Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension.
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2008
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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/ETA 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 (ETA receptor antagonist, 5 mg/
Kg/day). Cavernosal reactivity to ET-1, phenylephrine (PE), ETB receptor agonist (IRL-1620) and electric field
stimulation (EFS) were evaluated in vitro. Expression of ROCKa, ROCKb, 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 ETA 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. ETA 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/ETA pathway contributes to mineralocorticoid hypertension-associated ED.
ETA 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.
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Rho-kinase, Corpus Cavernosum, Atrasentan
Citação
CARNEIRO, F. S. et. al. Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension. The Journal of Sexual Medicine, v. 5, p. 2793-2807, 2008. Disponível em: <http://onlinelibrary.wiley.com/doi/10.1111/j.1743-6109.2008.01009.x/abstract>. Acesso em: 10 jan. 2017.