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Pharmacological characterization of the in vitro and in vivo effects of the phosphodiesterase type 9 inhibitor bay 73-6691 in mouse corpus cavernosum

Grant number: 07/06643-0
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): December 01, 2007
Effective date (End): November 30, 2008
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Edson Antunes
Grantee:Marlon Nascimento Pereira
Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Nitrergic nerves and sinusoidal endothelial cells represent important sources of nitric oxide (NO) in the penis. Upon NO release, the cavernosal smooth muscle relaxes due to increases in intracellular cGMP. The levels of cGMP are controlled by both its rate of synthesis caused by stimulation of soluble guanylyl cyclase and its degradation by phosphodiesterases (PDEs). Alterations in NO-cGMP signaling result in erectile dysfunction, which has been lately treated by oral administration of PDE5 inhibitors, such as sildenafil, vardenafil and tadalafil. However, in some circumstances that include endothelial dysfunction or neuropathies that affect the erectile function, the use of PDE5 inhibitors causes only moderate therapeutic effects, as a complete and satisfactory response is not obtained in all patients. Therefore, we aimed to investigate in the present project the role of PDE9 in the regulation of cavernosal smooth muscle tone as well as in the responses mediated by NO in this tissue. These effects will be studied using the selective PDE9 inhibitor BAY 73-6691 (1-(2-chlorophenyl)-6-[(2R)-3,3,3-trifluor-2-methylpropyl]-1,5-dihydro-4H-pyrazol[3,4-d]pyrimidin-4-one), which will be assayed in mouse corpus cavernosum in vitro, using organ bath techniques, therefore allowing the study of contractile and relaxant properties of this preparation, as well as in in vivo experiments, in which erectile responses are induced in anesthetizes animals through either the stimulation of the cavernous nerve located in the dorsolateral aspect of the prostate or following intracavernosal administration of vasoactive agents. In addition, the effects of BAY 73-6691 on intracellular cGMP levels will be evaluated in corpus cavernosum segments in the absence and in the presence of NO donors. The therapeutic potential of this inhibitor may include the management of erectile dysfunction in patients who do not present adequate responses following treatment with PDE5 inhibitors.