bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute non‐insulin‐like stimulation of rat muscle glucose metabolism by troglitazone in vitro
Authors: Fürnsinn C. , Neschen S. , Noe C. , Bisschop M. , Roden M. , Vogl C. , Schneider B. , Waldhäusl W. 
Published: January 2005

The direct short‐term effects of troglitazone on parameters of glucose metabolism were investigated in rat soleus muscle strips.
In muscle strips from Sprague‐Dawley rats, troglitazone (3.25 μmol l−1) increased basal and insulin‐stimulated glucose transport by 24% and 41%, respectively (P<0.01 each).
In the presence of 5 nmol l−1 insulin, stimulation of glucose transport by 3.25 μmol l−1 troglitazone was accompanied by a 36% decrease in glycogen synthesis, while glycolysis was increased (112% increase in lactate production) suggesting a catabolic response of intracellular glucose handling.
Whereas insulin retained its stimulant effect on [3H]‐2‐deoxy‐glucose transport in hypoxia‐stimulated muscle (by 44%; c.p.m. mg−1 h−1: 852±77 vs 1229±75, P<0.01), 3.25 μmol l−1 troglitazone failed to increase glucose transport under hypoxic conditions (789±40 vs 815±28, NS) suggesting that hypoxia and troglitazone address a similar, non‐insulin‐like mechanism.
No differences between troglitazone and hypoxia were identified in respective interactions with insulin.
Troglitazone acutely stimulated muscle glucose metabolism in a hypoxia/contraction‐like manner, but it remains to be elucidated whether this contributes to the long‐term antidiabetic and insulin enhancing potential in vivo or is to be regarded as an independent pharmacological effect.
Investigation of the inhibitory effect of NG‐nitro‐L‐arginine methyl ester on the antihypertensive effect of the angiotensin AT1 receptor antagonist, GR138950
Authors: Anderson Ian K. , Drew Geoffrey M. 
Published: January 2005

The effect of systemic administration of the nitric oxide synthase inhibitor, NG‐nitro‐L‐arginine methyl ester (L‐NAME) on the antihypertensive effects of the angiotensin AT1 receptor antagonist, GR138950, the angiotensin‐converting enzyme (ACE) inhibitor, enalapril, or hydralazine has been evaluated in unrestrained, conscious renal artery ligated hypertensive (RALH) rats. The effect of the phosphodiesterase type V inhibitor, zaprinast on the antihypertensive effect of GR138950 in RALH rats was also examined. The effect of GR138950 on blood pressure, and plasma and urine cyclic GMP levels was compared to that of zaprinast in conscious RALH rats.
GR138950, enalapril or hydralazine caused marked reductions in blood pressure associated with immediate tachycardia in conscious RALH rats. L‐NAME pretreatment attenuated the antihypertensive effects of GR138950 or enalapril but not that of hydralazine in conscious RALH rats. The initial tachycardia caused by GR138950 or enalapril but not hydralazine was attenuated by L‐NAME pretreatment. L‐NAME alone caused a transient (20 min) pressor response and a prolonged (6 h) bradycardia in conscious RALH rats.
Pretreatment with indomethacin did not affect the cardiovascular effect of GR138950 in conscious RALH rats. Indomethacin alone did not significantly change basal blood pressure or heart rate in RALH rats.
Zaprinast pretreatment did not affect the antihypertensive effect of GR138950 in conscious RALH rats but potentiated the depressor response to sodium nitroprusside. Zaprinast alone caused a small reduction in basal blood pressure but did not change basal heart rate in RALH rats.
The antihypertensive effect of GR138950 was not associated with an increase in plasma or urine cyclic GMP levels in conscious RALH rats, whereas zaprinast caused a small fall in blood pressure associated with increases in plasma and urine cyclic GMP.
The ability of L‐NAME to inhibit the antihypertensive action of GR138950 or enalapril suggests that these agents release nitric oxide (NO) and/or enhance the cardiovascular effects of NO as part of their mechanism of action. However, the inability of zaprinast to potentiate the antihypertensive effects of GR138950 and the finding that GR138950 did not increase urine and plasma cyclic GMP levels are not consistent with this view. Attenuation of the response to GR138950 or enalapril, but not hydralazine, suggests a selective interaction between L‐NAME and inhibitors of the renin‐angiotensin system, although the nature of this interaction is unknown.
Increased feeding in fatty Zucker rats by the thiazolidinedione BRL 49653 (rosiglitazone) and the possible involvement of leptin and hypothalamic neuropeptide Y
Authors: Wang Qiong , Dryden Simon , Frankish Helen M. , Bing Chen , Pickavance Lucy , Hopkins David , Buckingham Robin , Williams Gareth 
Published: January 2005

The thiazolidinedione BRL 49653 (rosiglitazone) induces hyperphagia and weight gain in obese, insulin‐resistant fatty Zucker rats but not in lean insulin‐sensitive rats. We investigated whether these responses might involve neuropeptide Y (NPY), leptin and insulin.
BRL 49653 (1 mg kg−1 day−1, orally) was given for 7 or 20 days to fatty and lean Zucker and Wistar rats.
In lean rats of either strain, BRL 49653 had no effect on food intake, body weight, plasma insulin and corticosterone, NPY or NPY mRNA levels.
Fatty rats given BRL 49653 showed a 30% increase in food intake and accelerated body weight gain (both P<0.01) after 7 and 20 days, but without significant changes in regional hypothalamic NPY or NPY mRNA levels.
Plasma leptin levels were twice as high in untreated fatty Zucker rats as in lean rats (P<0.01), but were unaffected by BRL 49653 given for 20 days. However, BRL 49653 reduced insulin levels by 42% and increased corticosterone levels by 124% in fatty rats (both P<0.01).
Hyperphagia induced in fatty Zucker rats by BRL 49653 does not appear to be mediated by either a fall in circulating leptin levels or increased activity of hypothalamic NPYergic neurones. The fall in plasma insulin and/or rise in corticosterone levels during BRL 49653 treatment may be involved, consistent with the postulated role of these hormones in the control of food intake.
The effect of losigamone (AO‐33) on electrical activity and excitatory amino acid release in mouse cortical slices
Authors: Srinivasan Jayashri , Richens Alan , Davies John A. 
Published: January 2005

Losigamone is a novel anticonvulsant the mechanism of action of which is not known. This study investigated the effect of losigamone on spontaneous, NMDA‐ and AMPA‐induced depolarizations in the cortical wedge preparation of the DBA/2 mouse (which are susceptible to sound‐induced seizures) and on endogenous amino acid release from BALB/c mouse cortical slices.
Cortical wedges exhibit spontaneous depolarizations in magnesium‐free medium and losigamone was effective in significantly reducing these spontaneous depolarizations at concentrations of 100 μM and above.
NMDA‐induced depolarizations were significantly reduced by losigamone at concentrations of 25 μM and above. Losigamone had no effect on AMPA‐induced depolarizations.
Veratridine (20 μM) and potassium (60 mM) were used to stimulate the release of amino acids from mouse cortex. Veratridine‐stimulated release of glutamate was significantly reduced by losigamone at concentrations of 100 μM and above, while potassium‐stimulated release was significantly reduced by losigamone at 200 μM.
NMDA antagonism and inhibition of excitatory amino acid release may contribute to the anticonvulsant effect of losigamone.
Modulation of dopamine release from rat striatum by protein kinase C: interaction with presynaptic D2‐dopamine‐autoreceptors
Authors: Iannazzo L. , Sathananthan S. , Majewski H. 
Published: January 2005

Interactions between dopamine receptors and protein kinase C (PKC) have been proposed from biochemical studies. The aim of the present study was to investigate the hypothesis that there is an interaction between protein kinase C and inhibitory D2‐dopamine receptors in the modulation of stimulation‐induced (S‐I) dopamine release from rat striatal slices incubated with [3H]‐dopamine. Dopamine release can be modulated by protein kinase C and inhibitory presynaptic D2 receptors since phorbol dibutyrate (PDB) and (−)‐sulpiride, respectively, elevated S‐I dopamine release.
The protein kinase C inhibitors polymyxin B (21 μm) and chelerythrine (3 μm) had no effect on stimulation‐induced (S‐I) dopamine release. However, when presynaptic dopamine D2 receptors were blocked by sulpiride (1 μm), an inhibitory effect of both PKC inhibitors on S‐I dopamine release was revealed. Thus, sulpiride unmasks an endogenous PKC effect on dopamine release which suggests that presynaptic D2 receptors normally suppress endogenous PKC activity. This is supported by results in striatal slices which were pretreated with PDB to down‐regulate PKC. In this case the facilitatory effect of sulpiride was completely abolished.
The inhibitory effect of the dopamine D2/D3 agonist quinpirole on S‐I dopamine release was partially attenuated by PKC down‐regulation. Since the effect of sulpiride was completely abolished under the same conditions, this suggests that exogenous agonists may target a PKC‐dependent as well as a PKC‐independent pathway. The inhibitory effect of apomorphine was not affected by either polymyxin B or PKC down‐regulation, suggesting that it operated exclusively through a PKC‐independent mechanism.
These results suggest that there are at least two pathways involved in the inhibition of dopamine release through dopamine receptors. One pathway involves dopamine receptor suppression of protein kinase C activity, perhaps through inhibition of phospholipase C activity and this is preferentially utilized by neuronally‐released dopamine. The other pathway which seems to be utilized by exogenous agonists does not involve PKC.
Age‐related changes in purinergic and adrenergic components of sympathetic neurotransmission in guinea‐pig seminal vesicles
Authors: Pinna Christian , Rubino Annalisa , Burnstock Geoffrey 
Published: January 2005

Purinergic and adrenergic components of sympathetic neurotransmission and contractile responses to exogenous α,β‐methylene ATP and noradrenaline have been investigated in the seminal vesicles of 1‐day (new‐born), 2‐weeks (young), 12‐weeks (adult) and 2‐years old (aged) guinea‐pigs.
In seminal vesicles of new‐born guinea‐pigs electrical field stimulation (EFS; 80 V, 0.5 ms for 30 s, 2–32 Hz) evoked tonic frequency‐related contractions. In 2‐weeks old guinea‐pigs the tonic contraction masked an initial phasic component of the neurogenic responses, whereas in 12‐weeks and 2‐years old guinea‐pigs, neurogenic responses were biphasic, a phasic response being followed by a tonic contraction. In all experimental groups, prazosin (10−6 M) blocked the tonic contraction while desensitization of P2X receptors by α,β‐methylene ATP (10−4 M) abolished the phasic responses.
The phasic purinergic component of the neurogenic response was significantly higher in 12‐weeks and 2‐years old animals, compared with 2‐weeks old guinea‐pigs. At 32 Hz phasic contractions were (mN mg−1 tissue): 0.047±0.012, 0.018±0.040 and 0.147±0.026 in 2‐weeks, 12‐weeks and 2‐years old guinea‐pigs, respectively. In contrast, the tonic adrenergic component of the neurogenic contraction significantly declined at 12‐weeks and 2‐years compared with 2‐weeks old guinea‐pigs.
Contractile responses (mN mg−1 tissue) to the highest concentration of α,β‐methylene ATP tested were significantly higher in 2‐weeks (0.248±0.022) than in 1‐day old animals (0.113±0.012) and decreased in 12‐weeks (0.163±0.016) and 2‐years old guinea‐pigs (0.200±0.008). The pD2 values for the purinoceptor agonist were also significantly lower in adult (4.74±0.20) and aged guinea‐pigs (5.22±0.08) compared with 2‐weeks old animals (5.91±0.27). Conversely, responses to the highest concentration of noradrenaline gradually decreased with age, without significant changes in the pD2 values. Contractile responses to KCl (240 mM) did not differ significantly between the experimental groups.
These results demonstrate age‐related changes in purinergic and adrenergic components of sympathetic neurotransmission in the guinea‐pig seminal vesicles. The purinergic component is absent in new‐born animals and it appears fully developed in adult and old guinea‐pigs, while the adrenergic component decreases with age. Pre‐ and postjunctional mechanisms contributing to the age‐related changes of sympathetic neurotransmission are discussed.
Neuropeptide Y (NPY) and peptide YY (PYY) effects in the epididymis of the guinea‐pig: evidence of a pre‐junctional PYY‐selective receptor
Authors: Haynes John M. , Hill Stephen J. , Selbie Lisa A. 
Published: January 2005

The effects of peptide YY (PYY), neuropeptide Y (NPY) and structurally related peptides upon field stimulation‐induced and phenylephrine‐mediated contractile responses in the cauda epididymis of the guinea‐pig were investigated.
Preparations of cauda epididymis responded to field stimulation with contractions which were completely attenuated by both the neurotoxin, tetrodotoxin (500 nM), and also by the α‐adrenoceptor antagonist, phentolamine (3 μM). PYY (n=7) and the truncated peptide analogue PYY(3–36) (n=5) inhibited field stimulation‐induced contractions (pIC50+s.e.mean: 8.9±0.2 and 9.4±0.2, respectively). Pancreatic polypeptide (PP, up to 1 μM, n=6), NPY (up to 100 nM, n=6) and the NPY analogues [Leu31,Pro34]NPY (n=6) and NPY (13–36) (both up to 1 μM, n=5) had no significant effect.
The NPY Y1 receptor antagonist BIBP3226 ((R)‐N2‐(diphenylacetyl)‐N[(4‐hydroxyphenyl)‐methyl]‐argininamide) at 750 nM (n=6) and 7.5 μM (n=6) did not affect the PYY‐mediated inhibition of field stimulation‐induced contractions (pIC50 8.9±0.3 and 9.0±0.3, respectively). In the presence of BIBP3226 (7.5 μM), NPY (n=6) inhibited field stimulation‐induced contractions (pIC50 8.0±0.2).
NPY, PYY and PYY(3–36) inhibited [3H]‐noradrenaline release from preparations of epididymis (pIC50 values 7.9±0.7, 9.6±0.8 and 10.0±0.9, respectively, all n=6). The agonists PP and [Leu31,Pro34]PYY (both up to 100 nM) were without significant effect (both n=6).
In preparations of cauda epididymis, stimulated with threshold concentrations of the α1‐adrenoceptor agonist, phenylephrine (1 μM), both NPY (n=6) and PYY (n=7) elicited concentration‐dependent increases in contractile force (with pEC50 values of 8.9±0.2 and 8.6±0.1, respectively). The effects of both NPY (n=6) and PYY (n=6) were antagonized by preincubation with BIBP3226 (75 nM; apparent pKB±s.e. values 8.3±1.0 and 8.2±0.6, respectively). The peptide analogues NPY(13–36) (n=5), PYY (3–36) (n=7) and [Leu31,Pro34]NPY (n=5) did not significantly augment responses to threshold concentrations of phenylephrine.
These results are consistent with the proposal that distinct NPY receptors mediate the (prejunctional) inhibition of field stimulation‐induced contractions and the (postjunctional) potentiation of responses to phenylephrine in the cauda epididymis of the guinea‐pig. The rank order of agonist potency (NPYPYY&Gt;NPY(13–36), [Leu31,Pro34]NPY and PYY(3–36) and the high potency of BIBP3226 indicate that the postjunctional receptor may be Y1‐like. The rank orders of agonist potency in inhibiting field stimulation‐induced contractile responses and [3H]‐noradrenaline release (PYY(3–36)PYY> NPY&Gt;PP, NPY(13–36), [Leu31,Pro34]NPY and PYY(3–36)PYY>NPY&Gt;;PP,[Leu31,Pro34]PYY, respectively) are consistent with the action of these peptides at a PYY‐preferring receptor subtype, which may be distinct from the presently characterized NPY receptor subtypes.
Synthesis of kininogen and degradation of bradykinin by PC12 cells
Authors: Dendorfer A. , Wellhöner P. , Braun A. , Roscher A. A. , Dominiak P. 
Published: January 2005

In this study, the abilities of PC12 cells to synthesize and degrade kinins were investigated. Kinin formation was assessed as kinin and kininogen content of cells and supernatants in serum‐free incubations by use of a bradykinin‐specific radioimmunoassay. Expression of kininogen mRNA was demonstrated by reverse‐transcriptase PCR. Kinin degradation pathways of intact PC12 cells were characterized by identification of the kinin fragments generated from tritiated bradykinin either in the absence or presence of the angiotensin I‐converting enzyme inhibitor ramiprilat.
Kinin immunoreactivity in the supernatant of PC12 cell cultures accumulated in a time‐dependent fashion during incubations in serum‐free media. This effect was solely due to de novo synthesis and release of kininogen (35 pg bradykinin  h−1 mg−1 protein) since it could be suppressed by cycloheximide. Continuous synthesis of kininogen was a specific property of PC12 cells, as it was not observed in cultured macro‐ or microvascular endothelial cells. PC12 cells contained only minor amounts of stored kininogen. The rate of kininogen synthesis was not affected by ramiprilat, bacterial lipopolysaccharide, nerve growth factor or dexamethasone, but was stimulated 1.4 fold when cells were pretreated for 1 day with 1 μm desoxycorticosterone.
By use of cDNA probes specific for kininogen subtype mRNAs, expression of low‐molecular‐weight kininogen and T‐kininogen in PC12 cells was confirmed. Expression of high molecular weight kininogen mRNA was also shown, though only at the lowest limit of detection of the assay.
Degradation of tritiated bradykinin by PC12 cells occurred with a half‐life of 48 min resulting in the main fragments [1–7]‐ and [1–5]‐bradykinin. The degradation rate of bradykinin decreased to 15% in the presence of ramiprilat (250 nm). Apart from angiotensin I‐converting enzyme direct cleavage of bradykinin to [1–7]‐ and [1–5]‐bradykinin still occurred under this condition as a result of additional kininase activities.
Along with previous findings of B2‐receptor‐mediated catecholamine release, these results now confirm the hypothesis that a cellular kinin system is expressed in PC12 cells. The presence of such a system may reflect a role of kinins as local neuromodulatory mediators in the peripheral sympathetic system.
Prostanoids synthesized by cyclo‐oxygenase isoforms in rat spinal cord and their contribution to the development of neuronal hyperexcitability
Authors: Willingale H. L. , Gardiner N. J. , McLymont N. , Giblett S. , Grubb B. D. 
Published: January 2005

The responses of wide dynamic range spinal dorsal horn neurones to noxious mechanical stimulation of the ankle or knee joint were tested before and after spinal administration of the non‐selective cyclo‐oxygenase (COX) inhibitors, indomethacin and meclofenamic acid. Neither of these drugs altered the responses of these neurones to noxious mechanical stimulation.
Wind‐up of a spinal nociceptive reflex evoked by electrical stimulation of the sural nerve at C‐fibre strength was dose‐dependently inhibited by intravenous administration of indomethacin, a non‐selective COX inhibitor, and SC58125, a selective COX‐2 inhibitor. Intrathecal administration of indomethacin also reduced the wind‐up of this nociceptive reflex.
Western blot analysis of proteins extracted from normal rat spinal cord revealed the presence of both cyclo‐oxygenase (COX)‐1 and COX‐2 proteins.
Immunocytochemistry of sections of normal rat spinal cord with specific COX‐1 antiserum revealed little specific COX‐1‐like immunoreactivity in the grey matter. With the same antiserum, intense COX‐1‐like immunoreactivity was observed in the cytoplasm, nuclear membrane and axonal processes of small to medium sized (<1000 μm2) dorsal root ganglion (DRG) cell bodies.
Immunocytochemistry of sections of normal rat spinal cord incubated with specific COX‐2 antiserum showed intense COX‐2‐like immunoreactivity (COX‐2‐li) in the superficial dorsal horn of the spinal cord (laminae I and II) and around the central canal (lamina X). COX‐2‐li was also observed in some neurones in deep dorsal horn and in individual motor neurones in ventral horn. COX‐2‐li was not observed in the cell bodies of DRG.
Superfusion of the lumbar spinal cord of normal rats with artificial CSF and subsequent radioimmunoassay revealed the presence of prostaglandin D2 (PGD2)<PGE2, but not PGI2 (determined by measurement of the stable metabolite, 6‐keto‐PGF1α) or PGF2α.
These data suggest that eicosanoids synthesized by an active COX pathway in the spinal cord of normal animals may contribute to nociceptive processing, but only when the spinal cord neurones are rendered hyperexcitable following C‐fibre stimulation. Selective inhibition of one or both of the COX isoforms in normal animals may represent a novel target for spinal analgesia.
Potency and kinetics of nitric oxide‐mediated vascular smooth muscle relaxation determined with flash photolysis of ruthenium nitrosyl chlorides
Authors: Carter T. D. , Bettache N. , Ogden D. 
Published: January 2005

Flash photolysis of thermally stable, photolabile ‘caged’ precursors permits rapid and precise changes of ligand concentration at their site of action. This approach was used to determine the concentration‐dependence and time course of NO‐mediated relaxation of aortic smooth muscle, by use of two photolabile NO donors, trichloronitrosylruthenium (Ru(NO)Cl3) and dipotassium pentachloronitrosylruthenate (K2Ru(NO)Cl5). At concentrations up to 500 μM, both compounds were non‐toxic before photolysis, and produced non‐toxic by‐products on photolysis. Photolytic release of NO produced relaxations of intact and endothelium‐denuded aortic rings precontracted with noradrenaline (0.1–0.5 μM), with an EC50 for NO‐mediated relaxations of 10.5 nM and 13 nM, respectively. NO‐mediated relaxations were reversibly blocked by 1 μM oxyhaemoglobin. The time course of NO‐mediated relaxation comprised a delay of 3–7 s, followed by a sigmoidal decline in tension with peak rates that were strongly dependent on NO concentration.British Journal of Pharmacology (1997) 122, 971–973; doi:10.1038/sj.bjp.0701549
Effects of oral administration of different doses of purified micronized flavonoid fraction on microvascular reactivity after ischaemia/reperfusion in the hamster cheek pouch
Authors: Bouskela E. , Cyrino F. Z. G. A. , Lerond L. 
Published: January 2005

The effects of a purified micronized flavonoid fraction (S5682) on mean internal diameter and blood flow of arterioles and venules, as well as the functional capillary density (FCD) were evaluated in the hamster cheek pouch microvasculature before and after 90 min of total ischaemia.
Male hamsters were treated for ten days, twice a day, with oral doses of S5682 (5, 20, 80 and 160 mg kg−1 day−1) or placebo (10% lactose solution). The cheek pouch preparation was placed under an intravital microscope coupled to a closed circuit TV system. Local ischaemia was obtained by a cuff mounted around the neck of the everted pouch where it leaves the mouth of the hamster.
Measurements were performed before ischaemia, at the onset of reperfusion and 10, 20, 30, 45 and 60 min thereafter. Diameters were measured by means of an image shearing device. Red blood cell (RBC) velocity was analysed by use of the dual‐slit photometric technique. Blood flow was calculated from diameters and RBC velocities. FCD, defined as the number of capillaries with flowing blood per field of observation, was also assessed.
During reperfusion, placebo‐treated animals showed a significant vasodilatation, a decrease in blood flow and FCD and S5682‐treated animals showed a clear trend, dose‐dependent, towards maintaining these parameters closer to the value found before ischaemia.
In conclusion, our results indicate that S5682 improves the microvascular reactivity and FCD after ischaemia/reperfusion. These data suggest that S5682 could function as an antioxidant, which may explain its beneficial therapeutic effect in chronic venous insufficiency where oxidative stress is involved in the pathological mechanism.