β-Adrenergic receptor subtype expression in myocyte and non-myocyte cells in human female bladder.
β(3)-Adrenergic receptor agonists are currently under clinical development for the treatment of overactive bladder, a condition that is prevalent in postmenopausal women. These agents purportedly relax bladder smooth muscle through a direct action at the myocyte β(3)-receptor. The aim of this study was to examine the expression of the individual beta-adrenergic receptors in full thickness sections from ageing human female bladder. We obtained a series of rabbit polyclonal antibodies generated against each of the three β-adrenergic receptors, and validated their receptor specificity in CHOK1 cells expressing each of the individual receptors. Immunostaining for β(1), β(2), and β(3) were each more prominent in the urothelium than in the detrusor, with all receptors expressed in the same cell types, indicating co-expression of all three receptors throughout the urothelium in addition to the detrusor. Staining of all receptors was also observed in suburothelial myofibroblast-like cells, intramural ganglion cells, and in Schwann cells of intramural nerves. The β(3)-receptor in the human urothelium appears to be functional, as two different selective β(3)-receptor agonists, TAK677 and BRL37344, stimulate cAMP formation in URO tsa cells. Densitometry analysis indicates a persistent expression of all receptors throughout the bladder with increasing age, with the exception of the β(2)-receptor in the urothelium of the trigone, which appears to decrease slightly in older women. These data indicate that β(3)-receptor expression is maintained with age, but may function in concert with other β-receptors. Activation of the myocyte receptor may be influenced by action on non-myocyte structures including the intramural ganglion cells and myofibroblasts.
Women's Health New Business Development, Procter & Gamble Pharmaceuticals now Warner Chilcott Pharmaceuticals Inc., Mason, OH, USA. limberg.bj@pg.com
Brian J
BJ
Limberg
Karl-Erik
KE
Andersson
F
F
Aura Kullmann
Glenna
G
Burmer
William C
WC
de Groat
Jan S
JS
Rosenbaum
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology; D005260:Female; D006801:Humans; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism*; D001743:Urinary Bladder / Q000166:cytology / Q000378:metabolism*; D019459:Urothelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D011943:Receptors, Adrenergic, beta; C057368:BRL 37344; D000242:Cyclic AMP