Effects of beta(3)-adrenoceptor stimulation on prostaglandin E(2)-induced bladder hyperactivity and on the cardiovascular system in conscious rats.
OBJECTIVE
To investigate the effects of selective beta(2)- and selective beta(3)-adrenoceptor (AR) agonists on prostaglandin (PG) E(2)-induced bladder hyperactivity in conscious free-moving rats.


METHODS
Female Sprague-Dawley rats were anesthetized for implantation of bladder, intravenous, and intra-arterial catheters. The effects of a beta(3)-AR agonist (CL316,243) on cystometric and cardiovascular parameters were assessed in conscious rats. Intravesical instillation of PGE(2) (20-60 microM, 6 mL/hr) in conscious rats produced a concentration-dependent increase in voiding frequency.


RESULTS
In this model i.v. CL316,243 (beta(3)-AR agonist) reduced basal bladder pressure, increased micturition volume, and prolonged micturition interval in a dose-dependent manner, without affecting threshold pressure or micturition pressure. On the other hand, i.v. procaterol (beta(2)-AR agonist) did not counteract the bladder hyperactivity. Atropine (muscarinic antagonist) reduced micturition pressure and micturition volume, and shortened micturition interval. CL316,243 slightly decreased mean blood pressure and increased heart rate only when given at high doses (10 and 100 microg/kg, i.v.). In contrast, procaterol caused a significant decrease in mean blood pressure and a significant increase in heart rate. Atropine significantly increased heart rate.


CONCLUSIONS
The present results clearly demonstrated that the beta(3)-AR agonist prolonged the micturition interval without producing significant cardiovascular side effects. The human detrusor, like the rat detrusor, relaxes on beta(3)-AR stimulation. Provided that these results are valid in humans, selective beta(3)-AR agonists might be clinically useful for controlling a certain type of bladder overactivity.
Takeda
Hiroo
H
Division of Discovery Research, Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., Hotaka, Japan. hiroo.takeda@pharm.kissei.co.jp
Yamazaki
Yoshinobu
Y
Igawa
Yasuhiko
Y
Kaidoh
Kouichi
K
Akahane
Satoshi
S
Miyata
Hiroshi
H
Nishizawa
Osamu
O
Akahane
Masuo
M
Andersson
Karl-Erik
KE
D058666:Adrenergic beta-2 Receptor Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002406:Catheterization, Peripheral; D015232:Dinoprostone / Q000502:physiology*; D004149:Dioxoles / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000494:pharmacology; D011312:Pressure; D017265:Procaterol / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D022702:Receptors, Adrenergic, beta-3 / Q000502:physiology*; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D014546:Urinary Catheterization
D058666:Adrenergic beta-2 Receptor Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D004149:Dioxoles; D018727:Muscarinic Antagonists; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D001285:Atropine; D015232:Dinoprostone; D017265:Procaterol