Soluble Guanylate Cyclase Modulators, BAY 41-2272 and BAY 60-2770, Inhibit Human and Rabbit Prostate Contractility

Author(s)

Calmasini, Fabiano B. ; Alexandre, Eduardo C. ; Silva, Fabio Henrique ; De Nucci, Gilberto ; Antunes, Edson ; D'Ancona, Carlos A. ; Monica, Fabiola Z.

• Document type: Journal article
• Source: UROLOGY; v. 94, p. 312-U392, AUG 2016.
• Web of Science Citations: 3

Abstract

OBJECTIVE To evaluate the inhibitory effect of soluble guanylate cyclase (sGC) stimulator, BAY 41-2272 (5-cyclopropyl-2-{[}1-(2-fluorobenzyl)-1H-pyrazolo{[}3,4-b] pyridine-3-yl] pyrimidin-4-ylamine) or activator, BAY 60-2770 (4-([(4-carboxybutyl) {[} 2-(5-fluoro-2-[{[} 40-(trifluoromethyl) biphenyl-4-yl] methoxy] phenyl) ethyl] amino] methyl) benzoic acid), in human and rabbit prostate smooth muscle contractility. MATERIALS AND METHODS In rabbit or human prostate, contractions induced by electrical field stimulation or phenylephrine (PE) were carried out in the presence of sGC stimulator, BAY 41-2272, or sGC activator, BAY 60-2770. The potency (pEC(50)) and maximal response (E-max) values were determined. Immunohistochemistry analysis for sGC alpha 1-subunit and quantification of intracellular levels of cyclic guanosine monophosphate (cGMP) were also performed. RESULTS In rabbit prostate, BAY 60-2770 (30 and 300 nM) inhibited the contractions induced by PE and electrical field stimulation. The coincubation with sGC inhibitor, ODQ, produced greater inhibitions on PE-induced contractions in comparison with BAY 60-2770 alone, mainly due to greater cGMP accumulation (70-and 5.7-fold, respectively). BAY 41-2272 (300 nM) increased and decreased, respectively, cGMP levels and PE-induced contractions, but in the presence of ODQ these effects were reversed. In human prostate, immunohistochemistry analysis revealed the presence of sGC a1-subunit on the transition zone. BAY 60-2770 (300 nM) reduced significantly Emax induced by PE in human prostate. CONCLUSION sGC activator seems to be a promising alternative to treat benign prostatic hyperplasia because it increases cGMP levels even when sGC is oxidized. (C) 2016 Elsevier Inc. (AU)

• FAPESP's process: 14/02195-6 - Functional and molecular alterations of prostatic smooth muscle by aging in rats: role of oxidation and degradation of soluble guanylyl ciclase
• Grantee: Fabiano Beraldi Calmasini
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/13907-4 - Evaluation of the effects of opiates agonists in isolated corpus cavernosum from rabbit and rat: does opiate system have role on erectile function?
• Grantee: Gilberto de Nucci
• Support Opportunities: Regular Research Grants