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The Journal of Neuroscience, September 15, 2002, 22(18):8063-8070
 -Adrenoceptor Agonists Stimulate Endothelial Nitric Oxide
Synthase in Rat Urinary Bladder Urothelial Cells
Lori A.
Birder1, 2,
Michele L.
Nealen4, 5,
Susanna
Kiss1,
William C.
de Groat2,
Michael J.
Caterina4, 5,
Edward
Wang1, 3,
Gerard
Apodaca1, 3, and
Anthony J.
Kanai1, 2
Laboratory of Epithelial Cell Biology, Renal-Electrolyte Division,
Departments of 1 Medicine, 2 Pharmacology, and
3 Cell Biology, University of Pittsburgh School of
Medicine, Pittsburgh, Pennsylvania 15213, and Departments of
4 Biological Chemistry and 5 Neuroscience,
Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
We have investigated the intracellular signaling mechanisms
underlying the release of nitric oxide (NO) evoked by  -adrenoceptor (AR) agonists in urinary bladder strips and cultured bladder urothelial cells from adult rats. Reverse transcription-PCR revealed that inducible NO synthase and endothelial NOS but not neuronal NOS genes were expressed in urothelial cells. NO release from both urothelial cells and bladder strips was decreased (37-42%) in the
absence of extracellular Ca2+ (100 µM
EGTA) and was ablated after incubation with BAPTA-AM (5 µM) or caffeine (10 mM), indicating that the
NO production is mediated in part by intracellular calcium
stores. NO release was reduced (18-24%) by nifedipine (10 µM) and potentiated (29-32%) by incubation with the
Ca2+ channel opener BAYK8644 (1-10
µM). In addition, -AR-evoked NO release
(isoproterenol; dobutamine; terbutaline; 10 9 to
105 M) was blocked by the NOS
inhibitors NG-nitro-L-arginine
methyl ester (30 µM) or
NG-monomethyl-L-arginine
(50 µM), by -adrenoceptor antagonists (propranol,
1/2; atenolol, 1; ICI
118551; 2; 100 µM), or by the
calmodulin antagonist trifluoperazine (50 µM). Incubating cells with the nonhydrolyzable GTP analog GTP S (1 µM)
or the membrane-permeant cAMP analog dibutyryl-cAMP (10-100
µM) directly evoked NO release. Forskolin (10 µM) or the phosphodiesterase IBMX (50 µM)
enhanced (39-42%) agonist-evoked NO release. These results indicate
that -adrenoceptor stimulation activates the adenylate cyclase
pathway in bladder epithelial cells and initiates an increase in
intracellular Ca2+ that triggers NO production and
release. These findings are considered in light of recent reports that
urothelial cells may exhibit a number of "neuron-like" properties,
including the expression of receptors/ion channels similar to those
found in sensory neurons.
Key words:
nitric oxide; adrenergic; urothelium; urinary bladder; eNOS; iNOS
Copyright © 2002 Society for Neuroscience 0270-6474/02/22188063-08$05.00/0
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