Activation of the ET-1/ETA Pathway Contributes to Erectile Dysfunction Associated with Mineralocorticoid Hypertension

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/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 ROCKα, 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 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. Conclusions 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.

Mechanisms of Penile Erection and Basis for Pharmacological Treatment of Erectile Dysfunction

“…ET-1 has been hypothesized to be directly involved in end-organ damage in saltsensitive forms of hypertension. In support of this hypothesis, Carneiro et al (2008b) found that activation of the ET-1/ET A pathway contributed to mineralocorticoid hypertension-associated ED. ET A receptor blockade may thus represent an alternative therapeutic approach for ED associated with salt-sensitive hypertension and in pathological conditions in which increased levels of ET-1 are present.…”

The Role Erectile Dysfunction Plays in Cardiovascular Diseases

“…Several studies have underlined the potential importance of ET-1 in the modulation of corpus cavernosum (CC) smooth muscle tone (60), since these cells can synthesize ET-1. The fetal human and adult penile cells, and several animal species, also express endothelin converting enzyme 1, the endothelin recepotors A (ETA) and B (ETB) subtypes (61)(62)(63). Furthermore, Melegy et al showed that ET-1 levels were significantly greater in patients with ED than the normal group (64).…”

The promise of inhibition of smooth muscle tone as a treatment for erectile dysfunction: where are we now?

“…Deoxycorticosterone acetate-salt-induced hypertensive animals showed increased cavernous contractile responses to both ET-1 and the a-adrenergic receptor agonist phenylephrine. 113,114 As to the downstream signaling, although protein expression levels of ROCK in the CC of deoxycorticosterone acetate-treated animals were similar to those of control animals, the phosphorylated form of myosin phosphatase regulatory subunit, a downstream effector of ROCK, was increased in cavernous tissue from deoxycorticosterone acetate animals. 114 In the spontaneously hypertensive rat, Wilkes et al 115 found that hypertension-related ED is associated with elevated penile RhoA levels and that inhibition of ROCK activity with Y-27632 was beneficial in attenuating the decline in erectile function.…”