Functional and molecular biological evidence for a possible beta3-adrenoceptor in the human detrusor muscle.
The possible existence of a beta3-adrenergic receptor (beta3-AR) in the human detrusor muscle was investigated by in vitro functional studies and analysis of mRNA expression. Isoprenaline, noradrenaline and adrenaline each produced a concentration-dependent relaxation of the human detrusor. The rank order for their relaxing potencies was isoprenaline (pD2 6.37+/-0.07) > or = noradrenaline (pD2 6.07+/-0.12) > or = adrenaline (pD2 5.88< or =0.11). Neither dobutamine (beta1- and beta2-AR agonist) nor procaterol (beta2-AR agonist) produced any significant relaxation at concentrations up to 10(-5) M. BRL37344A, CL316243 and CGP-12177A (beta3-AR agonists), relaxed the preparations significantly at concentrations higher than 10(-6) M. The pD2 values for BRL37344A, CL316243 and CGP-12177A were 6.42+/-0.25, 5.53+/-0.09 and 5.74+/-0.14, respectively. CGP-20712A (10(-7) - 10(-5) M), a beta1-AR antagonist, did not affect the isoprenaline-induced relaxation. On the other hand, ICI-118,551, a beta2-AR antagonist, produced a rightward parallel shift of the concentration-relaxation curve for isoprenaline only at the highest concentration used (10(-5) > M) and its pKB value was 5.71+/-0.19. Moreover, SR58894A (10(-7) - 10(-5) M), a beta3-AR antagonist, caused a rightward shift of the concentration-relaxation curve for isoprenaline in a concentration-dependent manner. The pA2 value and slope obtained from Schild plots were 6.24+/-0.20 and 0.68+/-0.31. The beta1-, beta2- and beta3-AR mRNAs were all positively expressed in detrusor smooth muscle preparations in a reverse transcription polymerase chain reaction assay. In conclusion, the present results provide the first evidence for the existence of the beta3-AR subtype in the human detrusor. They also suggest that the relaxation induced by adrenergic stimulation of the human detrusor is mediated mainly through beta3-AR activation.
Igawa
Y
Y
Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan. yxigawa@gipac.shinshu-u.ac.jp
Yamazaki
Y
Y
Takeda
H
H
Hayakawa
K
K
Akahane
M
M
Ajisawa
Y
Y
Yoneyama
T
T
Nishizawa
O
O
Andersson
K E
KE
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005576:Colforsin / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology; D004280:Dobutamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D022702:Receptors, Adrenergic, beta-3; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000316:Adrenergic alpha-Agonists; D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004149:Dioxoles; D004983:Ethanolamines; D007093:Imidazoles; D011412:Propanolamines; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D005576:Colforsin; D004280:Dobutamine; C026777:ICI 118551; C057368:BRL 37344; C049763:CGP 20712A; D007545:Isoproterenol; C033394:CGP 12177; D009638:Norepinephrine; D004837:Epinephrine