title: Phosphodiesterase-9 (PDE9) inhibition with BAY 73-6691 increases corpus cavernosum relaxations mediated by nitric oxide-cyclic GMP pathway in mice.
abstract: Phosphodiesterase-9 (PDE9) specifically hydrolyzes cyclic GMP, and was detected in human corpus cavernosum. However, no previous studies explored the selective PDE9 inhibition with BAY 73-6691 in corpus cavernosum relaxations. Therefore, this study aimed to characterize the PDE9 mRNA expression in mice corpus cavernosum, and investigate the effects of BAY 73-6691 in endothelium-dependent and -independent relaxations, along with the nitrergic corpus cavernosum relaxations. Male mice received daily gavage of BAY 73-6691 (or dimethylsulfoxide) at 3 mg kg(-1) per day for 21 days. Relaxant responses to acetylcholine (ACh), nitric oxide (NO) (as acidified sodium nitrite; NaNO2 solution), sildenafil and electrical-field stimulation (EFS) were obtained in corpus cavernosum in control and BAY 73-6691-treated mice. BAY 73-6691 was also added in vitro 30 min before construction of concentration-responses and frequency curves. PDE9A and PDE5 mRNA expression was detected in the mice corpus cavernosum in a similar manner. In vitro addition of BAY 73-6691 neither itself relaxed mice corpus cavernosum nor changed the NaNO2, sildenafil and EFS-induced relaxations. However, in mice treated chronically with BAY 73-6691, the potency (pEC50) values for ACh, NaNO2 and sildenafil were significantly greater compared with control group. The maximal responses (Emax) to NaNO2 and sildenafil were also significantly greater in BAY 73-6691-treated mice. BAY 73-6691 treatment also significantly increased the magnitude and duration of the nitrergic corpus cavernosum relaxations (8-32 Hz). In conclusion, murine corpus cavernosum expresses PDE9 mRNA. Prolonged PDE9 inhibition with BAY 73-6691 amplifies the NO-cGMP-mediated cavernosal responses, and may be of therapeutic value for erectile dysfunction.
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, University of Campinas Campinas, São Paulo, Brazil.
authors.forename: F H
authors.initials: FH
authors.lastname: da Silva
authors.forename: M N
authors.initials: MN
authors.lastname: Pereira
authors.forename: C F
authors.initials: CF
authors.lastname: Franco-Penteado
authors.forename: G
authors.initials: G
authors.lastname: De Nucci
authors.forename: E
authors.initials: E
authors.lastname: Antunes
authors.forename: M A
authors.initials: MA
authors.lastname: Claudino
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D000818:Animals; D006152:Cyclic GMP / Q000502:physiology*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics; D004558:Electric Stimulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009126:Muscle Relaxation / Q000187:drug effects; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D010413:Penis / Q000201:enzymology* / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology
chemical_list: C507056:BAY 73-6691; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C507055:Pde9a protein, mouse; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP