Superoxide Anion Production by NADPH Oxidase Plays a Major Role in Erectile Dysfunction in Middle-Aged Rats: Prevention by Antioxidant Therapy

Fábio H. Silva, Fabíola Z. Mónica, Fernando R. Báu, Ana F. Brugnerotto, Fernanda Priviero, Haroldo Alfredo Flores Toque, Edson Antunes

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Introduction.: Prevalence of erectile dysfunction (ED) increases progressively with aging, but the ED pathophysiology at its early stages is still poorly investigated. Aim.: This study aimed to evaluate the functional and molecular alterations of erectile function at middle age, focusing on the contribution of oxidative stress in erectile tissue for the ED. Methods.: Young (3.5-month) and middle-aged (10-month) male Wistar rats were used. Rat corpus cavernosum (RCC) was dissected free and mounted in 10-mL organ baths containing Krebs solution. Intracavernosal pressure (ICP) in anesthetized rats was evaluated. Main Outcome Measures.: Concentration-response curves to endothelium-dependent and endothelium-independent agents, as well as to electrical field stimulation (EFS), were obtained in RCC strips. Measurement of cyclic guanosine monophosphate (cGMP) and expressions of neuronal nitric oxide synthase (nNOS) and endothelial NOS (eNOS), gp91phox and superoxide dismutase-1 (SOD-1) expressions in RCC were evaluated. Results.: ICP was significantly reduced in middle-aged compared with young rats. RCC relaxations to acetylcholine (10-8 to 10-2M), sodium nitroprusside (10-8 to 10-2M), sildenafil (10-9 to 10-5M), BAY 41-2272 (10-9 to 10-5M), and EFS (4-32Hz) were decreased in middle-aged group, which were nearly normalized by apocynin (NADPH oxidase inhibitor; 10-4M) or SOD (75U/mL). Prolonged treatment with apocynin (85mg/rat/day, 4 weeks) also restored the impaired relaxations in middle-aged rats. Relaxations to 8-bromoguanosine 3′,5′-cyclic monophosphate sodium salt (8-Br-cGMP; 10-8 to 3×10-4M) remained unchanged between groups. Basal and stimulated cGMP production were lower in middle-aged group, an effect fully restored by apocynin and SOD. Protein expression of nNOS and phosphorylated eNOS (p-eNOS) (Ser-1177) reduced, whereas gp91phox mRNA expression increased in RCC from middle-aged rats. Conclusions.: ED in middle-aged rats is associated with decreased NO bioavailability in erectile tissue due to upregulation of NADPH oxidase subunit gp91phox and downregulation of nNOS/p-eNOS. Antioxidant therapies may be a good pharmacological approach to prevent ED at its early stages.

Original languageEnglish (US)
Pages (from-to)960-971
Number of pages12
JournalJournal of Sexual Medicine
Volume10
Issue number4
DOIs
StatePublished - Jan 1 2013

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NADPH Oxidase
Erectile Dysfunction
Superoxides
Antioxidants
Nitric Oxide Synthase Type I
Cyclic GMP
Therapeutics
Electric Stimulation
Endothelium
Pressure
Nitroprusside
Baths
Biological Availability
Acetylcholine
Wistar Rats
Oxidative Stress
Up-Regulation
Down-Regulation
Salts
Sodium

Keywords

  • Antioxidant Therapy
  • Apocynin
  • Corpus Cavernosum
  • Erectile Dysfunction
  • Oxidative Stress
  • Superoxide Dismutase

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology
  • Urology

Cite this

Superoxide Anion Production by NADPH Oxidase Plays a Major Role in Erectile Dysfunction in Middle-Aged Rats : Prevention by Antioxidant Therapy. / Silva, Fábio H.; Mónica, Fabíola Z.; Báu, Fernando R.; Brugnerotto, Ana F.; Priviero, Fernanda; Flores Toque, Haroldo Alfredo; Antunes, Edson.

In: Journal of Sexual Medicine, Vol. 10, No. 4, 01.01.2013, p. 960-971.

Research output: Contribution to journalArticle

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abstract = "Introduction.: Prevalence of erectile dysfunction (ED) increases progressively with aging, but the ED pathophysiology at its early stages is still poorly investigated. Aim.: This study aimed to evaluate the functional and molecular alterations of erectile function at middle age, focusing on the contribution of oxidative stress in erectile tissue for the ED. Methods.: Young (3.5-month) and middle-aged (10-month) male Wistar rats were used. Rat corpus cavernosum (RCC) was dissected free and mounted in 10-mL organ baths containing Krebs solution. Intracavernosal pressure (ICP) in anesthetized rats was evaluated. Main Outcome Measures.: Concentration-response curves to endothelium-dependent and endothelium-independent agents, as well as to electrical field stimulation (EFS), were obtained in RCC strips. Measurement of cyclic guanosine monophosphate (cGMP) and expressions of neuronal nitric oxide synthase (nNOS) and endothelial NOS (eNOS), gp91phox and superoxide dismutase-1 (SOD-1) expressions in RCC were evaluated. Results.: ICP was significantly reduced in middle-aged compared with young rats. RCC relaxations to acetylcholine (10-8 to 10-2M), sodium nitroprusside (10-8 to 10-2M), sildenafil (10-9 to 10-5M), BAY 41-2272 (10-9 to 10-5M), and EFS (4-32Hz) were decreased in middle-aged group, which were nearly normalized by apocynin (NADPH oxidase inhibitor; 10-4M) or SOD (75U/mL). Prolonged treatment with apocynin (85mg/rat/day, 4 weeks) also restored the impaired relaxations in middle-aged rats. Relaxations to 8-bromoguanosine 3′,5′-cyclic monophosphate sodium salt (8-Br-cGMP; 10-8 to 3×10-4M) remained unchanged between groups. Basal and stimulated cGMP production were lower in middle-aged group, an effect fully restored by apocynin and SOD. Protein expression of nNOS and phosphorylated eNOS (p-eNOS) (Ser-1177) reduced, whereas gp91phox mRNA expression increased in RCC from middle-aged rats. Conclusions.: ED in middle-aged rats is associated with decreased NO bioavailability in erectile tissue due to upregulation of NADPH oxidase subunit gp91phox and downregulation of nNOS/p-eNOS. Antioxidant therapies may be a good pharmacological approach to prevent ED at its early stages.",
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T2 - Prevention by Antioxidant Therapy

AU - Silva, Fábio H.

AU - Mónica, Fabíola Z.

AU - Báu, Fernando R.

AU - Brugnerotto, Ana F.

AU - Priviero, Fernanda

AU - Flores Toque, Haroldo Alfredo

AU - Antunes, Edson

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N2 - Introduction.: Prevalence of erectile dysfunction (ED) increases progressively with aging, but the ED pathophysiology at its early stages is still poorly investigated. Aim.: This study aimed to evaluate the functional and molecular alterations of erectile function at middle age, focusing on the contribution of oxidative stress in erectile tissue for the ED. Methods.: Young (3.5-month) and middle-aged (10-month) male Wistar rats were used. Rat corpus cavernosum (RCC) was dissected free and mounted in 10-mL organ baths containing Krebs solution. Intracavernosal pressure (ICP) in anesthetized rats was evaluated. Main Outcome Measures.: Concentration-response curves to endothelium-dependent and endothelium-independent agents, as well as to electrical field stimulation (EFS), were obtained in RCC strips. Measurement of cyclic guanosine monophosphate (cGMP) and expressions of neuronal nitric oxide synthase (nNOS) and endothelial NOS (eNOS), gp91phox and superoxide dismutase-1 (SOD-1) expressions in RCC were evaluated. Results.: ICP was significantly reduced in middle-aged compared with young rats. RCC relaxations to acetylcholine (10-8 to 10-2M), sodium nitroprusside (10-8 to 10-2M), sildenafil (10-9 to 10-5M), BAY 41-2272 (10-9 to 10-5M), and EFS (4-32Hz) were decreased in middle-aged group, which were nearly normalized by apocynin (NADPH oxidase inhibitor; 10-4M) or SOD (75U/mL). Prolonged treatment with apocynin (85mg/rat/day, 4 weeks) also restored the impaired relaxations in middle-aged rats. Relaxations to 8-bromoguanosine 3′,5′-cyclic monophosphate sodium salt (8-Br-cGMP; 10-8 to 3×10-4M) remained unchanged between groups. Basal and stimulated cGMP production were lower in middle-aged group, an effect fully restored by apocynin and SOD. Protein expression of nNOS and phosphorylated eNOS (p-eNOS) (Ser-1177) reduced, whereas gp91phox mRNA expression increased in RCC from middle-aged rats. Conclusions.: ED in middle-aged rats is associated with decreased NO bioavailability in erectile tissue due to upregulation of NADPH oxidase subunit gp91phox and downregulation of nNOS/p-eNOS. Antioxidant therapies may be a good pharmacological approach to prevent ED at its early stages.

AB - Introduction.: Prevalence of erectile dysfunction (ED) increases progressively with aging, but the ED pathophysiology at its early stages is still poorly investigated. Aim.: This study aimed to evaluate the functional and molecular alterations of erectile function at middle age, focusing on the contribution of oxidative stress in erectile tissue for the ED. Methods.: Young (3.5-month) and middle-aged (10-month) male Wistar rats were used. Rat corpus cavernosum (RCC) was dissected free and mounted in 10-mL organ baths containing Krebs solution. Intracavernosal pressure (ICP) in anesthetized rats was evaluated. Main Outcome Measures.: Concentration-response curves to endothelium-dependent and endothelium-independent agents, as well as to electrical field stimulation (EFS), were obtained in RCC strips. Measurement of cyclic guanosine monophosphate (cGMP) and expressions of neuronal nitric oxide synthase (nNOS) and endothelial NOS (eNOS), gp91phox and superoxide dismutase-1 (SOD-1) expressions in RCC were evaluated. Results.: ICP was significantly reduced in middle-aged compared with young rats. RCC relaxations to acetylcholine (10-8 to 10-2M), sodium nitroprusside (10-8 to 10-2M), sildenafil (10-9 to 10-5M), BAY 41-2272 (10-9 to 10-5M), and EFS (4-32Hz) were decreased in middle-aged group, which were nearly normalized by apocynin (NADPH oxidase inhibitor; 10-4M) or SOD (75U/mL). Prolonged treatment with apocynin (85mg/rat/day, 4 weeks) also restored the impaired relaxations in middle-aged rats. Relaxations to 8-bromoguanosine 3′,5′-cyclic monophosphate sodium salt (8-Br-cGMP; 10-8 to 3×10-4M) remained unchanged between groups. Basal and stimulated cGMP production were lower in middle-aged group, an effect fully restored by apocynin and SOD. Protein expression of nNOS and phosphorylated eNOS (p-eNOS) (Ser-1177) reduced, whereas gp91phox mRNA expression increased in RCC from middle-aged rats. Conclusions.: ED in middle-aged rats is associated with decreased NO bioavailability in erectile tissue due to upregulation of NADPH oxidase subunit gp91phox and downregulation of nNOS/p-eNOS. Antioxidant therapies may be a good pharmacological approach to prevent ED at its early stages.

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KW - Apocynin

KW - Corpus Cavernosum

KW - Erectile Dysfunction

KW - Oxidative Stress

KW - Superoxide Dismutase

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