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


OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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
Fernando S
FS
Medical College of Georgia, Department of Physiology, Augusta, GA, USA. fcarneiro@mcg.edu
Nunes
Kênia P
KP
Giachini
Fernanda R C
FR
Lima
Victor V
VV
Carneiro
Zidonia N
ZN
Nogueira
Edson F
EF
Leite
Romulo
R
Ergul
Adviye
A
Rainey
William E
WE
Clinton Webb
R
R
Tostes
Rita C
RC
D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone; D004305:Dose-Response Relationship, Drug; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D007172:Erectile Dysfunction / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D015870:Gene Expression / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010413:Penis / Q000098:blood supply; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D044022:Receptor, Endothelin A / Q000235:genetics*; D044023:Receptor, Endothelin B / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054460:rho-Associated Kinases / Q000235:genetics
D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D003900:Desoxycorticosterone; D054460:rho-Associated Kinases; D048052:Mitogen-Activated Protein Kinase 3; D000077868:Atrasentan