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  • 1
    Electronic Resource
    Electronic Resource
    Protein Kinases Are Involved in Prolonged Acetylcholine Release from Rat Hippocampus Induced by Thyrotropin-Releasing Hormone Analogue NS-3 (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 66 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The effects of various protein kinase inhibitors on acetylcholine release from the rat hippocampus induced by the local application of NS-3 (montirelin hydrate, CG-3703), a thyrotropin-releasing hormone analogue, into the medial septum-diagonal band were examined using in vivo microdialysis. Perfusion of NS-3 (1 µM) into the medial septum-diagonal band for 20 min produced a pronounced and prolonged increase in the hippocampal acetylcholine efflux. Pretreatment of the medial septum-diagonal band with either K-252a, a nonselective protein kinase inhibitor, or selective protein kinase A inhibitor H-89 almost completely blocked the acetylcholine efflux evoked by NS-3, and selective protein kinase C inhibitor calphostin C inhibited the action of NS-3. On the other hand, NS-3 (0.1–10 µM) or TRH (1–100 µM) increased the cyclic AMP efflux from the medial septum-diagonal band in a concentration-dependent manner, as measured by microdialysis. These findings suggest that protein kinases A and C in the neurons of the medial septum-diagonal band are involved in the mechanism of the prolonged stimulation of acetylcholine release from the hippocampus induced by thyrotropin-releasing hormone and its analogue, NS-3.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.66051889.x
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  • 2
    Electronic Resource
    Electronic Resource
    Inhibition of Ischemia-Induced Fodrin Breakdown by a Novel Phenylpyrimidine Derivative NS-7: An Implication for Its Neuroprotective Action in Rats with Middle Cerebral Artery Occlusion (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 68 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The effect of a novel neuroprotective compound, NS-7[4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride], on ischemia-induced fodrin breakdown was examined both in vitro and in vivo. The fodrin breakdown was measured by western blot followed by a densitometric analysis. In slices of the rat cerebral cortex, a pronounced fodrin breakdown was observed under hypoxic and hypoglycemic conditions. The enhancement of fodrin breakdown was completely blocked by omission of extracellular Ca2+ and significantly inhibited by calpain inhibitors such as E-64 and calpain inhibitor-I, thereby suggesting that the fodrin breakdown induced by hypoxia/hypoglycemia is due to the activation of Ca2+-stimulated neutral protease calpain. NS-7 (1–30 µM) produced a concentration-dependent inhibition of hypoxia/hypoglycemia-induced fodrin breakdown. In rats with unilateral middle cerebral artery occlusion (MCAO), a pronounced fodrin breakdown was observed in the cerebral cortex and striatum, although the time course for the development of the fodrin breakdown was much slower in the cerebral cortex than in the striatum. NS-7 (0.5 mg/kg i.v.), when injected immediately after MCAO, suppressed not only the fodrin breakdown but also the infarction in the cerebral cortex. From these results it is suggested that inhibition of calpain activation is implicated in the neuroprotective action of NS-7.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.68062507.x
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  • 3
    Electronic Resource
    Electronic Resource
    Mechanisms of the Suppression of the Bladder Activity by Flavoxate (1996)
    Oxford, UK : Blackwell Publishing Ltd
    International journal of urology 3 (1996), S. 0 
    Details
    ISSN: 1442-2042
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background: This study was designed to clarify the primary site of action of flavoxate, clinically used for the treatment of urinary frequency.Methods: In rats, the effect of flavoxate on contractile responses in isolated detrusor strips, bladder contraction induced by pelvic nerve stimulation, isovolumetric rhythmic bladder contractions, and pelvic nerve activity were examined. In decerebrated cats, flavoxate was microinjected into the nuclei in the pons, and its effect on reflex micturition was observed.Results: Flavoxate suppressed carbachol- and calcium ion (Ca2+)-induced contractions of isolated detrusor strips in a noncompetitive and a competitive manner, respectively. Intravenous flavoxate suppressed both initial phasic, and later tonic, bladder contractions induced by electrical stimulation of the distal end of the pelvic nerve. It abolished isovolumetric rhythmic bladder contractions and the associated efferent pelvic nerve activity, without affecting baseline vesical pressure and afferent pelvic nerve activity. When administered intracerebroventricularly or intrathecally, it abolished isovolumetric rhythmic bladder contractions. Flavoxate microinjected into the nucleus reticularis pontis oralis (PoO; pontine micturition inhibitory region) of decerebrated cats inhibited the reflex micturition, but had no effect when microinjected into the locus coeruleus alpha (pontine micturition center) or locus subcoeruleus (pontine urine storage center).Conclusions: Flavoxate suppressed the micturition reflex primarily by facilitating the inhibitory action of the PoO on the descending pathways from the pontine micturition center to the sacral arasympathetic intermediolateral nuclei.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1442-2042.1996.tb00520.x
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  • 4
    Electronic Resource
    Electronic Resource
    Effect of NS-21, an Anticholinergic Drug with Calcium Antagonistic Activity, on Lower Urinary Tract Function in a Rat Model of Urinary Frequency (1997)
    Oxford, UK : Blackwell Publishing Ltd
    International journal of urology 4 (1997), S. 0 
    Details
    ISSN: 1442-2042
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background: NS-21 is under development for the treatment of urinary frequency and urinary incontinence. The purpose of this study was to investigate the effects of NS-21 and its active metabolite, RCC-36, on lower urinary tract function in an experimental rat model of urinary frequency. Methods: Cystometrograms were recorded in anesthetized rats with bilaterally transected hypogastric nerves. All drugs were administered intraduodenally. Results: In sham-operated rats, NS-21 (≥ 50mg/kg) significantly increased the bladder capacity without significantly decreasing micturition pressure, while RCC-36 (100mg/kg) significantly increased bladder capacity, and at a dose of a 30mg/kg, also caused a decrease in micturition pressure. This increase in bladder capacity appeared at lower doses of both NS-21 and RCC-36 in the hypogastric nerve-transected rats. Propiverine (100mg/kg) increased bladder capacity and at a 30mg/kg, decreased micturition pressure in both sham-operated and nerve-transected rats. Oxybutynin (100mg/kg) and atropine (30mg/kg) decreased the micturition pressure in both sham-operated and nerve-transected rats without increasing the bladder capacity, while a similar anticholinergic calcium antagonist, terodiline (100mg/kg) had no effect on bladder capacity in either sham-operated or nerve-transected rats. Flavoxate (500mg/kg) significantly increased bladder capacity without significantly decreasing micturition pressure in both sham-operated and nerve-transected rats, while 50mg/kg of verapamil significantly increased bladder capacity without significantly decreasing the micturition pressure in nerve-transected rats. Conclusions: NS-21 and RCC-36 increased bladder capacity at lower doses in hypogastric nerve-transected rats than in sham-operated rats. Furthermore, NS-21 increased the bladder capacity without suppressing micturition pressure, suggesting that NS-21 may be a more effective therapeutic drug than propiverine, oxybutynin or flavoxate for the treatment of urinary frequency and urinary incontinence.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1442-2042.1997.tb00215.x
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  • 5
    Electronic Resource
    Electronic Resource
    Cardiac electrophysiological actions of NS-21 and its active metabolite, RCC-36, compared with terodiline (1997)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 355 (1997), S. 651-658 
    Details
    ISSN: 1432-1912
    Keywords: Key words Torsade de pointes ; Ca2+ Current ; Delayed rectifier K+ current ; Inward rectifier K+ current ; Guinea pig ; Ventricular myocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Terodiline, an anticholinergic drug with a Ca2+ blocking action, is thought to be associated with torsade de pointes, a serious ventricular tachycardia. NS-21 is a newly developed drug for the treatment of urinary frequency and urinary incontinence and it has pharmacological properties similar to those of terodiline. It remains unknown, however, whether NS-21 and its active metabolite, RCC-36, have any proarrhythmic activity. The electrophysiological properties of NS-21 and RCC-36 were examined in guinea pig ventricular myocytes and were compared with those of terodiline using the whole-cell patch-clamp technique. NS-21, RCC-36 and terodiline inhibited L-type Ca2+ currents in a concentration-dependent manner with IC50 values of 27.0, 27.0 and 33.5 μM, respectively. At a concentration of 10 μM, terodiline inhibited both the time-dependent current and the tail current of the delayed rectifier K+ current, with the latter being significantly inhibited at voltages more positive than +10 mV. In contrast, NS-21 and RCC-36 had almost no effect on either of these currents. Terodiline also inhibited the inward rectifier K+ current significantly at voltages more negative than -100 mV, whereas NS-21 and RCC-36 had little effect. If the proarrhythmic activity of terodiline resulted primarily from the combined inhibition of K+ and Ca2+ currents, one might expect that NS-21 and RCC-36, which inhibit L-type Ca2+ currents without affecting either the delayed rectifier K+ current or the inward rectifier K+ current, would not share the proarrhythmic activities of terodiline.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00004997
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  • 6
    Electronic Resource
    Electronic Resource
    Inhibitory effects of NS-21, a novel drug for urinary incontinence, and its active metabolite, RCC-36, on L-type calcium currents in isolated guinea pig detrusor smooth muscle cells (1997)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 355 (1997), S. 659-666 
    Details
    ISSN: 1432-1912
    Keywords: Key words Ca2+ Antagonist ; Inward current ; Calcium window current ; Voltage dependence ; Terodiline ; Patch clamp
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The inhibitory effects of NS-21, a newly developed drug for the treatment of urinary frequency and urinary incontinence, and its active metabolite, RCC-36, on L-type Ca2+ currents (ICa) in guinea pig detrusor smooth muscle cells have been compared to those of terodiline by a whole-cell patch-clamp technique. Like terodiline (10 μM), both NS-21 (10 μM) and RCC-36 (10 μM) induced a sizeable decrease in ICa elicited from a holding potential of -60 mV without changing the current-voltage relationship. The three drugs shifted the inactivation curves for ICa in the hyperpolarizing direction by 13 to 20 mV but had no effect on the activation curves for ICa, resulting in a decrease in the calcium window current. The inhibitory effects of NS-21 and RCC-36 were greater than those of terodiline. The three drugs inhibited ICa in a concentration- and holding-potential-dependent manner. The IC50 values at a holding potential of -60 mV were 7.9 μM for NS-21, 6.4 μM for RCC-36, and 5.9 μM for terodiline, and at -40 mV they were 1.3, 1.2, and 3.5 μM, respectively. The ratio calculated by dividing the IC50 value at -60 mV by the value at -40 mV was 6.1, 5.3 and 1.7, respectively, indicating that the inhibitory effects of NS-21 and RCC-36 on ICa were more sensitive to voltage than those of terodiline. These results suggest that NS-21 and RCC-36 could be more effective in the treatment of urinary bladder ailments, such as urinary frequency and urinary incontinence.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00004998
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  • 7
    Electronic Resource
    Electronic Resource
    A novel cognition enhancer NS-105 modulates adenylate cyclase activity through metabotropic glutamate receptors in primary neuronal culture (1997)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 356 (1997), S. 189-196 
    Details
    ISSN: 1432-1912
    Keywords: Key words Cognition enhancer ; Adenylate cyclase ; Phosphoinositides hydrolysis ; Metabotropic glutamate receptors ; GTP binding proteins ; Primary neuronal ; culture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of (+)-5-oxo-D-prolinepiperidinamide monohydrate (NS-105), a novel cognition enhancer, on adenylate cyclase activity was investigated in cultured neurons of the mouse cerebral cortex. NS-105 (10–7 and 10–6 M) inhibited forskolin-stimulated cyclic AMP formation, an action that was dependent on pertussis toxin-sensitive G proteins. Conversely, in pertussis toxin-pretreated neurons, NS-105 (10–7 –10–5 M) significantly enhanced the forskolin-stimulated cyclic AMP formation, and this action was completely reversed by cholera toxin. A metabotropic glutamate receptor agonist (1S, 3R)-1-aminocyclopentane-1, 3-dicarboxylic acid (1S, 3R-ACPD) produced similar bi-directional actions on the cyclic AMP formation. Both of these inhibitory and facilitatory actions of NS-105 and 1S, 3R-ACPD were blocked by L(+)-2-amino-3-phosphopropinoic acid (L-AP3). NS-105 (10–6 M) and 1S, 3R-ACPD (10–4 M) significantly enhanced isoproterenol- and adenosine-stimulated cyclic AMP formation. The enhancement of such Gs-coupled receptor agonists-stimulated cyclic AMP formation was also produced by quisqualate but not by L(+)-2-amino-4-phosphonobutanoate (L-AP4). The phosphoinositides hydrolysis was enhanced by 1S, 3R-ACPD (10–4 M) but not by NS-105 (10–6 M), however, 1S, 3R-ACPD-induced increase in phosphoinositides turnover was attenuated by NS-105. These findings suggest that NS-105 stimulates metabotropic glutamate receptor subclasses that are coupled both negatively and positively to adenylate cyclase, but it acts as an antagonist at the receptor subclasses that are linked to phosphoinositides hydrolysis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00005040
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  • 8
    Electronic Resource
    Electronic Resource
    Blockade of voltage-sensitive sodium channels by NS-7, a novel neuroprotective compound, in the rat brain (1997)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 355 (1997), S. 601-608 
    Details
    ISSN: 1432-1912
    Keywords: Key words Neuroprotectant ; Voltage-sensitive sodium channel ; Batrachotoxin ; Saxitoxin ; Glutamate release ; Cerebral cortex ; Cardiac myocyte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride (NS-7), a novel neuroprotective compound, on the voltage-sensitive sodium channels (VSSC) were examined in the rat brain and cardiac myocytes. NS-7 inhibited [3H]batrachotoxinin A 20α-benzoate (BTX) binding (neurotoxin receptor site 2) in brain membranes with a Ki value of 1 μM , while the compound was less effective in the cardiac myocytes (Ki = 13 μM). Aconitine, on the other hand, inhibited [3H]BTX binding to brain membranes and cardiac myocytes with the same potency. In contrast, NS-7 had no affinity for [3H]saxitoxin binding in brain (neurotoxin receptor site 1). In superfused slices of the rat cerebral cortex, NS-7 inhibited the veratridine (5 μM)-evoked glutamate release in a concentration-dependent manner, the IC50 value of which was 7.7 μM, whereas the compound showed a weak and not significant suppression of KCl-evoked glutamate release. The tissue concentrations of NS-7 in the rat cerebral cortex and heart were 89 and 28 nmole/g tissue, respectively, 5 min after its intravenous injection (8 mg/kg). Furthermore, in the cerebral cortex, NS-7 distributed preferentially to the membrane-enriched synaptosomal fraction. Since neurotoxin receptor site 2 is located in the transmembrane region of the VSSC moiety, the channel function may be substantially inhibited by a peripheral administration of NS-7. These results suggest that the blockade of neurotoxin receptor site 2 of VSSC in the brain contributes to the neuroprotective action of NS-7.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00004990
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  • 9
    Electronic Resource
    Electronic Resource
    A novel Na+/Ca2+ channel blocker, NS-7, suppresses hypoxic injury in rat cerebrocortical slices (1998)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 358 (1998), S. 191-196 
    Details
    ISSN: 1432-1912
    Keywords: Key words Neuroprotectant ; Calcium channel blocker ; Sodium channel blocker ; Hypoxic injury ; ATP ; Cerebral cortex
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The substance 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride (NS-7) has been developed recently as a cerebroprotective compound with Na+ and Ca2+ channel blocking action. In the present study, the effect of NS-7 in an in vitro model of hypoxic injury was examined and the possible involvement of Na+ and Ca2+ channels in the hypoxic injury subsequently determined. When slices of rat cerebral cortex were exposed to hypoxia/glucose deprivation followed by reoxygenation and restoration of the glucose supply, marked leakage of lactate dehydrogenase (LDH) occurred 3–6 h after reoxygenation. This hypoxia/reoxygenation-induced injury was blocked almost completely by the removal of extracellular Ca2+ or by chelating intracellular Ca2+ with 1,2-bis(o-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid tetra(acetoxymethyl)ester (BAPTA/AM). In addition, combined treatment with the N-type Ca2+ channel blocker ω-conotoxin GVIA and the P/Q-type Ca2+ channel blocker ω-agatoxin IVA significantly reduced LDH leakage, although neither of these Ca2+ channel blockers alone, nor nimodipine, an L-type Ca2+ channel blocker, was effective. On the other hand, several Na+ channel blockers, including tetrodotoxin, local anaesthetics and antiepileptics, significantly reduced the hypoxic injury. NS-7 (3–30 µM) concentration-dependently inhibited LDH leakage caused by hypoxia/reoxygenation, but had no influence on the reduction of tissue ATP content and energy charge during hypoxia and glucose deprivation. It is suggested that blockade of Na+ and Ca2+ channels is implicated in the cerebroprotective action of NS-7.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00005242
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