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

Author(s)

Lima, Antonio Tiago ; Britto-Junior, Jose ; Moraes, Manoel Odorico ; Moraes, Maria Elisabete A. ; Fregonesi, Adriano ; Monica, Fabiola Z. ; Antunes, Edson ; De Nucci, Gilberto

• Document type: Journal article
• Source: ANDROLOGY; v. 12, n. 6, p. 10-pg., 2023-12-29.

Abstract

Background6-Nitrodopamine (6-ND) is a novel endogenous catecholamine that has a potent relaxant action on vascular smooth muscle in vitro.ObjectivesTo evaluate the basal release of 6-ND and noradrenaline from rabbit-isolated corpus cavernosum (RbCC) and its relaxing action on this tissue.MethodsRabbit 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).ResultsRabbit 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 omega-nitro-l-arginine methyl ester (l-NAME) (100 mu M), whereas that of noradrenaline was unaffected. Tetrodotoxin (TTX, 1 mu M) 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 mu M) 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 conclusion6-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. (AU)

• FAPESP's process: 21/14414-8 - Evaluation of the action of nitro-catecholamines in the cardiovascular system
• Grantee: José Britto Júnior
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/15175-1 - Modulation of soluble guanylate cyclase and the intracellular levels of cyclic nucleotides in the lower urinary tract and prostate
• Grantee: Edson Antunes
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/16805-4 - Evaluation of the pathophysiological role of endothelial catecholamines
• Grantee: Gilberto de Nucci
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 21/13593-6 - Evaluation of chronic 6-nitrodopamine treatment in rats
• Grantee: Antonio Tiago Silva Lima
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)