Abstract
6-Nitrodopamine (6-ND) is released from human vas deferens and plays a modulatory role in the male ejaculation. Therapeutical use of α1-adrenoceptor antagonists is associated with ejaculatory abnormalities. To evaluate the effect of α1-adrenoceptor antagonists on the contractions induced by 6-ND, dopamine, noradrenaline, and adrenaline in the human epididymal vas deferens (HEVD). HEVD strips were suspended in glass chambers containing heated and oxygenated Krebs–Henseleit’s solution. Cumulative concentration–response curves to catecholamines (10 nM-300 μM) were constructed in HEVD strips pre-incubated (30 min) with doxazosin (0.1-1 nM), tamsulosin (1–10 nM), prazosin (10–100 nM) and/or silodosin (0.1–10 nM). The effects of these α1-adrenoceptor antagonists were also evaluated in the electric-field stimulation (EFS, 2–32 Hz)-induced contractions. Doxazosin (0.1 nM) caused significant reductions in 6-ND-induced HEVD contractions without affecting the contractions induced by dopamine, noradrenaline, and adrenaline. Similar results were observed with tamsulosin (1 nM) and prazosin (10 nM). At these concentrations, these α1-adrenoceptor antagonists largely reduced the EFS-induced contractions. Silodosin (1 nM) caused concentration-dependent rightward shifts of the concentration–response curves to 6-ND but had no effect on the contractions induced by dopamine and adrenaline. Silodosin (0.1 nM) only inhibited the contractions induced by noradrenaline. Silodosin at 1 nM, but not at 0.1 nM, caused significant reductions in the EFS-induced contractions. The results reinforce the concept that 6-ND plays a major role in the human vas deferens contractility and indicate that the ejaculation disorders caused by doxazosin, tamsulosin, prazosin and silodosin cause in man, may be due to inhibition of the contractions induced by 6-ND rather than by the classical catecholamines dopamine, noradrenaline, and adrenaline.
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Funding
Sao Paulo Research Foundation (FAPESP) grants 2021/14414–8 (JBJ), 2021/13593-6 (ATL), 2022/08022-2 (GQJ), 2017/15175–1 (EA), 2019/16805–4 (GDN).
National Council for Scientific and Technological Development (CNPq) grant 303,839/2019–8 (GDN).
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Conceptualization: JBJ, GDN. Data curation: JBJ, GDN. Formal analysis: GDN. Funding acquisition: EA, GDN. Investigation: RABG, JBJ, ATL, DLO, GQJ, GAOS. Methodology: RABG, ATL.Project administration: GDN. Supervision: EA and GDN.Visualization: AF, EA, GDN. Writing – original draft: JBJ, GDN. The authors declare that all data were generated in-house and that no paper mill was used.
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The investigation followed the principles outlined in the Declaration of Helsinki and the protocol was approved by the Ethics Committee of the Institute of Biomedical Sciences of the University of São Paulo – ICB/USP (protocol number 4.468.508), and the patients were asked to sign an informed consent.
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Britto-Júnior, J., Guimarães, R.A.B., Oliveira, D.L. et al. Alpha1-adrenergic blockers selectively antagonize the contractions induced by 6-nitrodopamine in the human vas deferens. Naunyn-Schmiedeberg's Arch Pharmacol (2023). https://doi.org/10.1007/s00210-023-02805-x
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DOI: https://doi.org/10.1007/s00210-023-02805-x