The effects of ovarian hormones on beta-adrenergic receptor-mediated responses in female rabbit detrusor smooth muscles were investigated. Ovariectomized mature female New Zealand white rabbits were untreated or treated with estrogen and/or progesterone for 2 weeks. The contractile responses to carbachol and KCl in the detrusor strips were not significantly different in all groups. As compared with dobutamine and GS-332, isoproterenol and procaterol significantly relaxed the detrusor strips derived from all groups on KCl-induced tonic contractions. Combined with estrogen treatment, isoproterenol, procaterol and GS-332 caused a significant increase in this muscle relaxation. Furthermore, estrogen treatment caused a significant increase in relaxation as a result of forskolin and the cyclic AMP (cAMP) production that was induced by isoproterenol, procaterol and GS-332. However, estrogen treatment did not affect the relaxant response to dibutyryl cyclic AMP. Progesterone treatment did not affect beta-adrenergic receptor-mediated responses. These results suggest that estrogen treatment causes the increased relaxant responses mediated by beta2- and beta3-adrenergic receptor subtypes, which may be related to the increased cAMP content in female rabbit detrusor smooth muscles.

01 Jan 2000·Journal of Smooth Muscle Research

Function and Distribution of .BETA.3-Adrenoceptors in Rat, Rabbit and Human Urinary Bladder and External Urethral Sphincter.

Article

Author: IIZUKA, Hiroyuki ; KONDO, Shun ; IWATA, Toshinari ; MORITA, Takashi

1. Activation of beta-adrenoceptors causes relaxation of the urinary bladder and contraction of the external urethral sphincter, which consists of fast-contracting skeletal muscles. A beta2-adrenoceptor agonist, clenbuterol, recently has been developed as a therapeutic drug for the treatment of urinary incontinence, however beta2-adrenoceptor agonists have undesirable effects on cardiac and striated muscle function. 2. In this study, we compared the effects of the beta2-adrenoceptor agonist, clenbuterol and of a novel beta3-adrenoceptor agonist, GS332, on urinary bladder and external urethral sphincter function in rat, rabbit and human. We also determined the distribution of beta3-adrenoceptors in human urinary bladder and external urethral sphincter, using radioligand-binding techniques. 3. Clenbuterol induced marked relaxations in rat, rabbit and human urinary bladder smooth muscles and also induced marked contractions in rat periurethral striated muscles (external urethral sphincter), while GS332 induced marked relaxations in rat and human, but not in rabbit, urinary bladder smooth muscles and induced small contractions in rat periurethral striated muscles. 4. The radioligand binding studies showed presence of beta2- and beta3-adrenoceptors in human urinary bladder, external urethral sphincter and abdominal rectus muscles. The affinities of GS332 were the highest in urinary bladder and the lowest in the skeletal (abdominal rectus) muscles, while the affinities of clenbuterol were similar in urinary bladder, external urethral sphincter and the skeletal (abdominal rectus) muscles. 5. These results suggest that GS332 could, similarly clenbuterol, have a role in the treatment of urinary frequency and urinary incontinence.

01 Jan 1998·Journal of Smooth Muscle Research

Effect of an Atypical Adrenergic .BETA.3-Agonist, GS-332: Sodium (2R)- (3- (3- (2-(3-Chlorophenyl)-2-Hydroxyethylamino) Cyclohexyl) Phenoxy) Acetate, on Urinary Bladder Function in Rats.

Article

Author: IIZUKA, Hiroyuki ; MORITA, Takashi ; OSAKA, Yoko ; KONDO, Shun

We have developed an atypical adrenergic beta3-agonist, GS 332: Sodium (2R)-[3-[3-[2-(3 Chlorophenyl)-2-hydroxyethylamino]cyclohexyl]phenoxy]acetate, which has an unique structure compared to other beta3 agonists. In vitro study, we compared effects of GS 332 on rat urinary bladder muscle strip contractility with those of clenbuterol hydrochloride (clenbuterol), an adrenergic beta2 agonist. GS-332 relaxed isolated rat urinary bladder strips in a concentration dependent manner with 50% effective concentration (EC50) of 15.7 nM, and the relaxant activity of GS 332 was as potent as that of clenbuterol(EC50; 30.8 nM). The concentration response curve of GS 332 on isolated rat urinary bladder was competed by a specific beta3-antagonist, SR59230A in a concentration-dependent manner, in which Schild slope was 1.1 and pA2 value of SR59230A was 7.1. In vivo study, cystometory investigated in anesthetized rats demonstrated that GS 332 was more potent in increasing the urinary storage volume than clenbuterol and less potent in inhibiting the contractile force of urinary bladder at micturition reflex than clenbuterol. These data demonstrate that GS 332, a new adrenergic beta3-agonist, may be more useful to maintain continence than clenbuterol, an adrenergic beta3 adrenergic agonist.

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Indication	Highest Phase	Country/Location	Organization	Date
Urinary Incontinence	Discovery	JP	Mitsubishi Pharma Corp.	-

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