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

J Sex Med. 2008 Dec;5(12):2793-807. doi: 10.1111/j.1743-6109.2008.01009.x. Epub 2008 Sep 24.

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 ROCKalpha, ROCKbeta, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrasentan
  • Blood Pressure / drug effects
  • Desoxycorticosterone
  • Dose-Response Relationship, Drug
  • Endothelin B Receptor Antagonists
  • Endothelin-1 / antagonists & inhibitors
  • Endothelin-1 / genetics*
  • Endothelin-1 / physiology
  • Erectile Dysfunction / chemically induced
  • Erectile Dysfunction / genetics*
  • Erectile Dysfunction / physiopathology
  • Gene Expression / drug effects
  • Hypertension / chemically induced
  • Hypertension / genetics*
  • Hypertension / physiopathology
  • In Vitro Techniques
  • Male
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology
  • Penis / blood supply
  • Pyrrolidines / pharmacology
  • RNA, Messenger / genetics
  • Rats
  • Receptor, Endothelin A / genetics*
  • Receptor, Endothelin B / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • rho-Associated Kinases / genetics

Substances

  • Endothelin B Receptor Antagonists
  • Endothelin-1
  • Pyrrolidines
  • RNA, Messenger
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Desoxycorticosterone
  • rho-Associated Kinases
  • Mitogen-Activated Protein Kinase 3
  • Atrasentan