Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension

Fernando S. Carneiro, Kênia P. Nunes, Fernanda R.C. Giachini, Victor V. Lima, Zidonia N. Carneiro, Edson F. Nogueira, Romulo Leite, Adviye Ergul, William E. Rainey, R Clinton Webb, Rita C. Tostes

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Introduction. The cavernosal tissue is highly responsive to endothelin-1 (ET-1), and penile smooth muscle cells not only respond to but also synthesize ET-1. Aim. Considering that ET-1 is directly involved in end-organ damage in salt-sensitive forms of hypertension, we hypothesized that activation of the ET-1/ET A receptor pathway contributes to erectile dysfunction (ED) associated with mineralocorticoid hypertension. Methods. Wistar rats were uninephrectomized and submitted to deoxycorticosterone acetate (DOCA)-salt treatment for 5 weeks. Control (Uni [uninephrectomized control]) animals were uninephrectomized and given tap water. Uni and DOCA-salt rats were simultaneously treated with vehicle or atrasentan (ET A receptor antagonist, 5 mg/Kg/day). Cavernosal reactivity to ET-1, phenylephrine (PE), ET B receptor agonist (IRL-1620) and electric field stimulation (EFS) were evaluated in vitro. Expression of ROCKγ, ROCKβ, myosin phosphatase target subunit 1 (MYPT-1), and extracellular signal-regulated kinase 1/2 (ERK 1/2) were evaluated by western blot analysis. ET-1 and ET A receptor mRNA expression was evaluated by real-time reverse-transcriptase polymerase chain reaction. Voltage-dependent increase in intracavernosal pressure/ mean arterial pressure (ICP/MAP) was used to evaluate erectile function in vivo. Main Outcome Measure. ET A receptor blockade prevents DOCA-salt-associated ED. Results. Cavernosal strips from DOCA-salt rats displayed augmented preproET-1 expression, increased contractile responses to ET-1 and decreased relaxation to IRL-1620. Contractile responses induced by EFS and PE were enhanced in cavernosal tissues from DOCA-salt hypertensive rats. These functional changes were associated with increased activation of the RhoA/Rho-kinase and ERK 1/2 pathways. Treatment of rats with atrasentan completely prevented changes in cavernosal reactivity in DOCA-salt rats and restored the decreased ICP/MAP, completely preventing ED in DOCA-salt rats. Conclusion. Activation of the ET-1/ET A pathway contributes to mineralocorticoid hypertension-associated ED. ET A receptor blockade may represent an alternative therapeutic approach for ED associated with salt-sensitive hypertension and in pathological conditions where increased levels of ET-1 are present. Carneiro FS, Nunes KP, Giachini FRC, Lima VV, Carneiro ZN, Nogueira EF, Leite R, Ergul A, Rainey WE, Webb RC, and Tostes RC. Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension.

Original languageEnglish (US)
Pages (from-to)2793-2807
Number of pages15
JournalJournal of Sexual Medicine
Volume5
Issue number12
DOIs
StatePublished - Jan 1 2008

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Mineralocorticoids
Endothelin-1
Erectile Dysfunction
Desoxycorticosterone
Salts
Hypertension
Acetates
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Phenylephrine
Electric Stimulation
Arterial Pressure
Myosin-Light-Chain Phosphatase
Pressure
rho-Associated Kinases
Reverse Transcriptase Polymerase Chain Reaction
Smooth Muscle Myocytes
Wistar Rats
Real-Time Polymerase Chain Reaction
Western Blotting

Keywords

  • Atrasentan
  • Corpus Cavernosum
  • DOCA-salt Hypertension
  • ET Receptor
  • Endothelin-1
  • Erectile Dysfunction
  • Rho-kinase

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology
  • Urology

Cite this

Carneiro, F. S., Nunes, K. P., Giachini, F. R. C., Lima, V. V., Carneiro, Z. N., Nogueira, E. F., ... Tostes, R. C. (2008). Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension. Journal of Sexual Medicine, 5(12), 2793-2807. https://doi.org/10.1111/j.1743-6109.2008.01009.x

Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension. / Carneiro, Fernando S.; Nunes, Kênia P.; Giachini, Fernanda R.C.; Lima, Victor V.; Carneiro, Zidonia N.; Nogueira, Edson F.; Leite, Romulo; Ergul, Adviye; Rainey, William E.; Webb, R Clinton; Tostes, Rita C.

In: Journal of Sexual Medicine, Vol. 5, No. 12, 01.01.2008, p. 2793-2807.

Research output: Contribution to journalArticle

Carneiro, FS, Nunes, KP, Giachini, FRC, Lima, VV, Carneiro, ZN, Nogueira, EF, Leite, R, Ergul, A, Rainey, WE, Webb, RC & Tostes, RC 2008, 'Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension', Journal of Sexual Medicine, vol. 5, no. 12, pp. 2793-2807. https://doi.org/10.1111/j.1743-6109.2008.01009.x
Carneiro, Fernando S. ; Nunes, Kênia P. ; Giachini, Fernanda R.C. ; Lima, Victor V. ; Carneiro, Zidonia N. ; Nogueira, Edson F. ; Leite, Romulo ; Ergul, Adviye ; Rainey, William E. ; Webb, R Clinton ; Tostes, Rita C. / Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension. In: Journal of Sexual Medicine. 2008 ; Vol. 5, No. 12. pp. 2793-2807.
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abstract = "Introduction. The cavernosal tissue is highly responsive to endothelin-1 (ET-1), and penile smooth muscle cells not only respond to but also synthesize ET-1. Aim. Considering that ET-1 is directly involved in end-organ damage in salt-sensitive forms of hypertension, we hypothesized that activation of the ET-1/ET A receptor pathway contributes to erectile dysfunction (ED) associated with mineralocorticoid hypertension. Methods. Wistar rats were uninephrectomized and submitted to deoxycorticosterone acetate (DOCA)-salt treatment for 5 weeks. Control (Uni [uninephrectomized control]) animals were uninephrectomized and given tap water. Uni and DOCA-salt rats were simultaneously treated with vehicle or atrasentan (ET A receptor antagonist, 5 mg/Kg/day). Cavernosal reactivity to ET-1, phenylephrine (PE), ET B receptor agonist (IRL-1620) and electric field stimulation (EFS) were evaluated in vitro. Expression of ROCKγ, ROCKβ, myosin phosphatase target subunit 1 (MYPT-1), and extracellular signal-regulated kinase 1/2 (ERK 1/2) were evaluated by western blot analysis. ET-1 and ET A receptor mRNA expression was evaluated by real-time reverse-transcriptase polymerase chain reaction. Voltage-dependent increase in intracavernosal pressure/ mean arterial pressure (ICP/MAP) was used to evaluate erectile function in vivo. Main Outcome Measure. ET A receptor blockade prevents DOCA-salt-associated ED. Results. Cavernosal strips from DOCA-salt rats displayed augmented preproET-1 expression, increased contractile responses to ET-1 and decreased relaxation to IRL-1620. Contractile responses induced by EFS and PE were enhanced in cavernosal tissues from DOCA-salt hypertensive rats. These functional changes were associated with increased activation of the RhoA/Rho-kinase and ERK 1/2 pathways. Treatment of rats with atrasentan completely prevented changes in cavernosal reactivity in DOCA-salt rats and restored the decreased ICP/MAP, completely preventing ED in DOCA-salt rats. Conclusion. Activation of the ET-1/ET A pathway contributes to mineralocorticoid hypertension-associated ED. ET A receptor blockade may represent an alternative therapeutic approach for ED associated with salt-sensitive hypertension and in pathological conditions where increased levels of ET-1 are present. Carneiro FS, Nunes KP, Giachini FRC, Lima VV, Carneiro ZN, Nogueira EF, Leite R, Ergul A, Rainey WE, Webb RC, and Tostes RC. Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension.",
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TY - JOUR

T1 - Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension

AU - Carneiro, Fernando S.

AU - Nunes, Kênia P.

AU - Giachini, Fernanda R.C.

AU - Lima, Victor V.

AU - Carneiro, Zidonia N.

AU - Nogueira, Edson F.

AU - Leite, Romulo

AU - Ergul, Adviye

AU - Rainey, William E.

AU - Webb, R Clinton

AU - Tostes, Rita C.

PY - 2008/1/1

Y1 - 2008/1/1

N2 - Introduction. The cavernosal tissue is highly responsive to endothelin-1 (ET-1), and penile smooth muscle cells not only respond to but also synthesize ET-1. Aim. Considering that ET-1 is directly involved in end-organ damage in salt-sensitive forms of hypertension, we hypothesized that activation of the ET-1/ET A receptor pathway contributes to erectile dysfunction (ED) associated with mineralocorticoid hypertension. Methods. Wistar rats were uninephrectomized and submitted to deoxycorticosterone acetate (DOCA)-salt treatment for 5 weeks. Control (Uni [uninephrectomized control]) animals were uninephrectomized and given tap water. Uni and DOCA-salt rats were simultaneously treated with vehicle or atrasentan (ET A receptor antagonist, 5 mg/Kg/day). Cavernosal reactivity to ET-1, phenylephrine (PE), ET B receptor agonist (IRL-1620) and electric field stimulation (EFS) were evaluated in vitro. Expression of ROCKγ, ROCKβ, myosin phosphatase target subunit 1 (MYPT-1), and extracellular signal-regulated kinase 1/2 (ERK 1/2) were evaluated by western blot analysis. ET-1 and ET A receptor mRNA expression was evaluated by real-time reverse-transcriptase polymerase chain reaction. Voltage-dependent increase in intracavernosal pressure/ mean arterial pressure (ICP/MAP) was used to evaluate erectile function in vivo. Main Outcome Measure. ET A receptor blockade prevents DOCA-salt-associated ED. Results. Cavernosal strips from DOCA-salt rats displayed augmented preproET-1 expression, increased contractile responses to ET-1 and decreased relaxation to IRL-1620. Contractile responses induced by EFS and PE were enhanced in cavernosal tissues from DOCA-salt hypertensive rats. These functional changes were associated with increased activation of the RhoA/Rho-kinase and ERK 1/2 pathways. Treatment of rats with atrasentan completely prevented changes in cavernosal reactivity in DOCA-salt rats and restored the decreased ICP/MAP, completely preventing ED in DOCA-salt rats. Conclusion. Activation of the ET-1/ET A pathway contributes to mineralocorticoid hypertension-associated ED. ET A receptor blockade may represent an alternative therapeutic approach for ED associated with salt-sensitive hypertension and in pathological conditions where increased levels of ET-1 are present. Carneiro FS, Nunes KP, Giachini FRC, Lima VV, Carneiro ZN, Nogueira EF, Leite R, Ergul A, Rainey WE, Webb RC, and Tostes RC. Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension.

AB - Introduction. The cavernosal tissue is highly responsive to endothelin-1 (ET-1), and penile smooth muscle cells not only respond to but also synthesize ET-1. Aim. Considering that ET-1 is directly involved in end-organ damage in salt-sensitive forms of hypertension, we hypothesized that activation of the ET-1/ET A receptor pathway contributes to erectile dysfunction (ED) associated with mineralocorticoid hypertension. Methods. Wistar rats were uninephrectomized and submitted to deoxycorticosterone acetate (DOCA)-salt treatment for 5 weeks. Control (Uni [uninephrectomized control]) animals were uninephrectomized and given tap water. Uni and DOCA-salt rats were simultaneously treated with vehicle or atrasentan (ET A receptor antagonist, 5 mg/Kg/day). Cavernosal reactivity to ET-1, phenylephrine (PE), ET B receptor agonist (IRL-1620) and electric field stimulation (EFS) were evaluated in vitro. Expression of ROCKγ, ROCKβ, myosin phosphatase target subunit 1 (MYPT-1), and extracellular signal-regulated kinase 1/2 (ERK 1/2) were evaluated by western blot analysis. ET-1 and ET A receptor mRNA expression was evaluated by real-time reverse-transcriptase polymerase chain reaction. Voltage-dependent increase in intracavernosal pressure/ mean arterial pressure (ICP/MAP) was used to evaluate erectile function in vivo. Main Outcome Measure. ET A receptor blockade prevents DOCA-salt-associated ED. Results. Cavernosal strips from DOCA-salt rats displayed augmented preproET-1 expression, increased contractile responses to ET-1 and decreased relaxation to IRL-1620. Contractile responses induced by EFS and PE were enhanced in cavernosal tissues from DOCA-salt hypertensive rats. These functional changes were associated with increased activation of the RhoA/Rho-kinase and ERK 1/2 pathways. Treatment of rats with atrasentan completely prevented changes in cavernosal reactivity in DOCA-salt rats and restored the decreased ICP/MAP, completely preventing ED in DOCA-salt rats. Conclusion. Activation of the ET-1/ET A pathway contributes to mineralocorticoid hypertension-associated ED. ET A receptor blockade may represent an alternative therapeutic approach for ED associated with salt-sensitive hypertension and in pathological conditions where increased levels of ET-1 are present. Carneiro FS, Nunes KP, Giachini FRC, Lima VV, Carneiro ZN, Nogueira EF, Leite R, Ergul A, Rainey WE, Webb RC, and Tostes RC. Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension.

KW - Atrasentan

KW - Corpus Cavernosum

KW - DOCA-salt Hypertension

KW - ET Receptor

KW - Endothelin-1

KW - Erectile Dysfunction

KW - Rho-kinase

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U2 - 10.1111/j.1743-6109.2008.01009.x

DO - 10.1111/j.1743-6109.2008.01009.x

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VL - 5

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JO - Journal of Sexual Medicine

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