bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sustained improvement in glucose homeostasis in lean and obese mice following chronic administration of the β3 agonist SR 58611A
Authors: Williams Celia A , Shih Mei‐Fen , Taberner Peter V 
Published: January 2005

Acute SR 58611A (0.25 mg kg−1), was effective in reducing the blood glucose response to a glucose tolerance test (GTT) in normal lean (control) and spontaneously obese/diabetic CBA/Ca mice and to be equipotent to 1.25 mg kg−1 glibenclamide in lean mice.
Neither brown (BAT) nor white (WAT) adipose tissue lipogenesis was altered by acute SR 58611A (2–8 mg kg−1) in lean mice, but both increased significantly at the higher doses in the obese mice.
Acute SR 58611A produced a hypoglycaemia 40 min after dosing in lean and obese animals, the duration and potency of which was less than that of glibenclamide. Plasma insulin levels increased 20 min after acute SR 58611A and glibenclamide in lean and obese mice.
Chronic treatment (0.25 mg kg−1, 15 days) with SR 58611A increased its effectiveness in improving glucose tolerance, but did not affect the body weight (BW) or food intake of either lean or obese mice.
Acute and chronic SR 58611A prolonged the hypoglycaemic effect of exogenous insulin in lean but not obese mice.
In fed and fasted lean mice and in fasted obese mice chronic SR 58611A produced an acute hypoglycaemia 30 min post administration which was greater than after a single dose.
SR 58611A maintained its effectiveness in improving glucose tolerance in lean and obese mice over a dosing period of 15 days. The improvement in glucose tolerance was achieved at a dose less than that required to stimulate adipose tissue lipogenesis and which did not affect food intake or body weight.

British Journal of Pharmacology (1999) 128, 1586–1592; doi:10.1038/sj.bjp.0702946
Adverse effects of an active fragment of parathyroid hormone on rat hippocampal organotypic cultures
Authors: Hirasawa Takae , Nakamura Takeshi , Mizushima Akiko , Morita Mitsuhiro , Ezawa Ikuko , Miyakawa Hiroyoshi , Kudo Yoshihisa 
Published: January 2005

Adverse effects of an active fragment of parathyroid hormone (PTH1–34), a blood Ca2+ level‐regulating hormone, were examined using rat hippocampal slices in organotypic culture.
Exposure of cultured slice preparations to 0.1 μM PTH1–34 for 60 min resulted in a gradual increase in the intracellular Ca2+ concentration ([Ca2+]i); this effect was most obvious in the apical dendritic region of CA1 subfield.
When PTH1–34 at a lower concentration (1 nM) was added to the culture medium and its toxic effects examined using a propidium iodide intercalation method, significant toxicity was seen 3 days after exposure and increased with time. Cells in the CA1 region seemed more vulnerable to the hormone than cells in other regions. At 1 week of exposure, the toxic effects were dose‐dependent over the range of 0.1 pM to 0.1 μM, the minimum effective dose being 10 pM.
The adverse effects were not induced either by the inactive fragment, PTH39–84, or by an active fragment of PTH‐related peptide (PTHrP1–34), an intrinsic ligand of the brain PTH receptor.
The PTH1–34‐induced adverse effects were significantly inhibited by co‐administration of 10 μM nifedipine, an L‐type Ca2+ channel blocker, but not by co‐administration of blockers of the other types of Ca2+ channel.
The present study demonstrates that sustained high levels of PTH in the brain might cause degeneration of specific brain regions due to Ca2+ overloading via activation of dihydropyridine‐sensitive Ca2+ channels, and suggests that PTH may be a risk factor for senile dementia.

British Journal of Pharmacology (2000) 129, 21–28; doi:10.1038/sj.bjp.0702949
Significant role of neuronal non‐N‐type calcium channels in the sympathetic neurogenic contraction of rat mesenteric artery
Authors: Tanaka Yoshio , Mochizuki Yumi , Tanaka Hikaru , Shigenobu Koki 
Published: January 2005

The possible involvement of pre‐junctional non‐N‐type Ca2+ channels in noradrenaline (NA)‐mediated neurogenic contraction by electrical field stimulation (EFS) was examined pharmacomechanically in the isolated rat mesenteric artery.
EFS‐generated contraction of endothelium‐denuded mesenteric artery was frequency‐dependent (2–32 Hz) and was abolished by tetrodotoxin (TTX, 1 μM), guanethidine (5 μM) or prazosin (100 nM), indicating that NA released from sympathetic nerve endings mediates the contractile response.
NA‐mediated neurogenic contractions to lower frequency stimulations (2–8 Hz) were almost abolished by an N‐type Ca2+ channel blocker, ω‐conotoxin‐GVIA (1 μM) whereas the responses to higher frequency stimulations (12–32 Hz) were less sensitive to ω‐conotoxin‐GVIA. The ω‐conotoxin‐GVIA‐resistant component of the contractile response to 32 Hz stimulation was inhibited partly (10–20%) by ω‐agatoxin‐IVA (10–100 nM; concentrations which are relatively selective for P‐type channels) and to a greater extent by ω‐agatoxin‐IVA (1 μM) and ω‐conotoxin‐MVIIC (3 μM), both of which block Q‐type channels at the concentrations used.
ω‐Agatoxin‐IVA (10–100 nM) alone inhibited 32 Hz EFS‐induced contraction by 10∼20% whereas ω‐conotoxin‐MVIIC (3 μM) alone inhibited the response by ∼60%.
These ω‐toxin treatments did not affect the contractions evoked by exogenously applied NA.
These findings show that P‐ and Q‐type as well as N‐type Ca2+ channels are involved in the sympathetic neurogenic vascular contraction, and suggest the significant role of non‐N‐type Ca2+ channels in NA release from adrenergic nerve endings when higher frequency stimulations are applied to the nerve.

British Journal of Pharmacology (1999) 128, 1602–1608; doi:10.1038/sj.bjp.0702954
Levcromakalim causes indirect endothelial hyperpolarization via a myo‐endothelial pathway
Authors: Murai Takeshi , Muraki Katsuhiko , Imaizumi Yuji , Watanabe Minoru 
Published: January 2005

Effects of K+ channel opener, levcromakalim, on vascular endothelial cells were examined. Under voltage‐ and current‐clamp conditions, application of acetylcholine to dispersed endothelial cells isolated from rabbit superior mesenteric artery (dispersed RMAECs) produced hyperpolarization and outward currents. On the other hand, dispersed RMAECs did not respond to levcromakalim.
When membrane potential was recorded from endothelium in a mesenteric arterial segment, exposure to levcromakalim in a concentration range of 0.1 to 3 μM caused concentration‐dependent hyperpolarization. The hyperpolarization was observed in the absence of external Ca2+ and was inhibited by 10 μM glibenclamide.
The presence of 1 mM heptanol did not affect the levcromakalin‐induced hyperpolarization, whereas treatment of the mesenteric arterial segment with 20 μM 18 β‐glycyrrhetinic acid significantly reduced the hyperpolarization. The response to acetylcholine of RMAECs in an arterial segment with 18 β‐glycyrrhetinic acid was, however, similar to that without 18 β‐glycyrrhetinic acid.
These suggest that although RMAECs themselves are functionally insensitive to levcromakalim, those in an arterial segment are hyperpolarized by levcromakalim via myo‐endothelial electrical communication.

British Journal of Pharmacology (1999) 128, 1491–1496; doi:10.1038/sj.bjp.0702956
Modulation of mPer1 gene expression by anxiolytic drugs in mouse cerebellum
Authors: Akiyama Masashi , Kirihara Tomoko , Takahashi Satomi , Minami Yoichi , Yoshinobu Yuko , Moriya Takahiro , Shibata Shigenobu 
Published: January 2005

The mPer1 and mPer2 genes are putative mouse clock genes that regulate circadian oscillator present in the suprachiasmatic nucleus (SCN) neuron. While they are also expressed in the granular cell layer in the cerebellum, their function is unknown. In a first step to verify the physiological roles of mPer1 and mPer2 genes in the cerebellum, we examined the effects of benzodiazepines on the expression of the mPer1 and mPer2 genes.
mPer2 mRNA expression was higher at ZT16 than ZT4 in the mouse cerebellum.
High‐dose administration of diazepam (10 mg kg−1) or triazolam (1 mg kg−1) reduced mPer1 mRNA level 1 h after treatment in the cerebellum.
Reduced expression of mPer1 by diazepam treatment was transient. No difference of mPer1 mRNA level between diazepam (10 mg kg−1)‐ and vehicle‐treated group was observed 6 h after treatment.
Administration of high doses of tandospirone (30 mg kg−1), a non‐benzodiazepine anxiolytic also reduced mPer1 mRNA expression 1 h after treatment.
Administration of high doses of clozapine (5 mg kg−1) or haloperidol (1 mg kg−1) impaired the rota‐rod performance without affecting on mPer1 mRNA level.
Diazepam and tandospirone inhibited the expression of mPer1 mRNA in the primary cultured cerebellum granule cells.
Transient reductions of mPer1 mRNA levels by various benzodiazepines and tandospirone is associated with impairment of coordinated movement, such as rota‐rod performance and equilibrium.

British Journal of Pharmacology (1999) 128, 1616–1622; doi:10.1038/sj.bjp.0702957
Vascular kinin B1 and B2 receptor‐mediated effects in the rat isolated perfused kidney–differential regulations
Authors: Bagaté Karim , Develioglu Leyla , Imbs Jean‐Louis , Michel Bruno , Helwig Jean‐Jacques , Barthelmebs Mariette 
Published: January 2005

Bradykinin (BK) and analogs acting preferentially at kinin B1 or B2 receptors were tested on the rat isolated perfused kidney. Kidneys were perfused in an open circuit with Tyrode's solution. Kidneys preconstricted with prostaglandin F2α were used for the analysis of vasodilator responses.
BK induced a concentration‐dependent renal relaxation (pD2=8.9±0.4); this vasodilator response was reproduced by a selective B2 receptor agonist, Tyr(Me)8‐BK (pD2=9.0±0.1) with a higher maximum effect (Emax=78.9±6.6 and 55.8±4.3% of ACh‐induced relaxation respectively, n=6 and 19, P<0.02). Icatibant (10 nM), a selective B2 receptor antagonist, abolished BK‐elicited relaxation. Tachyphylaxis of kinin B2 receptors appeared when repeatedly stimulated at 10 min intervals.
Des‐Arg9‐BK, a selective B1 receptor agonist, induced concentration‐dependent vasoconstriction at micromolar concentration. Maximum response was enhanced in the presence of lisinopril (1 μM) and inhibited by R 715 (8 μM), a selective B1 receptor antagonist. Des‐Arg9‐[Leu8]‐BK behaved as an agonist.
A contractile response to des‐Arg9‐BK occurred after 1 h of perfusion and increased with time by a factor of about three over a 3 h perfusion. This post‐isolation sensitization to des‐Arg9‐BK was abolished by dexamethasone (DEX, 30 mg kg−1 i.p., 3 h before the start of the experiment and 10 μM in perfusate) and actinomycin D (2 μM). Acute exposure to DEX (10 μM) had no effect on sensitized des‐Arg9‐BK response, in contrast to indomethacin (30 μM) that abolished it. DEX pretreatment however had no effect on BK‐induced renal vasodilation.
Present results indicate that the main renal vascular response to BK consists of relaxation linked to the activation of kinin B2 receptors which rapidly desensitize. Renal B1 receptors are also present and are time‐dependently sensitized during the in vitro perfusion of the rat kidneys.

British Journal of Pharmacology (1999) 128, 1643–1650; doi:10.1038/sj.bjp.0702961
Stereoselective central nervous system effects of the R‐ and S‐isomers of the GABA uptake blocker N‐(4,4‐di‐(3‐methylthien‐2‐yl)but‐3‐enyl) nipecotic acid in the rat
Authors: Cleton A , De Greef H J M M , Edelbroek P M , Voskuyl R A , Danhof M 
Published: January 2005

The ‘effect compartment’ model was applied to characterize the pharmacodynamics of the R‐ and S‐isomers of tiagabine in conscious rats in vivo using increase in the β activity of the EEG as a pharmacodynamic endpoint.
No pharmacokinetic differences in plasma were observed between R‐ and S‐tiagabine. The values for clearance and volume of distribution at steady‐state were 103±10 versus 90±6 ml min−1 kg−1 and 1.8±0.2 versus 1.6±0.2 l kg−1 for the R‐ and S‐isomer, respectively. In contrast, plasma protein binding showed a statistically significant difference with values of the free fraction of 5.7±0.5 and 11.4±0.6%. In addition the rate constant for transport to the effect compartment was also different with values of 0.027 versus 0.067 min−1.
For both isomers the relationship between concentration and EEG effect was non‐linear and successfully characterized on basis of the Hill equation. A statistically significant difference in the value of EC50 of 328±11 versus 604±18 ng ml−1 was observed for R‐ and S‐tiagabine respectively. The values of the other pharmacodynamic parameters were identical.
It is concluded that the differences in in vivo pharmacodynamics of R‐ and S‐tiagabine can be explained by stereoselective differences in both the affinity to the GABA‐uptake transporter and the degree of non‐specific protein binding in plasma and at the effect site.

British Journal of Pharmacology (1999) 128, 1651–1658; doi:10.1038/sj.bjp.0702962
Selective cyclo‐oxygenase‐2 inhibitors aggravate ischaemia‐reperfusion injury in the rat stomach
Authors: Maricic Nenad , Ehrlich Karlheinz , Gretzer Britta , Schuligoi Rufina , Respondek Michael , Peskar Brigitta M 
Published: January 2005

Effects of indomethacin, the selective cyclo‐oxygenase (COX)‐2 inhibitors NS‐398 and DFU, and dexamethasone on gastric damage induced by 30 min ischaemia followed by 60 min reperfusion (I‐R) were investigated in rats. Modulation of gastric levels of COX‐1 and COX‐2 mRNA by I‐R was evaluated using Northern blot and reverse transcription‐polymerase chain reaction.
I‐R‐induced gastric damage was dose‐dependently aggravated by administration of indomethacin (1–10 mg kg−1), NS‐398 (0.4–4 mg kg−1) or DFU (0.02–2 mg kg−1) as assessed macroscopically and histologically.
Likewise, administration of dexamethasone (1 mg kg−1) significantly increased I‐R damage.
Low doses of 16,16‐dimethyl‐prostaglandin(PG)E2, that did not protect against ethanol‐induced mucosal damage, reversed the effects of the selective COX‐2 inhibitors, indomethacin and dexamethasone.
I‐R had no effect on gastric COX‐1 mRNA levels but increased COX‐2 mRNA levels in a time‐dependent manner. Dexamethasone inhibited the I‐R‐induced expression of COX‐2 mRNA.
I‐R was not associated with a measurable increase in gastric mucosal formation of 6‐keto‐PGF1α and PGE2. PG formation was substantially inhibited by indomethacin (10 mg kg−1) but was not significantly reduced by NS‐398 (4 mg kg−1), DFU (2 mg kg−1) or dexamethasone (1 mg kg−1).
The findings indicate that selective COX‐2 inhibitors and dexamethasone markedly enhance gastric damage induced by I‐R. Thus, whereas COX‐2 has no essential role in the maintenance of gastric mucosal integrity under basal conditions, COX‐2 is rapidly induced in a pro‐ulcerogenic setting and contributes to mucosal defence by minimizing injury. This suggests that in certain situations selective COX‐2 inhibitors may have gastrotoxic effects.

British Journal of Pharmacology (1999) 128, 1659–1666; doi:10.1038/sj.bjp.0702966
Early intracellular signalling pathway of ethanol in vascular smooth muscle cells
Authors: Sachinidis Agapios , Gouni‐Berthold Ioanna , Seul Claudia , Seewald Stefan , Ko Yon , Schmitz Udo , Vetter Hans 
Published: January 2005

ERKs belong to MAP kinase family and are activated by several growth and stress factors. Although ethanol has been shown to modulate ERK1 and ERK2 (p44mapk and p42mapk) activity, it can also act as an antiproliferative agent in various mammalian cells. Since the nature of the antiproliferative effect of ethanol in VSMCs has not been defined, we examined its effects on growth and on early intracellular events normally induced by growth factors in VSMCs.
Measurement of cytosolic Ca2+ and pH in cell monolayers was performed using fura‐2/AM and BCECF/AM, respectively. The effect of ethanol on VSMCs growth was assessed by [3H]‐thymidine incorporation, by cell counting and by determination of the caspase 3 activity. Stimulation of ERK1 and ERK2 was examined by the chemiluminescence Western blotting method. The expression of c‐fos was quantitated by Northern blotting. Determination of inositolphosphates was performed after labelling of VSMCs with myo‐[2‐3H]‐inositol and separation of inositolphosphates by HPLC.
Ethanol (0.3–1.0% v v−1, 17–170 mM) induced a dose‐dependent maximal stimulation of p44mapk/p42mapk at 30 min and expression of c‐fos mRNA with a maximum at 120 min. Intracellular events upstream to MAP kinase, like an increase in [Ca2+]i, activation of the Na+/H+ exchanger and formation of phosphoinositol metabolites were also markedly activated by ethanol. Treatment of VSMCs with ethanol for 3–5 min induced an increase in DNA synthesis whereas treatment of the cells for more than 30 min was toxic. Caspase 3 activity was not modulated by ethanol treatment of VSMCs.
We may postulate that the activation of these mitogenic signals including the elevation of DNA synthesis reflects a cell effort to protect itself against the toxic effects of ethanol.

British Journal of Pharmacology (1999) 128, 1761–1771; doi:10.1038/sj.bjp.0702969
Intracellular pH alterations induced by tacrine in a rat liver biliary epithelial cell line
Authors: Lagadic‐Gossmann D , Rissel M , Galisteo M , Guillouzo A 
Published: January 2005

The effects of tacrine (THA) on intracellular pH (pHi) were examined in a rat liver biliary epithelial cell line (RLEC) in HEPES‐buffered medium. pHi was recorded using the pH‐sensitive fluoroprobe, carboxy‐SNARF‐1 (carboxy‐seminaphtorhodafluor).
In the steady state, short‐term exposures to THA resulted in alkalinization and re‐acidification at 0.1 and 0.25 mM. Following a 24 h‐treatment, no significant difference in pHi could be detected at 0.1 and 0.25 mM THA, whereas at 0.05 mM, pHi was slightly more acid (7.17±0.02, n=16 versus 7.21±0.02, n=24 [control]).
In control and short‐term treated cells, intracellular intrinsic buffering power (βi) increased roughly linearly as pHi decreased. This dependence was not seen following long‐term treatment. In all cases, βi was increased by THA (by 1.6 to 3.5 fold).
Following an acid load (induced by 20 mM NH4Cl removal), pHi recovery in RLEC relied upon Na+/H+ exchange. A short‐term treatment (0.25 mM THA) did not affect total acid extrusion. In contrast, a 24 h‐treatment with 0.05 mM THA reduced it (by ∼36% at a pHi of 6.73) while at 0.25 mM, a large increase was detected (by ∼109% at a pHi of 6.75).
In Na+‐free medium, THA (0.25 mM) still induced an alkalinization in the steady state. Following an acid load, THA stimulated a Na+‐independent acid efflux in a dose‐dependent manner, inhibitable by α‐cyano‐4‐hydroxy cinnamate (CHC, 4 mM) but not by quercetin (0.125 mM).
In conclusion, this work demonstrates that THA affects pHi in RLEC, through a decrease in Na+/H+ exchange and an increase in βi. Stimulation of a CHC‐inhibitable, Na+‐independent acid efflux is also detected.

British Journal of Pharmacology (1999) 128, 1673–1682; doi:10.1038/sj.bjp.0702972
Cardioprotection by the phytoestrogen genistein in experimental myocardial ischaemia‐reperfusion injury
Authors: Deodato Barbara , Altavilla Domenica , Squadrito Giovanni , Campo Giuseppe M , Arlotta Mariarita , Minutoli Letteria , Saitta Antonino , Cucinotta Domenico , Calapai Gioacchino , Caputi Achille P , Miano Maria , Squadrito Francesco 
Published: January 2005

Soybean phytoestrogens have no oestrogen agonist effects on the reproductive system and therefore it is reasonable to explore the potential of these naturally occurring plant oestrogens in the cardiovascular pathology. We therefore investigated the effects of genistein in a rat model of myocardial ischaemia‐reperfusion injury.
Anaesthetized rats were subjected to total occlusion (45 min) of the left main coronary artery followed by 5 h reperfusion (MI/R). Sham operated rats were used as controls. Myocardial necrosis, myocardial myeloperoxidase activity (MPO), serum creatinine phosphokinase activity (CPK), serum and macrophage Tumour Necrosis Factor‐α (TNF‐α), cardiac intercellular adhesion molecule‐1 (ICAM‐1) immunostaining, cardiac mRNA for ICAM‐1 evaluated by the means of reverse transcriptase polymerase chain reaction (RT–PCR), ventricular arrhythmias and myocardial contractility (left ventricle dP/dtmax) were evaluated.
Myocardial ischaemia and reperfusion in untreated rats produced marked myocardial necrosis, increased serum CPK activity and MPO activity both in the area‐at‐risk and in the necrotic area, reduced myocardial contractility, caused ventricular arrhythmias and induced a marked increase in serum and macrophage TNF‐α. Furthermore myocardial ischaemia‐reperfusion injury increased ICAM‐1 expression in the myocardium.
Administration of genistein (1 mg kg−1, i.v., 5 min after coronary artery occlusion) lowered myocardial necrosis and MPO activity in the area‐at‐risk and in the necrotic area, decreased serum CPK activity, increased myocardial contractility, decreased the occurrence of ventricular arrhythmias, reduced serum and macrophages levels of TNF‐α and blunted ICAM‐1 expression in the injured myocardium. Finally genistein added in vitro to peritoneal macrophages collected from untreated rats subjected to myocardial ischaemia‐reperfusion injury significantly reduced TNF‐α production.
Our data suggest that genistein limits the inflammatory response and protects against myocardial ischaemia‐reperfusion injury.

British Journal of Pharmacology (1999) 128, 1683–1690; doi:10.1038/sj.bjp.0702973
Role of nitric oxide‐ and vasoactive intestinal polypeptide‐containing neurones in human gastric fundus strip relaxations
Authors: Tonini M , De Giorgio R , De Ponti F , Sternini C , Spelta V , Dionigi P , Barbara G , Stanghellini V , Corinaldesi R 
Published: January 2005

The morphological pattern and motor correlates of nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) innervation in the human isolated gastric fundus was explored.
By using the nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)‐diaphorase and specific rabbit polyclonal NO‐synthase (NOS) and VIP antisera, NOS‐ and VIP‐containing varicose nerve fibres were identified throughout the muscle layer or wrapping ganglion cell bodies of the myenteric plexus. NOS‐immunoreactive (IR) neural cell bodies were more abundant than those positive for VIP‐IR. The majority of myenteric neurones containing VIP coexpressed NADPH‐diaphorase.
Electrical stimulation of fundus strips caused frequency‐dependent NANC relaxations. NG‐nitro‐L‐arginine (L‐NOARG: 300 μM) enhanced the basal tone, abolished relaxations to 0.3–3 Hz (5 s) and those to 1 Hz (5 min), markedly reduced (∼50%) those elicited by 10–50 Hz, and unmasked or potentiated excitatory cholinergic responses at frequencies 1 Hz. L‐NOARG‐resistant relaxations were virtually abolished by VIP (100 nM) desensitization at all frequencies.
Relaxations to graded low mechanical distension (1 g) were insensitive to tetrodotoxin (TTX: 1 μM) and L‐NOARG (300 μM), while those to higher distensions (2 g) were slightly inhibited by both agents to the same extent (∼25%).
In the human gastric fundus, NOS‐ and VIP immunoreactivities are colocalized in the majority of myenteric neurones. NO and VIP mediate electrically evoked relaxations: low frequency stimulation, irrespective of the duration, caused NO release only, whereas shortlasting stimulation at high frequencies induced NO and VIP release. Relaxations to graded mechanical distension were mostly due to passive viscoelastic properties, with a slight NO‐mediated neurogenic component at 2 g distension. The difference between NO and VIP release suggests that in human fundus accommodation is initiated by NO.

British Journal of Pharmacology (2000) 129, 12–20; doi:10.1038/sj.bjp.0702977