Abstract
6-Nitrodopamine (6-ND) is a novel endogenous catecholamine that is released from the rat isolated vas deferens, and has been characterized as a major modulator of the contractility of rat isolated epididymal vas deferens (RIEVD). Drugs such as tricyclic antidepressants, α1 and β1β2 adrenoceptor blockers, act as selective antagonists of the 6-ND receptor in the RIEVD. In the rat isolated atria, 6-ND has a potent positive chronotropic action and causes remarkable potentiation of the positive chronotropic effects induced by dopamine, noradrenaline, and adrenaline. Here, whether 6-ND interacts with the classical catecholamines in the rat isolated vas deferens was investigated. Incubation with 6-ND (0.1 and 1 nM; 30min) caused no contractions in the RIEVD but provoked significant leftward shifts in the concentration-response curves to noradrenaline, adrenaline, and dopamine. Pre-incubation of the RIEVD with 6-ND (1 nM), potentiated the contractions induced by electric-field stimulation (EFS), whereas pre-incubation with 1 nM of dopamine, noradrenaline or adrenaline, did not affect EFS-induced contractions. In tetrodotoxin (1 μM) pre-treated (30 min) RIEVD, pre-incubation with 6-ND (0.1 nM) did not cause leftward shifts in the concentration-dependent contractions induced by noradrenaline, adrenaline, or dopamine. Pre-incubation of the RIEVD with the α2A-adrenoceptor antagonist idazoxan (30 min, 10 nM) did not affect dopamine, noradrenaline, adrenaline, and EFS-induced contractions. However, when idazoxan (10 nM) and 6-ND (0.1 nM) were simultaneously pre-incubated (30 min), a significant potentiation of the EFS-induced contractions of the RIEVD was observed. 6-nitrodopamine causes remarkable potentiation of dopamine, noradrenaline, and adrenaline contractions on the RIEVD, due to activation of adrenergic terminals, possibly via pre-synaptic adrenoceptors.
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Acknowledgment
JBJ & RC thanks FAPESP for post-doctoral fellowship (2021/14414-8, 2022/08232-7).
LFNLS thanks FAPESP for scientific initiation fellowship (2022/06644-6). ATL thanks FAPESP for PhD fellowship (2021/13593-6). EA thanks FAPESP (2017/15175-1). GDN thanks FAPESP (2019/16805-4) and CNPq (303839/2019-8). Dr CES Nash (PhD) has proof-edited the manuscript.
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Conceptualization: JBJ, GDN. Data curation: JBJ, GDN. Formal analysis: GDN, Funding acquisition: EA, GDN. Investigation: JBJ, ATL, LFNL, RC, GDN. Methodology: JBJ, AAG, GDM, GDN. Project administration: GDN. Supervision: AF, EA. Visualization: AF, ASP, EA, GDN. Writing – original draft: JBJ, ASP, EA, GDN. The authors declare that all data were generated in-house and that no paper mill was used.
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JBJ & RC thanks FAPESP for post-doctoral fellowship (2021/14414-8, 2022/08232-7). LFNL thanks FAPESP for scientific initiation fellowship (2022/06644-6). ATL thanks FAPESP for PhD fellowship (2021/13593-6). EA thanks FAPESP (2017/15175-1). GDN thanks FAPESP (2019/16805-4) and CNPq (303839/2019-8).
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ESM 1
Figure S01 – Potentiation by 6-nitrodopamine (6-ND) of the concentration-dependent contractions induced by noradrenaline (NA), adrenaline (ADR), and dopamine (DA) in the rat isolated epididymal vas deferens (RIEVD). Pre-incubation of the RIEVD with 6-ND (30 min, 10 or 100 nM) caused significant leftward shift of the noradrenaline (10 nM – 300 μM; Panels A and D, respectively), adrenaline (10 nM – 300 μM; Panels B and E, respectively), and dopamine (10 nM – 1mM; Panels C and F, respectively) concentration-dependent contractions of the RIEVD. n represents the number of vas deferens employed in each experiment.
ESM 2
Figure S02 – Effect of the 6-nitrodopamine (6-ND; 0.1 nM) in the electric-field stimulation (EFS)-induced contraction in the rat isolated epididymal vas deferens (RIEVD). At 0.1 nM, 6-ND did not affect the contractions induced by EFS. n represents the number of vas deferens employed in each experiment.
ESM 3
Figure S03 – Effect of the idazoxan (10 nM) in the electric-field stimulation (EFS)-induced contraction in the rat isolated epididymal vas deferens (RIEVD). n represents the number of vas deferens employed in each experiment.
ESM 4
Figure S04 – Effect of the indomethacin and atropine on the potentiation by 6-nitrodopamine (6-ND) of the concentration-dependent contractions induced by noradrenaline (NA), adrenaline (ADR), and dopamine (DA) in the rat isolated epididymal vas deferens (RIEVD). Pre-incubation of the RIEVD with either indomethacin (10 μM, 30 min; Panels A, C and D) or atropine (10 nM, 30 min; Panels D, E and F) did not affect the potentiation induced by 6-ND (100 nM) on the RIEVD contractions induced by noradrenaline (Panels A and D), adrenaline (Panels B and E), and dopamine (Panels C and F). n represents the number of vas deferens employed in each experiment.
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Britto-Júnior, J., Lima, A.T., Campos, R. et al. 6-Nitrodopamine potentiates contractions of rat isolated vas deferens induced by noradrenaline, adrenaline, dopamine and electric field stimulation. Naunyn-Schmiedeberg's Arch Pharmacol 396, 2555–2570 (2023). https://doi.org/10.1007/s00210-023-02478-6
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DOI: https://doi.org/10.1007/s00210-023-02478-6