DOCA-salt treatment enhances responses to endothelin-1 in murine corpus cavernosum.
The penis is kept in the flaccid state mainly via a tonic activity of norepinephrine and endothelins (ETs). ET-1 is important in salt-sensitive forms of hypertension. We hypothesized that cavernosal responses to ET-1 are enhanced in deoxycorticosterone acetate (DOCA)-salt mice and that blockade of ETA receptors prevents abnormal responses of the corpus cavernosum in DOCA-salt hypertension. Male C57BL/6 mice were unilaterally nephrectomized and treated for 5 weeks with both DOCA and water containing 1% NaCl and 0.2% KCl. Control mice were uninephrectomized and received tap water with no added salt. Animals received either the ETA antagonist atrasentan (5 mg x day(-1) x kg(-1) body weight) or vehicle. DOCA-salt mice displayed increased systolic blood pressure (SBP), and treatment with atrasentan decreased SBP in DOCA-salt mice. Contractile responses in cavernosal strips from DOCA-salt mice were enhanced by ET-1, phenylephrine, and electrical field stimulation (EFS) of adrenergic nerves, whereas relaxations were not altered by IRL-1620 (an ETB agonist), acetylcholine, sodium nitroprusside, and EFS of nonadrenergic noncholinergic nerves. PD59089 (an ERK1/2 inhibitor), but not Y-27632 (a Rho-kinase inhibitor), abolished enhanced contractions to ET-1 in cavernosum from DOCA-salt mice. Treatment of DOCA-salt mice with atrasentan did not normalize cavernosal responses. In summary, DOCA-salt treatment in mice enhances cavernosal reactivity to contractile, but not to relaxant, stimuli, via ET-1/ETA receptor-independent mechanisms.
Medical College of Georgia, Department of Physiology, 1120 Fifteenth Street, CA-3141, Augusta, GA 30912-3000, USA. fcarneiro@mcg.edu
Fernando S
FS
Carneiro
Fernanda R C
FR
Giachini
Victor V
VV
Lima
Zidonia N
ZN
Carneiro
Kênia P
KP
Nunes
Adviye
A
Ergul
Romulo
R
Leite
Rita C
RC
Tostes
R Clinton
RC
Webb
D000818:Animals; D000077868:Atrasentan; D003900:Desoxycorticosterone / Q000008:administration & dosage*; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000235:genetics; D006973:Hypertension / Q000209:etiology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010410:Penile Erection / Q000187:drug effects / Q000502:physiology; D010413:Penis / Q000098:blood supply* / Q000187:drug effects* / Q000502:physiology; D011759:Pyrrolidines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012965:Sodium Chloride / Q000008:administration & dosage*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D012333:RNA, Messenger; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D000077868:Atrasentan