BAY 41-2272, a soluble guanylate cyclase stimulator, relaxes isolated human ureter in a standardized in vitro model.
OBJECTIVE
To characterize the relaxation induced by BAY 41-2272 in human ureteral segments.


METHODS
Ureter specimens (n = 17) from multiple organ human deceased donors (mean age 40 ± 3.2 years, male/female ratio 2:1) were used to characterize the relaxing response of BAY 41-2272. Immunohistochemical analysis for endothelial and neuronal nitric oxide synthase, guanylate cyclase stimulator (sGC) and type 5 phosphodiesterase was also performed. The potency values were determined as the negative log of the molar to produce 50% of the maximal relaxation in potassium chloride-precontracted specimens. The unpaired Student t test was used for the comparisons.


RESULTS
Immunohistochemistry revealed the presence of endothelial nitric oxide synthase in vessel endothelia and neuronal nitric oxide synthase in urothelium and nerve structures. sGC was expressed in the smooth muscle and urothelium layer, and type 5 phosphodiesterase was present in the smooth muscle only. BAY 41-2272 (0.001-100 μM) relaxed the isolated ureter in a concentration dependent manner, with a potency and maximal relaxation value of 5.82 ± 0.14 and 84% ± 5%, respectively. The addition of nitric oxide synthase and sGC inhibitors reduced the maximal relaxation values by 21% and 45%, respectively. However, the presence of sildenafil (100 nM) significantly potentiated (6.47 ± 0.10, P <.05) this response. Neither glibenclamide or tetraethylammonium nor ureteral urothelium removal influenced the relaxation response by BAY 41-2272.


CONCLUSIONS
BAY 41-2272 relaxes the human isolated ureter in a concentration-dependent manner, mainly by activating the sGC enzyme in smooth muscle cells rather than in the urothelium, although a cyclic guanosine monophosphate-independent mechanism might have a role. The potassium channels do not seem to be involved.
Division of Urology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil. Electronic address: rmiyaoka@uol.com.br.
Ricardo
R
Miyaoka
Department of Pharmacology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Camila
C
Mendes
Department of Pharmacology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
André
A
Schenka
Department of Pharmacology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Paulo Gabriel
PG
Gonzalez
Department of Pharmacology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Gilberto
G
de Nucci
Department of Pharmacology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Edson
E
Antunes
Department of Urology, Center for Endourology and Stone Disease, Cleveland Clinic Main Campus, Cleveland, OH.
Manoj
M
Monga
Division of Urology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Carlos Arturo
CA
Levi D'Ancona
Department of Pharmacology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Fabíola Zakia
FZ
Mónica
D000328:Adult; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D014513:Ureter / Q000187:drug effects*
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D011720:Pyrazoles; D011725:Pyridines