bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibitory action of betaxolol, a β‐selective adrenoceptor antagonist, on voltage‐dependent calcium channels in guinea‐pig artery and vein
Authors: Setoguchi Motoko , Ohya Yusuke , Abe Isao , Fujishima Masatoshi 
Published: July 2012

The effects of betaxolol, (±)‐l‐[4‐[2‐(cyclopropylmethoxy) ethyl] phenoxy]‐3‐(isopropylamino)‐2‐propanol hydrochloride, a β1‐selective adrenoceptor antagonist, on voltage‐dependent Ca2+ channels were investigated in single smooth muscle cells from guinea‐pig mesenteric artery and portal vein using a whole‐cell variant of the patch‐clamp technique. Ca2+ channel currents were recorded with bath solutions contained 10 mM Ba2+ for arterial cells and 2mMCa2+ for venous cells.
Betaxolol inhibited Ca2+ channel currents dose‐dependently in both mesenteric artery cells and portal vein cells. The two isomers, (+)‐betaxolol and (−)−betaxolol (relative β‐antagonistic efficacies of 0.1 and 1, respectively), had similar potencies for inhibiting Ca2+ channel currents in portal vein cells. Propranolol did not inhibit the currents. Thus the inhibitory action of betaxolol on Ca2+ channel currents was independent of the β‐adrenoceptor.
The inhibitory action of betaxolol on Ca2+ channel currents was compared with that of diltiazem and of nifedipine in mesenteric artery cells. The current inhibition depended on the stimulation frequency with all drugs (use‐dependent block). All drugs also accelerated the current decay and shifted the voltage‐dependent inactivation curve in a negative direction.
In conclusion, betaxolol inhibited Ca2+ channel currents in vascular smooth muscle cells. The mode of inhibitory action was similar to that of diltiazem and nifedipine. Our results suggest that betaxolol is a unique β‐adrenoceptor antagonist that has a direct inhibitory action on voltage‐dependent Ca2+ channels in vascular smooth muscle cells.
Electrophysiological actions of felbamate on rat striatal neurones
Authors: Pisani Antonio , Stefani Alessandro , Siniscalchi Antonio , Mercuri Nicola B. , Bemardi Giorgio , Calabresi Paolo 
Published: July 2012

We have investigated the effects of the anticonvulsant drug, felbamate (FBM), on striatal neurones, recorded in vitro by using both intracellular and extracellular conventional recordings in slices and whole‐cell recordings in acutely isolated neurones.
FBM, at therapeutically relevant concentrations (30–300 μM) showed multiple mechanisms of action. Like other antiepileptic drugs, FBM (30–300 μM) showed a direct inhibitory action on current‐evoked firing discharge of striatal neurones. A patch‐clamp analysis of this effect revealed a dose‐related reduction of voltage‐dependent sodium (Na+) currents (10–100 μM), with a half inhibition dose (IC50) value of 28 μM.
We also tested whether FBM affected corticostriatal glutamatergic transmission. In control medium (1.2 mM external magnesium), both extracellularly recorded field potentials and intracellularly recorded excitatory postsynaptic potentials (e.p.s.ps) evoked by cortical stimulation were not affected by bath application of 30–300 μM FBM.
When magnesium was removed from the perfusing solution, a procedure which reveals a N‐methyl‐D‐aspartate (NMDA)‐mediated component in the corticostriatal synaptic potential, FBM (30–300 μm) produced a dose‐dependent reduction of the amplitude of both the field potential and the e.p.s.p.
FBM reduced the inward currents produced either by bath or by focal applications of 30 μM NMDA, a finding consistent with the hypothesis that the observed reduction of the NMDA‐mediated component of the synaptic potentials may be caused at postsynaptic level.
The reduction of the NMDA‐mediated component of the synaptic transmission by FBM and its depressant effect on the voltage‐dependent Na+ channels, may account for the antiepileptic action of this drug. Moreover, the pharmacological properties of FBM might render this drug interesting as a neuroprotectant agent.
Differential effects of fibrates on the acyl composition of microsomal phospholipids in rats
Authors: Vázquez Manuel , Muñoz Sonia , Alegret Marta , Adzet Tomás , Merlos Manuel , Laguna Juan C. 
Published: July 2012

The time‐course and comparative effects of treatment with clofibrate (CFB), bezafibrate (BFB), and gemfibrozil (GFB) on the acyl composition of the main microsomal phospholipids, i.e. phosphatidylchoβ line and phosphatidylethanolamine, have been studied in male Sprague‐Dawley rats.
The administration of the three fibrates caused a strong peroxisomal induction and a hypolipidaemic effect. Concerning the changes in acyl composition, CFB and BFB behaved in a similar way, with differences which could be attributed to their different potency as peroxisome inducers, whereas GFB showed a somewhat distinct profile.
The three drugs increased the relative content of palmitic, palmitoleic and oleic acids, whereas the levels of stearic acid and also those of long chain, highly unsaturated fatty acids docosatetraenoic, docosapentaenoic and docosahexaenoic acids were reduced. In general, these effects appeared from the first day of treatment and were highly correlated with peroxisomal proliferation. In addition, they were more evident in the phosphatidylcholine than in the phosphatidylethanolamine fraction.
Fibrates increased total monounsaturated fatty acids, whereas a decrease in total polyunsaturated fatty acids in the phosphatidylcholine fraction was observed in CFB‐ and BFB‐, but not in GFB‐treated rats. Clear differences appeared between CFB and BFB on the one hand, and GFB on the other when the influence of fibrate treatment on the molar percentages of linoleic, eicosatrienoic, arachidonic and mead acids was analyzed.
GFB increased linoleic acid content in phosphatidylethanolamine, whereas CFB and BFB decreased its level in both phospholipid fractions. In contrast, CFB and BFB enhanced eicosatrienoic and mead acids in both fractions and arachidonic acid in phosphatidylethanolamine, whereas GFB had practically no effect.
The different behaviour of GFB may be explained on the basis of two different observations. First, GFB is the weakest peroxisomal inducer of the three fibrates tested. Second, GFB is the strongest inhibitor in vitro of some of the enzyme activities related to fatty acid chain modelling, particularly elongases and desaturases.
New high affinity peptide antagonists to the spinal galanin receptor
Authors: Xu Xiao‐Jun , Wiesenfeld‐Hallin Zsuzsanna , Langel Ülo , Bedecs Katarina , Bartfai Tamás 
Published: July 2012

The role of endogenous galanin in somatosensory processing has been studied with galanin receptor antagonists. The new galanin receptor ligands C7, M32, M38 and M40 bind with high affinity (Kd in nanomolar range) to spinal cord galanin receptors and possess oxidative stability as compared to earlier generations of peptide ligands. These peptides have been examined in the spinal flexor reflex model where exogenous galanin exhibited biphasic excitatory and inhibitory effects.
Intrathecal administration of C7 [galanin(l‐13)‐spantide] and M32 [galanin (1–13)‐neuropeptide Y(25–36) amide] blocked facilitation of the nociceptive flexor reflex induced by 30 pmol intrathecal galanin in decerebrate, spinalized rats in a dose‐dependent manner, thus behaving as antagonists of the galanin receptor. In contrast, M38 [galanin(l‐13)‐(Ala‐Leu)3‐Ala amide] and M40 [galanin(l‐13)‐Pro‐Pro‐(Ala‐Leu)2‐Ala amide], exhibited only weak antagonism at high doses in this model. Moreover, lower doses of M40 potentiated galanin‐induced reflex facilitation. C7 was neurotoxic at high doses in the rat spinal cord.
M32 and C7 were potent antagonists of galanin receptors in rat spinal cord, in correlation with their in vitro binding characteristics. In contrast, M38 and M40, despite their high in vitro affinity, exhibited only very weak antagonism. Moreover, M40 may also behave as a partial agonist.
Previous studies have shown that the galanin receptor may be heterogeneous. The discrepancy between in vitro binding and in vivo antagonistic potency of M38 and M40 may also suggest the presence of different galanin receptor subtypes within the rat spinal cord. However, other explanations for the discrepancy, such as differences in metabolic stability, diffusion rates and penetration to the site of action are also possible.
RS‐45041‐190: a selective, high‐affinity ligand for I2 imidazoline receptors
Authors: Brown C.M. , MacKinnon A.C. , Redfern W.S. , Williams A. , Linton C. , Stewart M. , Clague R.U. , Clark R. , Spedding M. 
Published: July 2012

RS‐45041‐190 (4‐chloro‐2‐(imidazolin‐2‐yl)isoindoUne) showed high affinity for I2 imidazoline receptors labelled by [3H]‐idazoxan in rat (pKi = 8.66 ±0.09), rabbit (pKi = 9.37 ± 0.07), dog (pKi = 9.32±0.18) and baboon kidney (pKi = 8.85 ±0.12), but had very low affinity for α2‐adrenoceptors in rat cerebral cortex (pKi = 5.7 ± 0.09)
RS‐45041‐190 showed low affinity for other adrenoceptors, dopamine, 5‐hydroxytryptamine, and muscarinic receptors and dihydropyridine binding sites (selectivity ratio > 1000)
RS‐45041‐190 showed moderate potency for the inhibition of monoamine oxidase A in vitro (pIC50 = 6.12), but had much lower potency for monoamine oxidase B (pIC50 = 4.47), neither of which equated with its affinity for I2 receptors
RS‐45041‐190 (0.001 to 3 mg kg−1, i.v. and 1 ng‐50 μ i.e.v.) had only small, transient effects on blood pressure and heart rate in anaesthetized rats. In conscious rats, RS‐45041‐190 had no effect on body core temperature or tail skin temperature (1 mg kg−1, s.c.) or on activity or rotarod performance (10 mg kg−1, i.p.). There were also no effects on barbiturate sleeping time in mice after doses of 1–10 mg kg−1, i.p
RS‐45041‐190 (10 and 25 mg kg−1, i.p.) significantly increased food consumption in rats for up to 4 h after dosing, but unlike idazoxan (10 mg kg−1, i.p.) did not increase water consumption
RS‐45041‐190 is therefore a selective, high‐affinity ligand at I2 imidazoline receptors and its hyperphagic effect may suggest a role for I2 imidazoline receptors in the modulation of appetite. However, in the absence of a selective agonist it is unclear whether this ligand is an agonist or an antagonist at I2 receptors.
Nitric oxide, an enteric nonadrenergic‐noncholinergic relaxant transmitter: evidence using phosphodiesterase V and nitric oxide synthase inhibition
Authors: Williams S.J. , Parsons M.E. 
Published: July 2012

The effects of NG‐nitro‐L‐arginine (L‐NOARG), a nitric oxide synthase inhibitor, and SK&F 96231, a phosphodiesterase type V inhibitor, on electrical field stimulated (EFS) nonadrenergic noncholinergic (NANC) relaxations of rat fundal strips, guinea‐pig isolated ileum longitudinal muscle with intact myenteric plexus, and guinea‐pig taenia caeci were investigated
Reproducible repeated control random EFS frequency‐response curves were obtained for all three tissues
> Depending on the frequency of stimulation, L‐NOARG (10−4‐5 × 10−3M) caused either a complete or partial inhibition of the NANC‐induced relaxations of the rat fundal strips and the guinea‐pig isolated ileum longitudinal muscle with intact myenteric plexus, but not of the guinea‐pig taenia caeci. The inhibitory action of L‐NOARG was partially or totally reversed, depending on the tissue, by L‐arginine (5 × 10−3 M)
SK&F 96231 (10−6‐10−4M) caused a concentration‐ and frequency‐dependent potentiation of both the size and duration of the EFS‐induced NANC relaxant response of rat fundal strips and guinea‐pig isolated ileum longitudinal muscle with intact myenteric plexus, but not of the guinea‐pig taenia caeci
Zaprinast, another phosphodiesterase type V inhibitor (10−6‐10−4 M) caused a concentration‐ and frequency‐dependent potentiation of the NANC relaxant responses to EFS of rat fundal strips
SK&F 96231 and zaprinast alone (10−6‐10−4M) caused a concentration‐dependent relaxation of the agonist‐induced tone of all three tissues with the maximum degree of relaxation found to be in the order stomach < ileum < caecum. This is the reverse order for ability of SK&F 96231 to potentiate relaxant responses to EFS
These results suggest NO is involved in the NANC nerve‐mediated relaxation of rat fundal strips and guinea‐pig isolated ileum longitudinal muscle with intact myenteric plexus, but not the guinea‐pig taenia caeci.
Inhibition of angiogenesis, tumour growth and metastasis by the NO‐releasing vasodilators, isosorbide mononitrate and dinitrate
Authors: Pipili‐Synetos Eva , Papageorgiou A. , Sakkoula Eleni , Sotiropoulou Georgia , Fotsis T. , Karakiulakis G. , Maragoudakis M.E. 
Published: July 2012

The effect of the nitric oxide (NO)‐producing nitrovasodilators isosorbide mononitrate (ISMN) and isosorbide dinitrate (ISDN) were assessed on (a) the in vivo model of angiogenesis of the chick chorioallantoic membrane (CAM) and (b) on the growth and metastatic properties of the Lewis Lung carcinoma (LLC) in mice
Isosorbide 5‐mononitrate (ISMN) and isosorbide dinitrate (ISDN), inhibited angiogenesis in the CAM dose‐dependently. ISMN was more potent in inhibiting this process. Both compounds were capable of completely reversing the angiogenic effect of α‐thrombin. These effects of ISMN and ISDN on angiogenesis were comparable to those previously observed with sodium nitroprusside which generates NO non‐enzymatically
Mice, implanted intramuscularly with LLC, received daily i.p. injections of ISMN for 14 days resulting in a significant decrease in the size of the primary tumour and a reduction in the number and size of metastatic foci in the lungs. ISDN had a similar but less pronounced effect than that observed with ISMN
Addition of ISMN or ISDN to cultures of bovine, rabbit and human endothelial cells and to cultures of LLC cells had no effect on their growth characteristics
These results indicate that ISMN and ISDN inhibit angiogenesis and tumour growth and metastasis in an animal tumour model. The possibility should therefore be considered that these nitrovasodilators which are widely used therapeutically and have well characterized pharmacological profiles, may also possess antitumour properties in the clinic.
Enhancement by benzodiazepines of the inhibitory effect of adenosine on skeletal neuromuscular transmission
Authors: Chiou L.C. , Ling J. Y. , Chang C.C. 
Published: July 2012

Interactions of benzodiazepines with adenosine on the neuromuscular transmission were studied in mouse diaphragm preparations
In tubocurarine (0.6‐0.8 μm)‐partially paralyzed preparations, diazepam (35 μm) and Ro 5–4864 (3∼30 μm), a peripheral type benzodiazepine receptor agonist, potentiated the inhibitory effect of adenosine on indirect twitch responses
The central type receptor agonist, clonazepam did not affect the inhibitory effect of adenosine
The peripheral benzodiazepine receptor antagonist, PK11195 (1–10 μm) attenuated the adenosine inhibition and antagonized the potentiation by Ro 5–4864
Ro 5–4864 failed to enhance further the inhibitory effect of adenosine in the presence of dipyridamole, an adenosine uptake inhibitor that also potentiated adenosine inhibition
Neither Ro 5–4864 nor PK 11195 affected the inhibition produced by a stable adenosine analogue, 2‐chloroadenosine, which is not a substrate for the adenosine uptake system
Ro 5–4864 did not affect endplate potentials (e.p.ps) in the absence of adenosine, but reduced the amplitude of e.p.ps in the presence of adenosine without affecting miniature e.p.ps
It is suggested that benzodiazepines potentiate the adenosine‐effected presynaptic inhibition of neuromuscular transmission by an inhibition of adenosine uptake through activation of peripheral type benzodiazepine receptors.
Pharmacological modulation of adrenal medullary GABAA receptor: consistent with its subunit composition
Authors: Parramón M. , González M.P. 
Published: July 2012

Muscimol, the specific GABAA receptor agonist, increased the secretion of catecholamines by chromaffin cells with an EC50 of 2.9 ± 0.4 μm
GABAA receptors of these cells were modulated by the same drugs which modulate GABAA receptors in brain tissue
Benzodiazepines enhanced muscimol‐evoked catecholamine secretion by between 20 and 80%. This effect seems to be mediated by binding to a central type of benzodiazepine receptor because it was completely blocked by the specific antagonist, Ro 15 1788. This antagonist was able to displace [3H]‐flunitrazepam binding with an EC50 of 0.26 ±0.05 nM
β‐Carbolines weakly inhibited muscimol‐induced catecholamine secretion and were able to displace [3H]‐flunitrazepam binding with an EC50 between 0.2 and 0.9 nM, depending on the β‐carboline used.
Pregnanolone and related neuroactive steroids enhanced muscimol‐evoked catecholamine secretion by up to 87%, in a dose‐dependent fashion. In contrast pregnenolone weakly inhibited muscimol‐evoked catecholamine secretion
Zn2+ did not affect GABAA receptor‐induced catecholamine secretion
These pharmacological results are absolutely concordant with the theoretical properties given by the GABAA receptor subunit composition of bovine adrenal medulla ‐α1 α4, β1–3, γ2‐ previously characterized by Western blot analysis.
Modulation of calcium channel currents by arachidonic acid in single smooth muscle cells from vas deferens of the guinea‐pig
Authors: Nagano Norihiro , Watanabe Minora 
Published: July 2012

Effects of arachidonic acid (AA) on voltage‐dependent Ca channel currents were investigated by whole‐cell‐clamp methods in single smooth muscle cells freshly isolated from vas deferens of the guinea‐pig
Ca channel current was decreased by application of 1–30 μm AA in a concentration‐dependent manner. When Ca2+ or Ba2+ was the charge carrier, Ca channel current (ICa or IBa) was reduced by AA to a similar extent (IC50= 10 and 6 μm, respectively). Addition of 15 mM BAPTA to the pipette solution did not affect the reduction of IBa by 10 μm AA
The effect of AA on IBa was not prevented by internal application of 1 mM nordihydroguaiaretic acid (NDGA) and 1 mM indomethacin (Indo). When the pipette solution contained 0.1 mM guanosine‐5′‐triphosphate (GTP), IBa was decreased slightly but significantly by application of 30 (M prostaglandin (PGF2α) but not by PGE2. This effect of PGF2α was irreversible or not observed when the pipette solution contained 0.3 mM guanosine‐5′‐(3‐thiotriphosphate) (GTPγS) or both GTP or guanosine‐5′‐0‐(2‐thiodiphosphate) (GDPβS), respectively
External application of 100 units ml−1 superoxide dismutase slightly but significantly attenuated the inhibition of IBa by 1–30 μm AA. Intracellular application of 1 mM GDPβS or 0.3 mM GTPγS did not significantly change the effect of AA. Intracellular application of 0.1 mM 1‐(5‐isoquinolinesulphonyl)‐2‐methylepiperazine (H‐7) also did not change the effect of AA
These results indicate that the decrease in Ca channel currents in vas deferens smooth muscle cells is mainly due to AA itself, as opposed to its metabolites. The effect of AA may be due to AA itself, as opposed to its metabolites. The effect of AA may be due to its direct action on Ca channels or membrane phospholipids, but may not be mediated by activation of GTP binding proteins or protein kinase C. The inhibition of Ca channel current by AA may be partly induced by superoxide radicals derived from AA oxidation. PGF2α also reduces Ca channel currents but probably by a separate mechanism via activation of a GTP binding protein.
Cardiovascular responses to intrathecal neuropeptide γ in conscious rats: receptor characterization and mechanism of action
Authors: Poulat Philippe , de Champlain Jacques , Couture Réjean 
Published: July 2012

In the conscious rat, cardiovascular responses to intrathecally (i.t.) administered neuropeptide γ (NPγ) were studied prior to and after the i.t. pretreatment with selective antagonists at NKi ((±)‐CP 96345 and RP 67580), NK2 (SR 48968) and NK3 (R 486) receptors. Pretreatment with a mixture of peptidase inhibitors (phosphoramidon, captopril, bacitracin, phenanthroline) was also tested to ascertain whether or not the effect of NPγ was mediated by a metabolite. The involvement of peripheral catecholamines was examined with intravenous injection of α‐adrenoceptor (phentolamine) and β‐adrenoceptor (propranolol) antagonists.
NPγ (0.078‐78 nmol) induced dose‐dependent increases in heart rate (HR) and mean arterial blood pressure (MAP). The highest dose of 78 nmol did not induce an increase of MAP greater than that with 7.8 nmol but was preceded by a transient decrease of MAP (1–3 min). No desensitization was observed when three injections of 7.8 nmol NPγ were given at 90 min intervals.
Cardiovascular and behavioural (biting/scratching) effects evoked by 0.78 nmol NPγ were significantly reduced by the NK1 antagonists, (±)‐CP 96345 (65 nmol) or RP 67580 (7.8 and 78 nmol). However, cardiovascular responses to NPγ were not affected by (±)‐CP 96345 (6.5 nmol), SR 48968 (7.8 and 78 nmol) or R 486 (25 nmol). Pretreatment with peptidase inhibitors significantly enhanced the cardiovascular and behavioural responses to NPγ.
The pressor response to 7.8 nmol NPγ was converted to a vasodepressor response by pretreatment with phentolamine (2 mg kg−1, i.v.) while the chronotropic response was markedly reduced by propranolol (2 mg kg−1, i.v.).
These results suggest that the cardiovascular responses to i.t. NPγ are mediated by NK1 receptors in the spinal cord leading to the peripheral release of catecholamines from sympathetic fibres or the adrenal medulla. It is unlikely that the spinal action of NPγ results from its metabolic conversion into neurokinin A or another major metabolite.
Alterations in the force‐frequency relationship by tert‐ butylbenzohydroquinone, a putative SR Ca2+ pump inhibitor, in rabbit and rat ventricular muscle
Authors: Baudet S. , Do E. , Noireaud J. , Le Marec H. 
Published: July 2012

The effects of 2,5 di‐(tert‐butyl)‐1,4‐benzohydroquinone (TBQ), a putative inhibitor of the sarcoplasmic reticulum (SR) Ca2+ pump, on twitch tension, time course and SR Ca2+ content have been studied at different stimulation frequencies (0.5‐3 Hz) in isolated preparations from the rabbit and rat right ventricle, at 37°C.
At 0.5Hz, 30 μm TBQ induced a marked negative inotropic effect in both species (— 57% in the rabbit and —68% in the rat) and decreased the rate of rise and fall of twitch tension. In parallel, SR Ca2+ content (assessed by rapid cooling contractures) was depressed in the rabbit by 42%. The force‐frequency relationship (positive for the rabbit and negative for the rat) was significantly attenuated. In the rabbit, this alteration was shown to rely on insufficient SR Ca2+ reloading with increasing frequencies.
Exposure of TBQ‐treated preparations to 8 mM extracellular Ca2+ or 5 μm isoprenaline were effective in reloading the SR with Ca2+ whereas 20 mM caffeine emptied this compartment.
In the rabbit ventricle, increase in stimulation frequency shortened control twitch time course by decreasing both the time to peak tension (TTP) and the time to half relaxation (t1/2). TBQ did not differentially affect the pattern for t1/2 but significantly attenuated the frequency‐induced decrease of TTP.
In rabbit ventricular muscle, the action potential duration increased between 0.5 and 3 Hz whether or not TBQ was present. However, TBQ induced a small but significant additional action potential shortening.
TBQ decreased twitch tension in the rat ventricle between 0.5 and 3 Hz but the negative staircase was not differentially affected by the SR Ca2+ pump inhibitor. In control conditions and in the presence of 30 μm TBQ, t1/2 was frequency‐independent but TBQ consistently increased this parameter (by ∽ 29%).
These data argue in favour of a specific and partial inhibition of the SR Ca2+ pump by 30 μm TBQ in the rabbit and rat ventricle and emphasise the importance of SR Ca2+ uptake in the force‐frequency phenomenon.