Effect of NS‐21, an Anticholinergic Drug with Calcium Antagonistic Activity, on Lower Urinary Tract Function in a Rat Model of Urinary Frequency

Sasaki, Yasuo; Hamada, Kozo; Yamazaki, Chiemi; Seto, Toshie; Kimura, Yutaka; Ukai, Yojiro; Yoshikuni, Yoshiaki; Kimura, Kiyoshi

doi:10.1111/j.1442-2042.1997.tb00215.x

Cited by 14 publications

(8 citation statements)

References 12 publications

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“…In this study, DEOB and oxybutynin did not affect the frequency of rhythmic urinary bladder contraction. Sasaki et al (23) reported no effect of oxybutynin on the bladder capacity in both sham-operated and nerve-transected rats. The reason for the difference in efficacy is not clear.…”

Section: Discussionmentioning

confidence: 99%

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Effects of 4-Ethylamino-2-butynyl(2-cyclohexyl-2-phenyl)glycolate Hydrochloride, a Metabolite of Oxybutynin, on Bladder Specimens and Rhythmic Bladder Contraction in Rats in Comparison With Oxybutynin

et al. 2004

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Abstract. Oxybutynin has been used for neurogenic bladder disorders and is known to have anti-cholinergic and antispasmodic properties. However, the anti-cholinergic and antispasmodic properties of 4-ethylamino-2-butynyl(2-cyclohexyl-2-phenyl)glycolate hydrochloride (N-desethyloxybutynin: DEOB), a metabolite of oxybutynin, have not been clarified. Therefore, in the present study, we studied these properties by using rat urinary bladder specimens in comparison with oxybutynin. Moreover, the effect of DEOB on rhythmic urinary bladder contraction was also evaluated using anesthetized rats. DEOB and oxybutynin concentration-dependently inhibited the carbachol-induced contraction, the pA 2 values being 7.19 and 7.11, respectively. DEOB and oxybutynin also concentration-dependently inhibited the 100 mM KCl-induced contraction, the ED 50 values being 12.1 and 10.4 mM, respectively. Intravenously administered DEOB and oxybutynin dose-dependently (0.03 -0.3 mg / kg) inhibited the amplitude of the rhythmic bladder contraction to similar degrees, but had no affect on the frequency. From the above results, it was determined that DEOB has anti-cholinergic and antispasmodic properties and that these activities were almost equal to those of oxybutynin. Therefore, DEOB may play an important role during oxybutynin therapy for neurogenic bladder disorder.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, Sasaki et al (23) reported that oxybutynin decreased the micturition pressure in both sham-operated and nervetransected rats without increasing the bladder capacity. Moreover, Guarneri et al (24,25) found the decrease of micturition pressure without effect on bladder capacity.…”

Section: Discussionmentioning

confidence: 99%

Effects of 4-Ethylamino-2-butynyl(2-cyclohexyl-2-phenyl)glycolate Hydrochloride, a Metabolite of Oxybutynin, on Bladder Specimens and Rhythmic Bladder Contraction in Rats in Comparison With Oxybutynin

et al. 2004

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“…In addition, in healthy subjects, tolterodine increased the bladder volume, evoking the normal desire to void (Stahl et al, 1995). In contrast, many studies in rats, the most frequently used preclinical species, failed to show an increase in bladder capacity with antimuscarinics (Sasaki et al, 1997;Angelico et al, 2005;Nagabukuro et al, 2010) or showed a bladder capacity increase only at the high doses (Ohtake et al, 2007;Hegde et al, 2009). Despite this paradox, these studies successfully demonstrated the inhibitory effects of antimuscarinics on detrusor contractility by demonstrating a significant decrease in the maximal micturition pressure and a significant increase in the residual urine volume.…”

Section: Introductionmentioning

confidence: 99%

“…Two other studies also showed a bladder capacity increase with atropine in either conscious or anesthetized rhesus monkeys (Craggs and Stephenson, 1985;Shoukry and Ghoniem, 1992). In contrast, many studies using either normal healthy or diseased rodent models did not show any bladder capacity increase with antimuscarinics or showed an increase only at the high doses (Sasaki et al, 1997;Angelico et al, 2005;Ohtake et al, 2007;Hegde et al, 2009;Nagabukuro et al, 2010), which were much higher than therapeutic doses. Only in certain disease models, such as cerebral infarction, did antimuscarinics, including tolterodine and solifenacin, increase bladder capacity at reasonable doses from clinical use of these drugs (Suzuki et al, 2005).…”

mentioning

confidence: 96%

Comparative Analysis of the Effects of Antimuscarinic Agents on Bladder Functions in Both Nonhuman Primates and Rodents

Nagabukuro¹,

Villa²,

Wickham³

et al. 2011

J Pharmacol Exp Ther

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Both the physiological role of muscarinic receptors for bladder function and the therapeutic efficacy of antimuscarinic agents for overactive bladder syndrome are well documented. We investigated the effect of antimuscarinic agents with different subtype selectivity on urodynamic parameters in nonhuman primates and rodents and compared plasma levels of these agents between species. Anesthetized rhesus monkeys were transurethrally catheterized, and the bladder was infused with saline. Urodynamic parameters were measured before and after intravenous drug administration. Tolterodine (nonselective) and oxybutynin (moderately M 3 -selective) increased bladder capacity at lower doses than those required to decrease micturition pressure. However, higher doses of darifenacin (M 3 -selective) were needed to increase the bladder capacity than those needed to decrease the micturition pressure. In rats, tolterodine had no effect on the bladder capacity but decreased the micturition pressure at all of the doses administered. Oxybutynin also decreased micturition pressure and increased bladder capacity at the highest dose. Plasma levels of these drugs overlap in both species. These results suggest that, in addition to the M 3 receptor, other muscarinic receptor subtypes contribute to regulate bladder storage function in nonhuman primates, since less subtype-selective tolterodine and oxybutynin showed higher specificity to the bladder capacity effect than the effect on micturition pressure compared with M 3 -selective darifenacin. In addition, the role of muscarinic receptors in bladder storage function varies between primates and rodents. Compared with rodents, muscarinic receptors may play a more active role during the storage phase to regulate the functional bladder capacity in primates.

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“…antimuscarinic actions, are useful for treatment of bladder overactivity (Anderson, 1988;Wein, 1995). New drugs with both calcium antagonistic and antimuscarinic effects and favourable side effect profiles (Sasaki et al 1997;Homma et al 1997) may find a place in therapy.…”

Section: Calcium Channelsmentioning

confidence: 99%

Advances in the pharmacological control of the bladder

Andersson

1999

Experimental Physiology

120

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Effect of NS‐21, an Anticholinergic Drug with Calcium Antagonistic Activity, on Lower Urinary Tract Function in a Rat Model of Urinary Frequency

Abstract: 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-

Cited by 14 publications

References 12 publications

Effects of 4-Ethylamino-2-butynyl(2-cyclohexyl-2-phenyl)glycolate Hydrochloride, a Metabolite of Oxybutynin, on Bladder Specimens and Rhythmic Bladder Contraction in Rats in Comparison With Oxybutynin

Effects of 4-Ethylamino-2-butynyl(2-cyclohexyl-2-phenyl)glycolate Hydrochloride, a Metabolite of Oxybutynin, on Bladder Specimens and Rhythmic Bladder Contraction in Rats in Comparison With Oxybutynin

Comparative Analysis of the Effects of Antimuscarinic Agents on Bladder Functions in Both Nonhuman Primates and Rodents

Advances in the pharmacological control of the bladder

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