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Biomedical subjects

Y Ukai

Publications and source records attributed to Y Ukai.

At least 37 records · Page 2Linked to original sources
PubMed1999

Blockade by NS-7, a neuroprotective compound, of both L-type and P/Q-type Ca2+ channels involving depolarization-stimulated nitric oxide synthase activity in primary neuronal culture.

The effect of 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride (NS-7), a neuroprotective compound, on Ca2+ channels involving the activation of nitric oxide synthase (NOS) was investigated in primary neuronal culture. The NOS activity was estimated from the cyclic GMP formation. The KCl (25 mM)-stimulated cyclic GMP formation was totally abolished by a combined treatment with nifedipine and omega-agatoxin IVA (omega-Aga), whereas spontaneous cyclic GMP formation was partially but significantly reduced by nifedipine. In contrast to nifedipine, NS-7 blocked KCl-stimulated cyclic GMP formation without affecting spontaneous cyclic GMP formation. Subsequently, the effects of nifedipine and NS-7 on L-type Ca2+ channels were compared. Nifedipine blocked equally the cyclic GMP formation stimulated by various concentrations of (+/-)-Bay K 8644, whereas NS-7 inhibited the maximal response without affecting the responses induced by low concentrations of (+/-)-Bay K 8644. The effects of NS-7 on L-type and P/Q-type Ca2+ channels involving KCl-stimulated cyclic GMP formation were subsequently examined. NS-7 suppressed the KCl-stimulated cyclic GMP formation measured in the presence of omega-Aga to almost the same extent as that determined in the presence of nifedipine. In contrast, NS-7 had no influence on ionomycin-induced enhancement of cyclic GMP formation. Finally, NS-7 reversed KCl-induced elevation of the intracellular free Ca2+ concentration. These findings suggest that NS-7 inhibits NOS activation in primary neuronal culture by reducing Ca2+ entry through L-type and P/Q-type Ca2+ channels, in which the inhibition is largely dependent on Ca2+ channel activity.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1998

A novel Na+/Ca2+ channel blocker NS-7 inhibits evoked but not spontaneous dopamine release from rat striatum, as measured by intracerebral microdialysis.

The spontaneous dopamine release from rat striatum, measured by intracerebral microdialysis, was markedly reduced by local perfusion of tetrodotoxin (1 microM) through the dialysis probe. In addition, striatal microinjection of omega-conotoxin GVIA (10 pmol) or omega-agatoxin i.v.A (1 pmol), but not local perfusion of nimodipine, suppressed the spontaneous dopamine release. Therefore, the spontaneous dopamine release may depend on the activity of both Na+ channel as well as N-type and P/Q-type Ca2+ channels. In contrast, local perfusion of a novel Na+- and Ca2+-channel blocker NS-7 (10 microM) did not affect spontaneous dopamine release, whereas it markedly blocked KCl- and veratridine-evoked dopamine release. Therefore, NS-7 may block Na+- and Ca2+-channels only when the ion channels are highly activated.

Animals↗
PubMed1998

A novel Na+/Ca2+ channel blocker, NS-7, suppresses hypoxic injury in rat cerebrocortical slices.

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 omega-conotoxin GVIA and the P/Q-type Ca2+ channel blocker omega-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 microM) 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.

Adenosine Triphosphate↗
PubMed1998

Comparison of the effects of NS-21 and terodiline on the QTc interval in dogs.

1. NS-21 [(+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate], its active metabolite, RCC-36, and terodiline, are mixed anticholinergic-Ca2+ antagonistic drugs. Among them, terodiline has been shown to cause torsade de pointes, a serious polymorphic ventricular tachycardia. It remains unknown, however, whether NS-21 or its active metabolite, RCC-36, produces torsade de pointes. 2. In anesthetized dogs, terodiline (10 mg/kg i.v.) significantly prolonged the QTc interval by 6-8%, an effect thought to be associated with torsade de pointes. In contrast, neither NS-21 nor RCC-36 (10 mg/kg i.v.) prolonged the QTc interval; therefore NS-21 is unlikely to cause ventricular tachyarrhythmias, such as those associated with terodiline. 3. The effects of NS-21, RCC-36 and terodiline on the action potential were investigated in guinea pig papillary muscle. However, none of these drugs prolonged the duration of the action potential, although only terodiline caused the muscle preparation to lose its excitability.

Animals↗
PubMed1998

The alpha1L-adrenoceptor subtype in the lower urinary tract: a comparison of human urethra and prostate.

OBJECTIVE: To identify the alpha1-adrenoceptor subtypes present in the human urethra, by comparing the affinity of prazosin for alpha1-adrenoceptors in the rabbit, dog and human prostatic urethra, and in the dog and human prostate. MATERIALS AND METHODS: The study comprised samples of human prostate and prostatic urethra, obtained by open prostatectomy of patients with benign prostatic hyperplasia, and of the proximal urethra and prostate from male Beagle dogs and rabbits. Specimens were homogenized, filtered and pelleted by centrifugation. Nonspecific binding was determined in the presence of 1 mmol/L prazosin when assessing [3H]YM-617 (tamsulosin) binding, and 10 mmol/L phentolamine when assessing [3H]prazosin binding. Specific binding was defined as the difference between total binding and nonspecific binding. RESULTS: The dissociation constant for [3H]prazosin in the human prostate (0.088 nmol/L) was less than that in the rabbit urethra (0.299 nmol/L), dog urethra (0.604 nmol/L), dog prostate (0.482 nmol/L) and human urethra (0.254 nmol/L). The affinity of prazosin was also investigated by determining the potency of the inhibition of [3H]YM-617 binding. The affinity of prazosin for alpha1-adrenoceptors in the human urethra (Ki, 2.5 nmol/L) was lower than its affinity for alpha1-adrenoceptors in the human prostate (Ki, 0.25 nmol/L) and all of the cloned subtypes (Ki, 0.26-0.44 nmol/L). CONCLUSION: The alpha1L-adrenoceptor subtype is more prominent in the human, rabbit and dog urethra and dog prostate than in the human prostate.

Adrenergic alpha-Antagonists↗
PubMed1998

Inhibition of depolarization-induced nitric oxide synthase activation by NS-7, a phenylpyrimidine derivative, in primary neuronal culture.

Neuronal nitric oxide synthase (NOS) is considered to be involved in the pathogenesis of ischemic brain damage. In the present study, the effect of a novel neuroprotective phenylpyrimidine derivative, 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride (NS-7), on depolarization-stimulated NOS activity was examined in cultured neurons of mouse cerebral cortex. Various depolarizing stimuli such as veratridine, KCl, and N-methyl-D-aspartate increased the NOS activity determined by cyclic GMP formation. NS-7 concentration-dependently inhibited both the veratridine- and KCl-induced NOS activation with IC50 values of 9.3 and 9.6 microM, respectively. The reversal of KCl-evoked NOS activity by NS-7 was also observed under blockade of both ionotropic glutamate receptors and the Na+ channel with MK-801, 6-cyano-7-nitroquinoxaline-2,3-dione, and tetrodotoxin. In contrast, NS-7, even at 100 microM, did not affect N-methyl-D-aspartate-stimulated NOS activity, nor did it have any influence on NOS activity determined in the soluble fraction of rat hippocampus. Because NS-7 has already been shown to block both Na+ and Ca2+ channels, the present findings suggest that this compound inhibits depolarization-induced NOS activation by reducing Ca2+ influx through blockade of Na+ and Ca2+ channels in primary neuronal culture.

Animals↗
PubMed1997

Effect of a novel cognition enhancer NS-105 on learned helplessness in rats: possible involvement of GABA(B) receptor up-regulation after repeated treatment.

We have previously found that a cognition enhancer [(+)-5-oxo-D-prolinepiperidinamide monohydrate] (NS-105) reversed the inhibition of cyclic AMP formation induced by the GABA(B) receptor agonist baclofen. The GABA(B) receptor has been implicated in the pathophysiology of depressive illness. The present experiment was designed to evaluate the antidepressant activity of NS-105 in the forced swimming and learned helplessness tests in rats. NS-105 (1-100 mg/kg, p.o.) significantly decreased immobility time in the forced swimming test, an effect similar to that of desipramine. Repeated administration of NS-105 also reversed the failure to escape in the shuttle-box test of rats previously exposed to inescapable footshock. Biochemical data showed that repeated administration of NS-105 increased the number of GABA(B) receptors in rat cerebral cortex without affecting the binding properties of beta-adrenoceptors and 5-HT2 receptors. In contrast to other antidepressants, NS-105 did not inhibit monoamine uptake in vitro, nor did it change monoamine concentrations in brain tissues or extracellular fluids. These findings suggest that NS-105, which lacks an effect on monoaminergic systems, has potent antidepressant activity, which may involve up-regulation of GABA(B) receptors after repeated administration.

Animals↗
PubMed1997

Na+ and high-voltage-activated Ca2+ channel blocking actions of NS-7, a novel neuroprotective agent, in NG108-15 cells.

The actions of a novel neuroprotective compound, 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride (NS-7), on voltage-gated Na+, Ca2+ and K+ channels were investigated in a mouse neuroblastoma and rat glioma hybrid cell line, NG108-15, using a whole-cell voltage clamp technique. NG108-15 cells have a tetrodotoxin-sensitive Na+ channel, three types of Ca2+ channel (L, N and T) and voltage-gated K+ channels, all of which were inhibited by NS-7 in a concentration-dependent manner. However, there was a considerable difference in its potency: the IC50 values for the tetrodotoxin-sensitive Na+ channel, L-type Ca2+ channel and N-type Ca2+ channel were similar (7.8, 4.5 and 7.3 microM, respectively), lower than the IC50 value for the T-type Ca2+ channel (17.1 microM), and much lower than the IC50 value for the voltage-gated K+ channel (160.5 microM). NS-7 altered neither the shape nor the reversal potential of the current-voltage curves for Na+, L-type or N-type Ca2+ channels, although the currents were reduced at every potential tested. These results indicate that NS-7 is a Na+ and high-voltage-activated (L- and N-type) Ca2+ channel blocker, and its channel-blocking properties may contribute to its neuroprotective action.

Animals↗
PubMed1997

Involvement of metabotropic glutamate receptors in Gi- and Gs-dependent modulation of adenylate cyclase activity induced by a novel cognition enhancer NS-105 in rat brain.

The effect of a novel cognition enhancer [(+)-5-oxo-D-prolinepiperidinamide monohydrate] (NS-105) on cAMP formation was investigated in both slices and membranes of the rat cerebral cortex. NS-105 (10(-8)-10(-6) M) inhibited forskolin-stimulated cAMP formation in membranes, however, the compound significantly enhanced the cAMP formation in pertussis toxin-pre-treated membranes, an action that was abolished by cholera toxin. In contrast, in digitonin-permeabilized membranes, NS-105 had no influence on Mn2+-stimulated cAMP formation. Both of the inhibitory and facilitatory actions of NS-105 on cAMP formation were mimicked by a metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) and an adrenergic alpha2 agonist UK-14,304, and blocked by a mGluR antagonist 2-amino-3-phosphonopropanoate but not by an alpha2 antagonist yohimbine. In cortical slices, NS-105 (10(-8)-10(-7) M) inhibited forskolin-stimulated cAMP accumulation but enhanced isoproterenol-stimulated cAMP accumulation, as did by a GABA(B) agonist (-)baclofen. On the other hand, (-)baclofen, while it significantly inhibited cAMP accumulation in slices, did no longer inhibit cAMP accumulation, when treated with NS-105 (10(-8)-10(-5) M). Similarly, (-)baclofen-induced inhibition of the cAMP accumulation was reversed by 1S,3R-ACPD and UK-14,304. NS-105 (10(-6)) increased [35S]GTPgammaS binding in the intact but not digitonin-permeabilized cortical membranes, as produced by UK-14,304, although the compound (10(-9)-10(-3) M) had no influence on various neurotransmitter receptor bindings, including alpha2 receptors. These results suggest that NS-105 modulates adenylate cyclase activity by stimulating mGluRs which might coupled to both Gi/Go and Gs.

Adenylate Cyclase Toxin↗
PubMed1997

Identification of alpha 1-adrenoceptor subtypes in the human prostatic urethra.

To identify the alpha 1-adrenoceptor subtypes in the human prostatic urethra, we compared the potencies of various alpha 1-adrenoceptor agonists and antagonists in inhibiting [3H]tamsulosin binding to human prostatic urethral membranes with their potencies in inhibiting the binding of (+)-beta-([125I]iodo-4-hydroxyphenyl)ethylaminomethyl-tetralone ([125I]HEAT) to cloned human alpha 1a, alpha 1b and alpha 1d subtypes. The alpha 1A-selective antagonists 5-methylurapidil and (+)niguldipine showed higher affinities for both cloned alpha 1a and urethral alpha 1-adrenoceptors than for cloned alpha 1b- and alpha 1d-adrenoceptors. NS-49, (R)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide hydrochloride, recently characterized as an alpha 1A-selective agonist, also showed high affinity for the cloned alpha 1a subtype and urethral alpha 1-adrenoceptors. Prazosin showed lower affinity for alpha 1-adrenoceptors in the human prostatic urethra than for any of the three cloned alpha 1-adrenoceptors. Comparison of the affinities of alpha 1-adrenoceptor agonists and antagonists for human prostatic urethral alpha 1-adrenoceptors to their affinities for the three cloned alpha 1 subtypes indicated a close correlation between the affinities for human urethral alpha 1 and the cloned alpha 1a-adrenoceptors. However, prazosin did not conform to this pattern. These findings suggest that the predominant alpha 1-adrenoceptor in the human urethra is the alpha 1A subtype, and that an alpha 1L subtype which has been characterised by its low affinity for prazosin, may also be present.

Adrenergic alpha-Agonists↗
PubMed1997

Blockade of voltage-sensitive sodium channels by NS-7, a novel neuroprotective compound, in the rat brain.

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 20 alpha-benzoate (BTX) binding (neurotoxin receptor site 2) in brain membranes with a Ki value of 1 microM, while the compound was less effective in the cardiac myocytes (Ki = 13 microM). 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 microM)-evoked glutamate release in a concentration-dependent manner, the IC50 value of which was 7.7 microM, 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.

Aconitine↗
PubMed1997

Cardiac electrophysiological actions of NS-21 and its active metabolite, RCC-36, compared with terodiline.

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 microM, respectively. At a concentration of 10 microM, 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.

Animals↗
PubMed1997

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.

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 microM), both NS-21 (10 microM) and RCC-36 (10 microM) 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 microM for NS-21, 6.4 microM for RCC-36, and 5.9 microM for terodiline, and at -40 mV they were 1.3, 1.2, and 3.5 microM, 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.

Animals↗
PubMed1997

A novel cognition enhancer NS-105 modulates adenylate cyclase activity through metabotropic glutamate receptors in primary neuronal culture.

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.

Adenylate Cyclase Toxin↗
PubMed1997

Permeability of a neuroprotective compound NS-7 into brain: comparison between normal and middle cerebral artery-occluded rats.

The pharmacokinetics of 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride (NS-7), a novel neuroprotective compound, in brains of normal and ischemic rats were investigated. In normal rats, the concentrations of NS-7 in the cerebral cortex and striatum were more than 10-folds higher than those in plasma during 5 min and 12 h after intravenous injection. The time course changes in plasma concentration of NS-7 were fitted to the two-compartment open model, in which elimination half-life (t(1/2)beta) was 6.0 h and distribution volume (V1) was 4.4. The estimated striatal interstitial concentration of NS-7 measured by microdialysis was unexpectedly low and almost constant after intravenous injection. Subsequently, the level of NS-7 in brain was compared between sham-operated and middle cerebral artery (MCA)-occluded rats. In MCA-occluded rats, the concentrations of NS-7 in the ischemic cerebral cortex and striatum were 64-71% of those in sham-operated group at 1 h after injection, although the initial concentrations (at 2-5 min) were much lower (about 20%) in MCA-occluded rats. The t(max) was observed at 1 h after injection, which was later than that (5 min) determined in sham-operated rats. Moreover, its elimination half-life was longer in MCA-occluded rats than in sham-operated animals. From these results it is suggested that peripherally administered NS-7 readily penetrates into brain, in which it exists for the most part in parenchymal fraction. In addition, substantial amount of NS-7 may distribute to the ischemic brain regions when it was injected after MCA occlusion.

Animals↗
PubMed1997

Anticholinergic and calcium antagonistic activities of NS-21 contribute to the inhibition of rat urinary bladder contractions.

1. Pharmacological characteristics of NS-21 and its main metabolite, RCC-36, in the inhibition of rat urinary bladder contractions were investigated both in vitro and in vivo. 2. NS-21 and RCC-36 inhibited muscarinic receptor bindings to rat bladder membranes with [3H]3-quinuclidinyl bezilate (pKi 6.19 and 7.24, respectively), whereas they failed to inhibit the following receptor bindings: adrenergic (alpha 1, alpha 2 and beta), dopaminergic (D1 and D2), adenosine (A1 and A2), histaminergic (H1) and opioid (mu, delta and kappa) receptors. 3. NS-21 and RCC-36 suppressed carbachol-induced contractions of isolated rat detrusor strips in competitive (pA2 6.80 and 7.93, respectively) and noncompetitive (pD'2 5.93 and 5.77, respectively) manners. 4. NS-21 and RCC-36 inhibited CaCl2-induced contractions of rat detrusor strips in the presence of 100 mM K+ (pIC50 6.54 and 5.76, respectively), as well as the 100 mM K(+)-induced 45Ca influx into the isolated bladder strips at > or = 1 microM. 5. Electrical stimulation of the peripheral end of the pelvic nerve in anesthetized rats induced bladder contractions composed of two phases: an initial phasic contraction that was weakly suppressed by atropine, and a tonic contraction that was strongly suppressed by atropine. NS-21 suppressed both contractions to the same degree (ID50 2.65 and 2.19 mg/kg, i.v., respectively). RCC-36 suppressed the tonic contraction (ID50 1.20 mg/kg, i.v.) more markedly than the initial contraction (ID50 7.43 mg/kg, i.v.). 6. These results suggest that NS-21 and RCC-36 suppressed bladder contractions owing to their anticholinergic and calcium antagonistic activities.

Animals↗
PubMed1997

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.

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 microM) 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.

Animals↗