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

Hamada, Kozo; Sasaki, Yasuo; Taniguchi, N; Fukui, Hisashi; Miyatsuka, Yoko; Kimura, Yutaka; Ukai, Yojiro; Yoshikuni, Yoshiaki; Kimura, Kiyoshi

doi:10.1016/s0306-3623(97)00259-0

Cited by 14 publications

(19 citation statements)

References 18 publications

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“…This analysis revealed that NS-21, RCC-36 and terodiline had respectively 57.3, 41.5 and 16.5 times higher affinity for the inactivated than the resting state (Table 2). This result is consistent with the observation that NS-21 most potently inhibited the muscle contractions induced by CaCl 2 and the 45 Ca uptake induced by high-K + in isolated rat urinary bladder strips (Hamada et al 1997), under which conditions the Ca 2+ channel should be fully inactivated.…”

Section: Discussionsupporting

confidence: 91%

“…Terodiline had similar inhibitory effects, and our results agree with those reported previously (Kura et al 1992). Our findings on the Ca 2+ channel blocking activity of NS-21 and RCC-36 are also consistent with a observation of their Ca 2+ antagonistic properties in studies on muscle contraction induced by CaCl 2 and on 45 Ca uptake induced by high-K + in isolated rat urinary bladder strips (Hamada et al 1997). NS-21, RCC-36 and terodiline induced tonic block of I Ca , an effect previously demonstrated with organic Ca 2+ antagonists (Uehara and Hume 1985;Terada et al 1987) and interpreted as preferential binding of the drug to resting and inactivated channels (Hille 1977;Hondeghem and Katzung 1977).…”

Section: Discussionsupporting

confidence: 91%

“…NS-21 ((±)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate), which, like terodiline, has anticholinergic and Ca 2+ antagonistic activities in detrusor smooth muscle (Hamada et al 1997), is a novel compound selected for the treatment of urinary frequency and urinary incontinence (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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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

Hayashi

Natsukawa

Ukai

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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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

Hayashi

Natsukawa

Ukai

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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“…The EFS caused frequency-dependent bimodal phasic and tonic contractions of the bladder in all rats of both groups. It has been reported that the former contraction is related to the combination of purinergic (adenosine 5)-triphosphate; ATP) and cholinergic neurotransmissions and that the latter contraction is related only to cholinergic neurotransmission [16,22]. In our preliminary experiments, treatment with atropine almost completely inhibited the tonic detrusor contraction induced by EFS of the pelvic nerve in rats of both groups, while the phasic contraction was inhibited by treatment with both atropine and ·,ß-methylene-ATP.…”

Section: Biological Datamentioning

confidence: 54%

“…The peripheral end of one of the pelvic nerves (referred to as pelvic nerve below) was placed on a bipolar platinum electrode. EFS of the pelvic nerve (supramaximum voltage, pulse duration 0.1 ms, frequency 1-10 Hz, train of pulse 60 s) was applied, and the detrusor pressure was recorded, as previously described [16].…”

Section: Animals and Microdialysis Proceduresmentioning

confidence: 99%

Acetylcholine Release from Urinary Bladder Smooth Muscles of Non-Insulin-Dependent Diabetic Rats

Miyamae

Yoshida²,

Inadome³

et al. 2004

Urol Int

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Introduction: To investigate the mechanism of voiding dysfunction in non-insulin-dependent diabetes mellitus, we attempted to measure the acetylcholine (ACh) release using an in vivo microdialysis technique and measuring the detrusor pressure after electrical field stimulation (EFS) of the pelvic nerve. Materials and Methods: Eight- and 32-week-old female Goto-Kakizaki (GK) rats (non-insulin-dependent diabetes mellitus model) and age-matched female Wistar rats (controls) were used in this study. The pelvic nerve was exposed on a bipolar platinum electrode to EFS, and a cannula was inserted into the bladder to measure the detrusor pressure. The microdialysis probe was inserted into the bladder wall and was connected to a microinfusion syringe pump. Dialysate was constantly perfused, collected in a microtube, and then injected into the ACh assay system. Histological examinations were performed by staining with hematoxylin and eosin and S-100 immunohistochemical staining in bladder preparations of both GK and control rats. Results: In 8-week-old rats, both detrusor pressures and amounts of ACh release of GK rats were not significantly different from those of control rats. In 32-week-old rats, both detrusor pressures and ACh releases were only significantly increased at 5 and 10 Hz of EFS. In the histological study, the number of nerve fibers or bundles of 32-week-old GK rats was significantly decreased as compared with control rats. Conclusion: The present data suggest that the decrease in EFS-induced ACh release in GK rats, which may be caused by the decreased number of nerve fibers, may contribute to the decrease in bladder contractions.

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Effect of herbal extract mixture on menopausal urinary incontinence in ovariectomized rats

2006

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The decline of estrogen production after menopause is contributing factor to urinary incontinence (UI), and particularly stress urinary incontinence (SUI). We determined the preventive effects of herbal extract mixture (HEM) on UI in ovariectomized Sprague Dawley rats. Female 9-weeks old rats were ovariectomized and treated with HEM (2.2, 11, or 55 mg/kg/day) for 8 weeks. The index of urinary bladder weight to body weight in the HEM and non-ovariectomized and non-treated (SHAM) groups were slightly higher than the ovariectomized, non-treated group (OVX). The contraction index of acetylcholine to KCl on detrusor smooth muscle strips in the HEM groups showed a dose-dependent recovery. HEM treatment also significantly improved collagen levels, as shown by Masson trichrome staining, as well as hydroxyproline levels in the urinary bladder. Serum estradiol levels in the HEM groups were higher than the OVX group. In conclusion, HEM increased estradiol levels in serum and improved factors related to urinary incontinence. The improvements in estradiol levels were related to changes in urinary incontinence.

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

Cited by 14 publications

References 18 publications

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

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

Acetylcholine Release from Urinary Bladder Smooth Muscles of Non-Insulin-Dependent Diabetic Rats

Effect of herbal extract mixture on menopausal urinary incontinence in ovariectomized rats

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