| Bladder selectivity of the novel β₃-agonist ritobegron (KUC-7483) explored by in vitro and in vivo studies in the rat. | |
| | |
MedLine Citation:
|
PMID: 22552730 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
We performed in vitro and in vivo experiments to evaluate the pharmacological profile of ritobegron and its effects on the bladder in rats. β(3)-AR selectivity was assessed using CHO cells expressing various subtypes of the human β-adrenoceptor (AR). Effects on isolated organs were evaluated using the organ-bath method. Effects on intravesical pressure, heart rate, and mean blood pressure were evaluated in urethane-anesthetized rats. Ritobegron increased cAMP accumulation in a concentration-dependent manner in CHO cells expressing any one of three human β-AR, its selectivity for β(3)-AR being 301-fold and 32-fold higher versus β(1)-AR and β(2)-AR, respectively. Ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC(50), 7.7 × 10(-8) mol/L; maximal relaxation, 97.0 %), and the β(3)-AR antagonist SR58894A produced a parallel rightward-shift of this concentration-response curve without altering the maximal response [pK(B) value, 6.43]. Ritobegron concentration-dependently increased atrial rate and decreased myometrial contractions in vitro, and its selectivity for the bladder was 2,078-fold higher versus the atria and 14-fold higher versus the uterus. In vivo, ritobegron induced a dose-dependent decrease in intravesical pressure (ED(50) 0.4 mg/kg), without affecting heart rate and only slightly lowering mean blood pressure. Thus, ritobegron displayed potent and selective β(3)-AR agonistic activity toward transfected human β-AR and exhibited a high selectivity for the bladder versus other organs in rats. Moreover, it decreased intravesical pressure with minimal effects on the cardiovascular system in anesthetized rats. These results suggest that ritobegron shows promise as a potential agent for the treatment of overactive bladder. |
| | |
Authors:
|
Itaru Maruyama; Yoshiaki Goi; Satoshi Tatemichi; Kazuyasu Maruyama; Yuji Hoyano; Yoshinobu Yamazaki; Hiroshi Kusama |
Publication Detail:
|
Type: In Vitro; Journal Article Date: 2012-05-03 |
Journal Detail:
|
Title: Naunyn-Schmiedeberg's archives of pharmacology Volume: 385 ISSN: 1432-1912 ISO Abbreviation: Naunyn Schmiedebergs Arch. Pharmacol. Publication Date: 2012 Aug |
Date Detail:
|
Created Date: 2012-07-16 Completed Date: 2012-11-26 Revised Date: 2012-12-21 |
Medline Journal Info:
|
Nlm Unique ID: 0326264 Medline TA: Naunyn Schmiedebergs Arch Pharmacol Country: Germany |
Other Details:
|
Languages: eng Pagination: 845-52 Citation Subset: IM |
Affiliation:
|
Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., Nagano, Japan. itaru_maruyama@pharm.kissei.co.jp |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Acetates
/
pharmacology* Adrenergic beta-3 Receptor Agonists / pharmacology* Adrenergic beta-3 Receptor Antagonists / pharmacology Adrenergic beta-Agonists / pharmacology Animals CHO Cells Cricetinae Cricetulus Cyclic AMP / metabolism Female Forskolin / pharmacology Heart Rate / drug effects Humans Isoproterenol / pharmacology Male Muscle Relaxation / drug effects Organ Specificity Rats Rats, Sprague-Dawley Substrate Specificity Urinary Bladder / drug effects* Urinary Bladder, Overactive / drug therapy p-Hydroxyamphetamine / analogs & derivatives*, pharmacology |
| Chemical | |
Reg. No./Substance:
|
0/Acetates; 0/Adrenergic beta-3 Receptor Agonists; 0/Adrenergic beta-3 Receptor Antagonists; 0/Adrenergic beta-Agonists; 0/ritobegron ethyl; 103-86-6/p-Hydroxyamphetamine; 60-92-4/Cyclic AMP; 66428-89-5/Forskolin; 7683-59-2/Isoproterenol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Antioxidant treatment protects against matrix metalloproteinase activation and cardiomyocyte injury ...
Next Document: Impairment of adenylyl cyclase 2 function and expression in hypoxanthine phosphoribosyltransferase-d...