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. 2008 Jun;86(6):320-8.
doi: 10.1139/Y08-031.

DOCA-salt treatment enhances responses to endothelin-1 in murine corpus cavernosum

Fernando S Carneiro  1 , Fernanda R C Giachini, Victor V Lima, Zidonia N Carneiro, Kênia P Nunes, Adviye Ergul, Romulo Leite, Rita C Tostes, R Clinton Webb
Affiliations

DOCA-salt treatment enhances responses to endothelin-1 in murine corpus cavernosum

Fernando S Carneiro et al. Can J Physiol Pharmacol. 2008 Jun.

Abstract

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.

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Figures

Fig. 1
Fig. 1
Response of cavernosal strips from Uni control (■) and DOCA-salt (●) mice to ET-1 (A), and the ETB agonist IRL-1620 (B). Relaxation induced by IRL-1620 was calculated relative to the maximal changes from the contraction produced by phenylephrine in each tissue, which was taken as 100%. Data are means ± SE, n = 5–7 each group. Significant at *, p < 0.05 vs. Uni mice.
Fig. 2
Fig. 2
Contractile response to stimulation of adrenergic nerves or α1-adrenergic receptors in cavernosal strips from Uni control (■) and DOCA-salt (●) mice. (A) Frequency–response curves elicited by electrical field stimulation (1–64 Hz) performed in the presence of 10−4 mol/L l-NAME plus 10−6 mol/L atropine (n = 14 each group). (B) Phenylephrine concentration–response curves in the absence of l-NAME (n = 7 each group). Data are means ± SE. Significant at *, p < 0.05 vs. Uni mice.
Fig. 3
Fig. 3
Relaxant response in cavernosal strips from Uni control (■) and DOCA-salt (●) mice. (A) Frequency–response curves elicited by electrical field (1–64 Hz) stimulation of NANC nerves in the presence of 3 × 10−5 mol/L bretylium tosylate plus 10−6 mol/L atropine (n = 7 each group). Relaxation induced by (B) acetylcholine (n = 12 each group) and (C) sodium nitroprusside (n = 4–5 each group) was calculated relative to the maximal changes from the contraction produced by phenylephrine in each tissue, which was taken as 100%. Data are means ± SE. NANC, nonadrenergic noncholinergic.
Fig. 4
Fig. 4
Effect of chronic treatment with the ETA antagonist atrasentan (open symbols) or vehicle (closed symbols) on contractile response of cavernosal strips from Uni control (■, □) and DOCA-salt (●, ○) mice. (A) ET-1 concentration–response curves in the absence of l-NAME (n = 5–7 each group). (B) Frequency–response curves elicited by electrical field (1–64 Hz) stimulation of adrenergic nerves in the presence of 10−4 mol/L l-NAME plus 10−6 mol/L atropine (n = 10–12 each group). (C) phenylephrine (α1-adrenergic receptor agonist) concentration–response curves in the absence of l-NAME (n = 5–7 each group). Data are means ± SE. Significant at *, p < 0.05 vs. Uni mice.
Fig. 5
Fig. 5
Effect on ET-1-contracted tissue in cavernosal strips from Uni control (■,□) and DOCA-salt (●,○) mice of (A) Y-27632, a Rhokinase inhibitor (n = 5 each group), and (B) PD59089, an ERK1/2 inhibitor (n = 6 each group). Relaxation induced by Y-27632 was calculated relative to the maximal changes from the contraction produced by ET-1 in each tissue, which was taken as 100%. Data are means ± SE.
Fig. 6
Fig. 6
PreproET-1 mRNA expression, determined by real-time qPCR, of 1 µg total RNA extracted from cavernosal tissue of Uni control (open bar) and DOCA-salt (filled bar) mice. Graph shows fold change in preproET-1 mRNA expression. Values were normalized by the corresponding 18s rRNA of each sample. Results are means ± SE (n = 5–6 each sample).
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