6-Nitrodopamine is an endogenous mediator of the rabbit corpus cavernosum relaxation

Antonio Tiago Lima; José Britto-Júnior; Manoel Odorico Moraes; Maria Elisabete A Moraes; Adriano Fregonesi; Fabíola Z Monica; Edson Antunes; Gilberto De Nucci

doi:10.1111/andr.13585

6-Nitrodopamine is an endogenous mediator of the rabbit corpus cavernosum relaxation

Andrology. 2023 Dec 29. doi: 10.1111/andr.13585. Online ahead of print.

Authors

Antonio Tiago Lima¹, José Britto-Júnior¹, Manoel Odorico Moraes², Maria Elisabete A Moraes², Adriano Fregonesi¹, Fabíola Z Monica¹, Edson Antunes¹, Gilberto De Nucci^{1

2

3}

Affiliations

¹ Faculty of Medical Sciences, Department of Pharmacology, University of Campinas (UNICAMP), Campinas, Brazil.
² Clinical Pharmacology Unit, Drug Research and Development Center, Federal University of Ceará (UFC), Fortaleza, Brazil.
³ Department of Pharmacology, Institute of Biomedical Sciences (ICB), University of São Paulo (USP), São Paulo, Brazil.

PMID: 38156727
DOI: 10.1111/andr.13585

Abstract

Background: 6-Nitrodopamine (6-ND) is a novel endogenous catecholamine that has a potent relaxant action on vascular smooth muscle in vitro.

Objectives: To evaluate the basal release of 6-ND and noradrenaline from rabbit-isolated corpus cavernosum (RbCC) and its relaxing action on this tissue.

Methods: Rabbit corpus cavernosa were dissected and suspended in a 5-mL organ bath containing oxygenated Krebs-Henseleit's solution. 6-ND and noradrenaline release was quantified by liquid chromatography coupled to tandem mass spectrometry. The relaxant activity of 6-ND was assessed in RbCC strips pre-contracted with endothelin-1 (10 nM).

Results: Rabbit corpus cavernosum presented basal release of both 6-ND (2.9 ± 0.8 ng/mL, n = 12) and noradrenaline (1.7 ± 1.3 ng/mL, n = 12). The 6-ND release was reduced by pre-treatment with N^ω -nitro-l-arginine methyl ester (l-NAME) (100 µM), whereas that of noradrenaline was unaffected. Tetrodotoxin (TTX, 1 µM) abolished the noradrenaline release but had no effect on 6-ND release, indicating a non-neurogenic origin for 6-ND. 6-ND and the selective dopamine D₂ -agonist L-741,626 caused concentration-dependent RbCC relaxations (pEC₅₀ of 11 ± 0.15 and 11.15 ± 0.28, respectively). Pre-treatment with either l-NAME or the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-on (ODQ) (100 µM) caused a rightward shift of the concentration-response curve to 6-ND, without affecting the L-741,626 responses. In TTX (100 nM)-pre-treated preparations, neither l-NAME nor ODQ shifted the 6-ND concentration-response curve. Dopamine, noradrenaline, and adrenaline caused concentration-dependent RbCC contractions. Pre-incubation with 6-ND concentration-dependently inhibited the dopamine-induced contractions, without affecting those induced by either noradrenaline or adrenaline.

Discussion and conclusion: 6-Nitrodopamine is the most potent endogenous relaxant agent in RbCC ever described and represents a novel mechanism by which NO causes corpus cavernosum smooth muscle relaxation. The finding that 6-ND acts as a truly selective dopamine D₂ -receptor antagonist indicates that the balance of dopamine and 6-ND release/synthesis may be the main mechanism that modulates corpus cavernosum smooth muscle tonus in vivo.

Keywords: LC-MS/MS; adrenergic terminals; nitrocatecholamine; penile erection; sodium channel.

Abstract

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