RELAXANT EFFECTS OF ISOPROTERENOL AND SELECTIVE Β3-Adrenoceptor AGONISTS ON NORMAL, LOW COMPLIANT AND HYPERREFLEXIC HUMAN BLADDERS

Igawa, Yasuhiko; Yamazaki, Yoshinobu; Takeda, Hiroo; Kaidoh, Kouichi; Akahane, Masuo; Ajisawa, Yukiyoshi; Yoneyama, T; Nishizawa, Osamu; Andersson, Karl‐Erik

doi:10.1097/00005392-200101000-00071

Cited by 98 publications

(72 citation statements)

References 16 publications

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“…Moreover, CL316,243 displayed evidence of partial agonistic activity, with the maximum relaxing effect even at the highest concentration being only 73.9%. These results are consistent with previous reports that classic selective ␤ 3 -AR agonists, such as CL316,243 and BRL37344, exhibit partial agonistic activities in both the monkey and human bladder at the same concentration as the maximal concentration used in this study (1 ϫ 10 Ϫ4 M) (Igawa et al, 1999(Igawa et al, , 2001Takeda et al, 2002a). The above results suggest that in humans ritobegron might produce sufficient bladder relaxation and be more potent than classic ␤ 3 -AR agonists.…”

Section: Discussionsupporting

confidence: 93%

Effects of Ritobegron (KUC-7483), a Novel Selective β₃-Adrenoceptor Agonist, on Bladder Function in Cynomolgus Monkey

Maruyama¹,

Tatemichi²,

Goi³

et al. 2012

J Pharmacol Exp Ther

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We evaluated the pharmacological profile of ritobegron [KUC-7483; (Ϫ)-ethyl 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)-2,5-dimethylphenyloxy]acetate monohydrochloride] and its effects on the bladder in cynomolgus monkeys by in vitro and in vivo experiments. In vitro, ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC 50 8.2 Ϯ 2.3 ϫ 10 Ϫ7 M; maximal relaxation 88.7 Ϯ 3.7%). The ␤ 3 -adrenoceptor (AR) antagonist 3-(2-allylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol hydrochloride (SR58894A) produced a rightward shift of this concentration-response curve without altering the maximal response (pK B value 6.56 Ϯ 0.35). In isolated atria, ritobegron increased the atrial rate only at high concentrations (EC 50 6.5 Ϯ 1.2 ϫ 10 Ϫ5 M). Ritobegron had no effect on tracheal contraction at concentrations from 10 Ϫ9 to 10 Ϫ4 M, and even at the highest concentration tested, 10 Ϫ3 M, the maximal relaxation it induced was only 26.7 Ϯ 8.1%. Tests of the selectivity of ritobegron for the bladder gave values of 79.3-and 1200-fold higher versus atria and trachea, respectively. In the in vivo study ritobegron significantly decreased intravesical pressure (ED 50 1.44 mg/kg) without affecting either mean blood pressure or heart rate. In conclusion, ritobegron displayed potent and selective ␤ 3 -AR agonistic activity and relaxed the monkey isolated bladder, and in vivo it decreased intravesical pressure without affecting cardiovascular parameters. These results suggest that ritobegron may be a promising potential agent for the treatment of overactive bladder.

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Section: Discussionsupporting

confidence: 93%

Effects of Ritobegron (KUC-7483), a Novel Selective β₃-Adrenoceptor Agonist, on Bladder Function in Cynomolgus Monkey

Maruyama¹,

Tatemichi²,

Goi³

et al. 2012

J Pharmacol Exp Ther

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“…CL 316,243 appears to be a rodent-selective agonist, as its potency to stimulate cAMP formation in transfected CHO cells was much higher at the mouse than at the human β 3 -adrenoceptor (pEC 50 8.7 vs. 4.3) (Hutchinson et al 2006). CL 316,243 has repeatedly been used in studies on the rat (Kaidoh et al 2002;Takeda et al 2000Takeda et al , 2002bTakeda et al , 2003Woods et al 2001) and human urinary bladder (Igawa et al 1999(Igawa et al , 2001) and also in the ureter (Murakami et al 2000;Park et al 2000), esophagus (Sarma et al 2003), colon (Kaumann and Molenaar 1996) and blood vessels (Atef et al 1996;Kuratani et al 1994;Leblais et al 2005). In line with the above differences in potency between mouse and human receptors, it also exhibited a consistently higher potency at rat compared with human tissues.…”

Section: Adrenaline and Noradrenalinementioning

confidence: 99%

Tools to study β3-adrenoceptors

Vrydag

Michel

2007

Naunyn-Schmied Arch Pharmacol

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β 3 -adrenoceptors mediate some of the effects of catecholamines on tissues such as blood vessels or the urinary bladder and are putative targets for the treatment of diseases such as the overactive bladder syndrome. Progress in the understanding of the presence, function, and regulation of β 3 -adrenoceptors has been hampered by a lack of highly specific tools. "Classical" is not selective for β 3 -adrenoceptors, at least in humans, and may actually be a partial agonist. Radioligands, which are suitable either for the selective labeling of β 3 -adrenoceptors or for the nonselective labeling of all β-adrenoceptor subtypes, are also missing. β 3 -and β 1 /β 2 double knockout mice have been reported, but their usefulness for extrapolations in humans is questionable based upon major differences between humans and rodents with regard to the ligand recognition and expression profiles of β 3 -adrenoceptors. While the common availability of more selective agonists and antagonists at the β 3 -adrenoceptor is urgently awaited, the limitations of the currently available tools need to be considered in studies of β 3 -adrenoceptor for the time being.

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“…The three defined -AR subtypes ( 1 , 2 , and 3 ) have been identified in the detrusor of most species [Michel and Vrydag, 2006;Andersson and Arner, 2004]. Also the human urothelium contains all three receptor subtypes [Otsuka et al 2008], but in both detrusor and urothelium there is a predominant expression of 3 -AR mRNA [Michel and Vrydag, 2006;Nomiya and Yamaguchi, 2003] and there is convincing evidence from both normal and neurogenic bladders that these receptors are functionally active [Leon et al 2008;Badawi et al 2007;Biers et al 2006;Michel and Vrydag, 2006;Igawa et al 2001;Morita et al 2000;Fujumura et al 1999;Igawa et al 1999;Takeda et al 1999]. The human detrusor also contains 2 -ARs, and most probably both receptor subtypes are involved in the physiological effects (relaxation) of noradrenaline in this structure [Michel and Vrydag, 2006;Andersson and Arner 2004].…”

Section: Introductionmentioning

confidence: 99%

Prospective pharmacologic therapies for the overactive bladder

Andersson

2009

Therapeutic Advances in Urology

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Lower urinary tract symptoms (LUTS), overactive bladder syndrome (OAB) and detrusor overactivity (DO) are all conditions that can have major effects on quality of life and social functioning. Antimuscarinic drugs are first-line treatment-they often have good initial response rates, but adverse effects and decreasing efficacy cause long-term compliance problems, and alternatives are needed. The recognition of the functional contribution of the urothelium, the spontaneous myocyte activity during bladder filling, and the diversity of nerve transmitters has sparked interest in both peripheral and central modulation of LUTS/OAB/DO pathophysiology. There may be several new possibilities to treat LUTS/OAB/DO. 3 -AR agonists (YM178), PDE 5 inhibitors (sildenafil, tadalafil, vardenafil), vitamin D analogs (elocalcitol), combinations ( 1 -AR antagonist þ antimuscarinic), and drugs with a central mode of action (tramadol, aprepitant) all have Randomized controlled trial (RCT) documented efficacy. Which of these therapeutic principles will be developed to clinically useful treatments remains to be established.

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RELAXANT EFFECTS OF ISOPROTERENOL AND SELECTIVE Β3-Adrenoceptor AGONISTS ON NORMAL, LOW COMPLIANT AND HYPERREFLEXIC HUMAN BLADDERS

Cited by 98 publications

References 16 publications

Effects of Ritobegron (KUC-7483), a Novel Selective β₃-Adrenoceptor Agonist, on Bladder Function in Cynomolgus Monkey

Effects of Ritobegron (KUC-7483), a Novel Selective β₃-Adrenoceptor Agonist, on Bladder Function in Cynomolgus Monkey

Tools to study β3-adrenoceptors

Prospective pharmacologic therapies for the overactive bladder

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RELAXANT EFFECTS OF ISOPROTERENOL AND SELECTIVE Β3-Adrenoceptor AGONISTS ON NORMAL, LOW COMPLIANT AND HYPERREFLEXIC HUMAN BLADDERS

Cited by 98 publications

References 16 publications

Effects of Ritobegron (KUC-7483), a Novel Selective β3-Adrenoceptor Agonist, on Bladder Function in Cynomolgus Monkey

Effects of Ritobegron (KUC-7483), a Novel Selective β3-Adrenoceptor Agonist, on Bladder Function in Cynomolgus Monkey

Tools to study β3-adrenoceptors

Prospective pharmacologic therapies for the overactive bladder

Contact Info

Product

Resources

About

Effects of Ritobegron (KUC-7483), a Novel Selective β₃-Adrenoceptor Agonist, on Bladder Function in Cynomolgus Monkey

Effects of Ritobegron (KUC-7483), a Novel Selective β₃-Adrenoceptor Agonist, on Bladder Function in Cynomolgus Monkey