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.

Iizuka, Hiroyuki; Osaka, Yoko; Kondo, Shun; Morita, Takashi

doi:10.1540/jsmr.34.139

Cited by 10 publications

(3 citation statements)

References 19 publications

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“…Limited data are available, but the effective concentration (EC 50 ) for clenbuterol was lower for humans and other higher mammals than for rodents. For example, the EC 50 for clenbuterol for the relaxation of rat smooth muscle was ~10‐fold higher than the EC 50 for equine or human smooth muscle (26–28). Moreover, the standard dosages of clenbuterol used clinically have increased muscle strength or increased muscle mass in several studies.…”

Section: Discussionmentioning

confidence: 95%

Adjunctive β ₂ ‐agonist treatment reduces glycogen independently of receptor‐mediated acid α‐glucosidase uptake in the limb muscles of mice with Pompe disease

Farah

Madden²,

et al. 2014

FASEB j.

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Enzyme or gene replacement therapy with acid α-glucosidase (GAA) has achieved only partial efficacy in Pompe disease. We evaluated the effect of adjunctive clenbuterol treatment on cation-independent mannose-6-phosphate receptor (CI-MPR)-mediated uptake and intracellular trafficking of GAA during muscle-specific GAA expression with an adeno-associated virus (AAV) vector in GAA-knockout (KO) mice. Clenbuterol, which increases expression of CI-MPR in muscle, was administered with the AAV vector. This combination therapy increased latency during rotarod and wirehang testing at 12 wk, in comparison with vector alone. The mean urinary glucose tetrasaccharide (Glc4), a urinary biomarker, was lower in GAA-KO mice following combination therapy, compared with vector alone. Similarly, glycogen content was lower in cardiac and skeletal muscle following 12 wk of combination therapy in heart, quadriceps, diaphragm, and soleus, compared with vector alone. These data suggested that clenbuterol treatment enhanced trafficking of GAA to lysosomes, given that GAA was expressed within myofibers. The integral role of CI-MPR was demonstrated by the lack of effectiveness from clenbuterol in GAA-KO mice that lacked CI-MPR in muscle, where it failed to reverse the high glycogen content of the heart and diaphragm or impaired wirehang performance. However, the glycogen content of skeletal muscle was reduced by the addition of clenbuterol in the absence of CI-MPR, as was lysosomal vacuolation, which correlated with increased AKT signaling. In summary, β2-agonist treatment enhanced CI-MPR-mediated uptake and trafficking of GAA in mice with Pompe disease, and a similarly enhanced benefit might be expected in other lysosomal storage disorders.

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Section: Discussionmentioning

confidence: 95%

Adjunctive β ₂ ‐agonist treatment reduces glycogen independently of receptor‐mediated acid α‐glucosidase uptake in the limb muscles of mice with Pompe disease

Farah

Madden²,

et al. 2014

FASEB j.

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show abstract

“…Limited data are available, but the effective concentration (EC 50 ) for clenbuterol was lower for humans and other higher mammals than for rodents. For example, the EC 50 for clenbuterol with regard to the relaxation of rat smooth muscle was ~10‐fold higher than the EC 50 for equine or human smooth muscle (39–41). Furthermore, the EC 50 in horses and humans were similar to the EC 50 , when clenbuterol was dosed as a bronchodilator (40, 42).…”

Section: Discussionmentioning

confidence: 96%

Adjunctive β2‐agonists reverse neuromuscular involvement in murine Pompe disease

Sun

Nilsson

et al. 2012

FASEB j.

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Pompe disease has resisted enzyme replacement therapy with acid α-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated β2-agonist drugs, which increased CI-MPR expression in GAA knockout (KO) mice. Clenbuterol along with a low-dose adeno-associated virus vector increased Rotarod latency by 75% at 4 wk, in comparison with vector alone (P<2×10(-5)). Glycogen content was lower in skeletal muscles, including soleus (P<0.01), extensor digitorum longus (EDL; P<0.001), and tibialis anterior (P<0.05) following combination therapy, in comparison with vector alone. Glycogen remained elevated in the muscles following clenbuterol alone, indicating an adjunctive effect with gene therapy. Elderly GAA-KO mice treated with combination therapy demonstrated 2-fold increased wirehang latency, in comparison with vector or clenbuterol alone (P<0.001). The glycogen content of skeletal muscle decreased following combination therapy in elderly mice (P<0.05). Finally, CI-MPR-KO/GAA-KO mice did not respond to combination therapy, indicating that clenbuterol's effect depended on CI-MPR expression. In summary, adjunctive β2-agonist treatment increased CI-MPR expression and enhanced efficacy from gene therapy in Pompe disease, which has implications for other lysosomal storage disorders that involve primarily the brain.

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“…There are no reports on the β 3 -AR agonist's stereochemistry of the two vicinal chiral carbons involved in the β 3 -AR agonistic activity except for the study of ephedrine isomers, which are not selective β 3 -AR agonists. Most of the β 3 -AR agonists do not possess vicinal chiral carbons atoms but are constructed with separated asymmetrical carbon atoms that are connected by the aminomethylene group. − Some reports have examined the agonistic activity of the four isomers on β-ARs. , Our previous investigation of (α S ,β R )-4‘-hydroxynorephedrine-structured β 3 -AR agonists was based on the evidence that β 2 -AR agonistic activity was enhanced on the (α S ,β R )-configuration . First, it was necessary to define whether the (α S ,β R )-configuration was important in determining β 3 -AR agonistic activity.…”

Section: Introductionmentioning

confidence: 99%

Relationship between Stereochemistry and the β₃-Adrenoceptor Agonistic Activity of 4‘-Hydroxynorephedrine Derivative as an Agent for Treatment of Frequent Urination and Urinary Incontinence

et al. 2002

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This report proposes a beta(3)-adrenoceptor (AR) selective agonist, 2-[2-chloro-4-(2-([(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino)ethyl)phenoxy]acetic acid (1a), as a novel agent for treating urinary bladder dysfunction. This compound and its relatives have a unique feature among beta(3)-AR agonists: two chiral carbons are adjacently structured on the left side of the molecule. To study the relationship between the stereoconfiguration of the vicinal chiral carbons in 1a and beta-AR agonistic activity, the four stereoisomers were synthesized via oxazolidinone prepared by intracyclization involving inversion of the beta-hydroxy group. The in vitro assays using rat atria for beta(1)-AR, rat uteri for beta(2)-AR, and ferret detrusor for beta(3)-AR showed that 1a possessed potent beta(3)-AR agonistic activity (EC(50) = 3.85 nM) and 3700- and 1700-fold selectivity for beta(3)-AR relative to beta(1)- and beta(2)-AR, respectively. Comparison of the four isomers revealed that the (alphaS,betaR)-compound (1a) was not only the most potent agonist but was also the most selective for beta(3)-AR. In the anesthetized rat, intravenous administration of 1a brought about a sufficient decrement of the intrabladder pressure (ED(50) = 12 microg/kg), and intraduodenal administration of 2a, which is the ethyl ester of 1a, led to same result (ED(50) = 0.65 mg/kg). Moreover, no effects on the cardiovascular system were observed in either test.

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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.

Cited by 10 publications

References 19 publications

Adjunctive β ₂ ‐agonist treatment reduces glycogen independently of receptor‐mediated acid α‐glucosidase uptake in the limb muscles of mice with Pompe disease

Adjunctive β ₂ ‐agonist treatment reduces glycogen independently of receptor‐mediated acid α‐glucosidase uptake in the limb muscles of mice with Pompe disease

Adjunctive β2‐agonists reverse neuromuscular involvement in murine Pompe disease

Relationship between Stereochemistry and the β₃-Adrenoceptor Agonistic Activity of 4‘-Hydroxynorephedrine Derivative as an Agent for Treatment of Frequent Urination and Urinary Incontinence

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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.

Cited by 10 publications

References 19 publications

Adjunctive β 2 ‐agonist treatment reduces glycogen independently of receptor‐mediated acid α‐glucosidase uptake in the limb muscles of mice with Pompe disease

Adjunctive β 2 ‐agonist treatment reduces glycogen independently of receptor‐mediated acid α‐glucosidase uptake in the limb muscles of mice with Pompe disease

Adjunctive β2‐agonists reverse neuromuscular involvement in murine Pompe disease

Relationship between Stereochemistry and the β3-Adrenoceptor Agonistic Activity of 4‘-Hydroxynorephedrine Derivative as an Agent for Treatment of Frequent Urination and Urinary Incontinence

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Adjunctive β ₂ ‐agonist treatment reduces glycogen independently of receptor‐mediated acid α‐glucosidase uptake in the limb muscles of mice with Pompe disease

Adjunctive β ₂ ‐agonist treatment reduces glycogen independently of receptor‐mediated acid α‐glucosidase uptake in the limb muscles of mice with Pompe disease

Relationship between Stereochemistry and the β₃-Adrenoceptor Agonistic Activity of 4‘-Hydroxynorephedrine Derivative as an Agent for Treatment of Frequent Urination and Urinary Incontinence