrally acting specific antagonists will be most helpful. In this study it was found that the hexapeptide acetyl‐RYYRIK‐NH2 (Ac‐RYYRIK‐NH2), described in literature as partial agonist on ORL1 transfected in CHO cells, antagonizes the stimulation of [35S]‐GTPγS binding to G proteins by noc/OFQ in membranes and sections of rat brain. The antagonism of the peptide was competitive, of high affinity (Schild constant 6.58 nM), and specific for noc/OFQ in that the stimulation of GTP binding by agonists for the μ‐, δ‐, and κ‐opioid receptor was not inhibited. The hexapeptide also fully inhibited the chronotropic effect of noc/OFQ on neonatal rat cardiomyocytes. It is suggested that Ac‐RYYRIK‐NH2 may provide a promising starting point for in vivo tests for antagonism of the action of noc/OFQ and for the further development of highly active and specific antagonists.British Journal of Pharmacology (1999) 126, 555–558; doi:10.1038/sj.bjp.0702353
Hyperbaric oxygen increases plasma exudation in rat trachea: involvement of nitric oxide
Authors: Bernareggi M , Radice S , Rossoni G , Oriani G , Chiesara E , Berti F 
Published: January 2005

This study investigates the microvascular permeability changes in tracheal tissue of rats exposed to hyperbaric oxygen (HBO).
Rats, following exposure to HBO or ambient air (control animals) for 1.5, 3 and 6 h, were prepared for recording of nitric oxide exhaled (FENO) in air using a chemiluminescence analyser. The level of FENO was not statistically different in the two groups. Plasma exudation, evaluated by measuring the leakage of Evans blue (EB) dye into the tracheal tissue, was significantly elevated (48, 86 and 105% at 1.5, 3 and 6 h, respectively) in HBO‐treated rats.
Plasma exudation in the trachea of control rats was significantly increased (42%, P<0.05) by NG‐nitro‐L‐arginine methyl ester (L‐NAME), whereas it was significantly reduced (31%, P<0.05) in rats exposed to HBO for 3 h.
N‐acetylcysteine (NAC) and flunisolide significantly prevented the increase in plasma leakage in HBO‐treated rats. In contrast, indomethacin was devoid of anti‐exudative activity in these experiments.
Western immunoblot showed a significant increase in the level of inducible nitric oxide synthase (iNOS) protein in the tracheal homogenates of HBO‐treated rats, as compared to basal levels.
These results indicate that nitric oxide (NO) is involved in the maintenance of microvascular permeability in tracheal tissue of rats. The protective effect observed with the steroid seems to support this hypothesis. Furthermore, the beneficial action of NAC underlines that reactive oxygen species participate in the microvascular permeability changes observed in tracheal tissue of rats exposed to HBO.

British Journal of Pharmacology (1999) 126, 794–800; doi:10.1038/sj.bjp.0702354
Suppression of nitric oxide synthase and the down‐regulation of the activation of NFκB in macrophages by resveratrol
Authors: Tsai Shu‐Huei , Lin‐Shiau Shoei‐Yn , Lin Jen‐Kun 
Published: January 2005

Resveratrol, naringenin and naringin are naturally occurring flavonoids in grapes and grapefruits. The anti‐inflammatory effects of these flavonoids have been well documented, but the mechanism is poorly characterized. High concentration of NO are produced by inducible NO synthase (iNOS) in inflammation, and the prevention of the expression of iNOS may be an important anti‐inflammatory mechanism. In this study, the effects of these flavonoids on the induction of NO synthase (NOS) in RAW 264.7 cells activated with bacterial lipopolysaccharide (LPS, 50 ng ml−1) were investigated.
Resveratrol was found strongly to inhibit NO generation in activated macrophages, as measured by the amount of nitrite released into the culture medium, and resveratrol strongly reduced the amount of cytosolic iNOS protein and steady state mRNA levels. However, the inhibitory abilities of naringenin were lower, and the inhibitory abilities of naringin were almost negligible.
In electrophoretic mobility shift assays, the activation of NFκB induced by LPS for 1 h was inhibited by resveratrol (30 μM). Furthermore, in immunoblotting analysis, cells treated with LPS plus resveratrol showed an inhibition of phosphorylation as well as degradation of IκBα, and a reduced nuclear content of NFκB subunits.
The flavonoids may be of value for inhibiting the enhanced expression of iNOS in inflammation through down‐regulation of NFκB binding activity.

British Journal of Pharmacology (1999) 126, 673–680; doi:10.1038/sj.bjp.0702357
ATP‐ and glutathione‐dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1
Authors: Renes Johan , De Vries Elisabeth G E , Nienhuis Edith F , Jansen Peter L M , Müller Michael 
Published: January 2005

The present study was performed to investigate the ability of the multidrug resistance protein (MRP1) to transport different cationic substrates in comparison with MDR1‐P‐glycoprotein (MDR1). Transport studies were performed with isolated membrane vesicles from in vitro selected multidrug resistant cell lines overexpressing MDR1 (A2780AD) or MRP1 (GLC4/Adr) and a MRP1‐transfected cell line (S1(MRP)).
As substrates we used 3H‐labelled derivatives of the hydrophilic monoquaternary cation N‐(4′,4′‐azo‐n‐pentyl)‐21‐deoxy‐ajmalinium (APDA), the basic drug vincristine and the more hydrophobic basic drug daunorubicin. All three are known MDR1‐substrates.
MRP1 did not mediate transport of these substrates per se. In the presence of reduced glutathione (GSH), there was an ATP‐dependent uptake of vincristine and daunorubicin, but not of APDA, into GLC4/Adr and S1(MRP) membrane vesicles which could be inhibited by the MRP1‐inhibitor MK571.
ATP‐ and GSH‐dependent transport of daunorubicin and vincristine into GLC4/Adr membrane vesicles was inhibited by the MRP1‐specific monoclonal antibody QCRL‐3.
MRP1‐mediated daunorubicin transport rates were dependent on the concentration of GSH and were maximal at concentrations 10 mM. The apparent KM value for GSH was 2.7 mM. Transport of daunorubicin in the presence of 10 mM GSH was inhibited by MK571 with an IC50 of 0.4 μM.
In conclusion, these results demonstrate that MRP1 transports vincristine and daunorubicin in an ATP‐ and GSH‐dependent manner. APDA is not a substrate for MRP1.

British Journal of Pharmacology (1999) 126, 681–688; doi:10.1038/sj.bjp.0702360
Effects of angiotensin II receptor blockade on proximal fluid uptake in the rat kidney
Authors: Smart M L , Hiranyachattada S , Harris P J 
Published: January 2005

Angiotensin II has a well described dose‐dependent biphasic action on proximal tubule fluid uptake, although the concentration and effect of endogenous luminal angiotensin II remain controversial.
Shrinking split‐droplet micropuncture was used to examine the fluid uptake in response to the luminal application of three AT1 antagonists (losartan, EXP3174, candesartan).
Addition of losartan at 10−8 M decreased fluid uptake rate (Jva) by 17.5±2.2% (P<0.05). Luminal addition of EXP3174 at concentrations between 10−9–10−5 M caused a dose‐dependent decrease in fluid uptake, with a maximum decrease of 41.0±9.5% (P<0.01) at 10−6 M. Candesartan also decreased fluid uptake, by 21.9±4.9% (P<0.05) at 10−8 M and 23.6±5.5% (P<0.05) at 10−5 M.
All three antagonists at a low concentration (10−8 M) decreased fluid uptake. EXP3174 and candesartan at a higher concentration (10−5 M) also decreased fluid uptake in contrast to the previously reported effect of losartan.
We conclude that the endogenous concentration of antiotensin II in the proximal luminal fluid is low and exerts a stimulatory effect on fluid absorption. Losartan at concentrations greater than 10−6 M may have a non‐selective action on fluid uptake.

British Journal of Pharmacology (1999) 126, 697–700; doi:10.1038/sj.bjp.0702366