Sympathetic hyperactivity, increased tyrosine hydroxylase and exaggerated corpus cavernosum relaxations associated with oxidative stress plays a major role in the penis dysfunction in Townes sickle cell mouse

Fábio H. Silva, Mário A. Claudino, Fabiano B. Calmasini, Eduardo C. Alexandre, Carla Franco-Penteado, Arthur Burnett, Edson Antunes, Fernando F. Costa

Research output: Contribution to journalArticle

Abstract

Background: Sickle cell disease patients display priapism that may progress to erectile dysfunction. However, little is known about the pathophysiological alterations of corpus cavernosum in sickle cell disease. Objective: Thus, this study aimed to evaluate the functional and molecular alterations of sympathetic machinery and nitric oxide-cyclic guanosine monophosphate signaling pathway in Townes transgenic sickle cell disease mice. Methods: Concentration-response curves to contractile (phenylephrine) and relaxant agents (acetylcholine and sodium nitroprusside) were obtained in corpus cavernosum strips from sickle and C57BL/6 (control) mice. Neurogenic contractions and nitrergic relaxations were obtained using electrical-field stimulation. Measurements of endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), phosphodiesterase-5 (PDE5) and α1A-, α1B- and α1D-adrenoceptor mRNA expressions and reactive-oxygen species were performed. Tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expressions in cavernosal tissues were also measured. Results: The neurogenic contractions were higher in the sickle cell disease group, in association with elevated tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expression, as well as increased tyrosine hydroxylase mRNA expression. Likewise, phenylephrine-induced contractions were greater in the sickle mice, whereas α1A-, α1B- and α1D-adrenoceptor mRNA expression remained unchanged. Cavernosal relaxations to acetylcholine, sodium nitroprusside and EFS were higher in sickle mice, accompanied by decreased eNOS and nNOS, along with lower PDE5 mRNA expression. An increase of about 40% in reactive-oxygen species generation in corpus cavernosum from sickle mice was also detected. Conclusion: Our study shows that decreased nitric oxide bioavailability in erectile tissue due to increased oxidative stress leads to both sympathetic hyperactivity and dysregulation of nitric oxide signaling in corpus cavernosum from Townes sickle mice.

Original languageEnglish (US)
Article numbere0166291
JournalPLoS One
Volume11
Issue number12
DOIs
StatePublished - Dec 1 2016

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tyrosine 3-monooxygenase
Oxidative stress
penis
Penis
Tyrosine 3-Monooxygenase
sickle cell anemia
Oxidative Stress
oxidative stress
Sickle Cell Anemia
Type 5 Cyclic Nucleotide Phosphodiesterases
mice
Nitric Oxide Synthase Type I
Messenger RNA
Nitric Oxide
Nitric Oxide Synthase Type III
nitric oxide
Nitroprusside
Phenylephrine
phenylephrine
Adrenergic Receptors

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Sympathetic hyperactivity, increased tyrosine hydroxylase and exaggerated corpus cavernosum relaxations associated with oxidative stress plays a major role in the penis dysfunction in Townes sickle cell mouse. / Silva, Fábio H.; Claudino, Mário A.; Calmasini, Fabiano B.; Alexandre, Eduardo C.; Franco-Penteado, Carla; Burnett, Arthur; Antunes, Edson; Costa, Fernando F.

In: PLoS One, Vol. 11, No. 12, e0166291, 01.12.2016.

Research output: Contribution to journalArticle

Silva, Fábio H. ; Claudino, Mário A. ; Calmasini, Fabiano B. ; Alexandre, Eduardo C. ; Franco-Penteado, Carla ; Burnett, Arthur ; Antunes, Edson ; Costa, Fernando F. / Sympathetic hyperactivity, increased tyrosine hydroxylase and exaggerated corpus cavernosum relaxations associated with oxidative stress plays a major role in the penis dysfunction in Townes sickle cell mouse. In: PLoS One. 2016 ; Vol. 11, No. 12.
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abstract = "Background: Sickle cell disease patients display priapism that may progress to erectile dysfunction. However, little is known about the pathophysiological alterations of corpus cavernosum in sickle cell disease. Objective: Thus, this study aimed to evaluate the functional and molecular alterations of sympathetic machinery and nitric oxide-cyclic guanosine monophosphate signaling pathway in Townes transgenic sickle cell disease mice. Methods: Concentration-response curves to contractile (phenylephrine) and relaxant agents (acetylcholine and sodium nitroprusside) were obtained in corpus cavernosum strips from sickle and C57BL/6 (control) mice. Neurogenic contractions and nitrergic relaxations were obtained using electrical-field stimulation. Measurements of endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), phosphodiesterase-5 (PDE5) and α1A-, α1B- and α1D-adrenoceptor mRNA expressions and reactive-oxygen species were performed. Tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expressions in cavernosal tissues were also measured. Results: The neurogenic contractions were higher in the sickle cell disease group, in association with elevated tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expression, as well as increased tyrosine hydroxylase mRNA expression. Likewise, phenylephrine-induced contractions were greater in the sickle mice, whereas α1A-, α1B- and α1D-adrenoceptor mRNA expression remained unchanged. Cavernosal relaxations to acetylcholine, sodium nitroprusside and EFS were higher in sickle mice, accompanied by decreased eNOS and nNOS, along with lower PDE5 mRNA expression. An increase of about 40{\%} in reactive-oxygen species generation in corpus cavernosum from sickle mice was also detected. Conclusion: Our study shows that decreased nitric oxide bioavailability in erectile tissue due to increased oxidative stress leads to both sympathetic hyperactivity and dysregulation of nitric oxide signaling in corpus cavernosum from Townes sickle mice.",
author = "Silva, {F{\'a}bio H.} and Claudino, {M{\'a}rio A.} and Calmasini, {Fabiano B.} and Alexandre, {Eduardo C.} and Carla Franco-Penteado and Arthur Burnett and Edson Antunes and Costa, {Fernando F.}",
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T1 - Sympathetic hyperactivity, increased tyrosine hydroxylase and exaggerated corpus cavernosum relaxations associated with oxidative stress plays a major role in the penis dysfunction in Townes sickle cell mouse

AU - Silva, Fábio H.

AU - Claudino, Mário A.

AU - Calmasini, Fabiano B.

AU - Alexandre, Eduardo C.

AU - Franco-Penteado, Carla

AU - Burnett, Arthur

AU - Antunes, Edson

AU - Costa, Fernando F.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Background: Sickle cell disease patients display priapism that may progress to erectile dysfunction. However, little is known about the pathophysiological alterations of corpus cavernosum in sickle cell disease. Objective: Thus, this study aimed to evaluate the functional and molecular alterations of sympathetic machinery and nitric oxide-cyclic guanosine monophosphate signaling pathway in Townes transgenic sickle cell disease mice. Methods: Concentration-response curves to contractile (phenylephrine) and relaxant agents (acetylcholine and sodium nitroprusside) were obtained in corpus cavernosum strips from sickle and C57BL/6 (control) mice. Neurogenic contractions and nitrergic relaxations were obtained using electrical-field stimulation. Measurements of endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), phosphodiesterase-5 (PDE5) and α1A-, α1B- and α1D-adrenoceptor mRNA expressions and reactive-oxygen species were performed. Tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expressions in cavernosal tissues were also measured. Results: The neurogenic contractions were higher in the sickle cell disease group, in association with elevated tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expression, as well as increased tyrosine hydroxylase mRNA expression. Likewise, phenylephrine-induced contractions were greater in the sickle mice, whereas α1A-, α1B- and α1D-adrenoceptor mRNA expression remained unchanged. Cavernosal relaxations to acetylcholine, sodium nitroprusside and EFS were higher in sickle mice, accompanied by decreased eNOS and nNOS, along with lower PDE5 mRNA expression. An increase of about 40% in reactive-oxygen species generation in corpus cavernosum from sickle mice was also detected. Conclusion: Our study shows that decreased nitric oxide bioavailability in erectile tissue due to increased oxidative stress leads to both sympathetic hyperactivity and dysregulation of nitric oxide signaling in corpus cavernosum from Townes sickle mice.

AB - Background: Sickle cell disease patients display priapism that may progress to erectile dysfunction. However, little is known about the pathophysiological alterations of corpus cavernosum in sickle cell disease. Objective: Thus, this study aimed to evaluate the functional and molecular alterations of sympathetic machinery and nitric oxide-cyclic guanosine monophosphate signaling pathway in Townes transgenic sickle cell disease mice. Methods: Concentration-response curves to contractile (phenylephrine) and relaxant agents (acetylcholine and sodium nitroprusside) were obtained in corpus cavernosum strips from sickle and C57BL/6 (control) mice. Neurogenic contractions and nitrergic relaxations were obtained using electrical-field stimulation. Measurements of endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), phosphodiesterase-5 (PDE5) and α1A-, α1B- and α1D-adrenoceptor mRNA expressions and reactive-oxygen species were performed. Tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expressions in cavernosal tissues were also measured. Results: The neurogenic contractions were higher in the sickle cell disease group, in association with elevated tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expression, as well as increased tyrosine hydroxylase mRNA expression. Likewise, phenylephrine-induced contractions were greater in the sickle mice, whereas α1A-, α1B- and α1D-adrenoceptor mRNA expression remained unchanged. Cavernosal relaxations to acetylcholine, sodium nitroprusside and EFS were higher in sickle mice, accompanied by decreased eNOS and nNOS, along with lower PDE5 mRNA expression. An increase of about 40% in reactive-oxygen species generation in corpus cavernosum from sickle mice was also detected. Conclusion: Our study shows that decreased nitric oxide bioavailability in erectile tissue due to increased oxidative stress leads to both sympathetic hyperactivity and dysregulation of nitric oxide signaling in corpus cavernosum from Townes sickle mice.

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