Evaluation of 6-Nitrodopamine effects on renal and urogenital function

• Grant number: 23/01376-6
• Support Opportunities: Regular Research Grants
• Duration: July 01, 2023 - June 30, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Autonomic Pharmacology
• Convênio/Acordo: CNPq
• Principal Investigator: Roberto Zatz
• Grantee: Roberto Zatz
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/16805-4 - Evaluation of the pathophysiological role of endothelial catecholamines, AP.TEM

Abstract

6-nitrodopamine (6-ND), a product of the nitric oxide (NO) dependent nitration of dopamine (DA), produced endogenously. Increased evidence shows its role as the most potent mediator of in vivo and in vitro chronotropism in rats, and the spasmogenic activity of the vas deferens in rats and humans. In other tissues of the genitourinary tract, the production, release and function of 6-ND is still unknown. This study seeks to broaden the understanding of the actions of the autonomic nervous system on the function of the genitourinary tract organs, with the hypothesis that 6-ND is an important endogenous modulator of renal, vesical and erectile function in physiological and pathological conditions. Our preliminary studies showed the release of 6-ND in the bladder of mice and a potent in vitro relaxing response of the smooth muscles of the bladder, urethra, prostate and corpora cavernosa. Thus, the objective of the project is: i) to determine the concentrations of 6-ND, as well as noradrenaline (NOR), adrenaline (ADR) and DA in samples of kidney, bladder, urethra, prostate and corpora cavernosa isolated from rats, mice and humans; ii) characterize the actions of 6-ND in vitro on the contractile pathways and iii) bladder, urethra, prostate and corpora cavernosa relaxants isolated from rats and mice; iv) in vivo, evaluate renal and voiding function (metabolic cage, filter paper technique and cystometry) and v) erectile dysfunction (intracavernous pressure) in rats and mice after acute or chronic treatment with 6-ND; and vi) determine the generation of cyclic nucleotides (cAMP and cGMP) in the presence of 6-ND, NOR, ADR and DA, at different times and concentrations, in bladder, urethra, prostate and corpora cavernosa samples isolated from rats, mice and humans; vii) in a model of kidney injury induced by chronic blockade of NO production by L-NAME in rats and mice, to evaluate hemodynamic changes, diuresis, albuminuria and histological changes in the kidneys. Investigating the effects of 6-ND will allow a better assessment of its pathophysiological importance and therapeutic potential. (AU)