Evaluation of the pathophysiological role of endothelial catecholamines

• Grant number: 19/16805-4
• Support Opportunities: Research Projects - Thematic Grants
• Start date: October 01, 2021
• End date: December 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Principal Investigator: Gilberto de Nucci
• Grantee: Gilberto de Nucci
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Pesquisadores principais: Roberto Zatz ; Rodrigo Alvaro Brandão Lopes Martins
• Associated researchers: André Almeida Schenka
• Associated research grant(s): 25/01520-5 - Role of 6-nitrodopamine and adenylyl cyclase on the acid secretion from the snake Crotalus durissus terrificus, AV.EXT; 25/01272-1 - Interactions of hydrogen sulfide (H2S) with the novel endogenous catecholamines 6-nitrodopamine and 6-cyanodopamine in rabbit isolated vascular tissues., AV.EXT; 23/01267-2 - An evolutionary perspective on endothelial cardiovascular control in vertebrates and its functions, AP.R; 23/04217-6 - A reappraisal of the regulatory role of the endothelium over the cardiovascular system from a comparative perspective, AV.EXT; 23/01376-6 - Evaluation of 6-Nitrodopamine effects on renal and urogenital function, AP.R
• Associated scholarship(s): 25/00804-0 - ROLE OF 6-NITRODOPAMINE IN MOTILITY OF ISOLATED RABBIT URETER, BP.DD; 24/12679-2 - Evaluation of the in vitro and in vivo cardiovascular effects of 6-nitrodopa in the rat, BP.DD; 24/12688-1 - Evaluation of the in vitro and in vivo cardiovascular effects of 6-bromodopamine in rats, BP.DD; + associated scholarships 24/13789-6 - Evaluation of the new catecholamine 6-Nitrodopa in the seminal vesicle of rats, BP.IC; 24/08982-1 - EVALUATION OF THE CARDIOVASCULAR EFFECTS OF 6-NITRODOPA IN VITRO AND IN VIVO, BP.PD; 24/08067-1 - Assessment of the stability of new endogenous catecholamines in biological liquids and identification of possible metabolites, BP.PD; 23/13692-0 - In vitro and in vivo evaluation of nitrated derivatives of propranolol and atenolol, BP.PD; 23/03503-5 - Evaluation of the action of 6-nitrodopamine on the cardiovascular system in eNOS, nNOS and iNOS knockout mice, BP.IC; 23/03460-4 - Effects of different antioxidant agents on 6-nitrodopamine production/release by human umbilical artery in vitro, BP.IC; 21/14414-8 - Evaluation of the action of nitro-catecholamines in the cardiovascular system, BP.PD; 22/08232-7 - Pharmacological characterization of 6-Nitrodopamine in the systemic and renal hemodynamics of mammals and reptiles, BP.PD; 22/07737-8 - Evaluation of the cardiovascular effect of 6-nitrodopamine in isolated atrium and perfused rat heart, BP.DD; 22/08022-2 - Evaluation of chronic treatment of 6-nitronoradrenaline in rats, BP.DD; 22/06644-6 - Evaluation of 6-nitronoradrenaline in rat vas deferens, BP.IC; 21/13593-6 - Evaluation of chronic 6-nitrodopamine treatment in rats, BP.DD; 21/13726-6 - Identification of molecules related to the synthesis of adrenaline, noradrenaline and dopamine in the endothelium of reptiles and mammals by immunohistochemistry and in situ hibridization, BP.PD; 21/14120-4 - Evaluation of adrenergic beta antagonists in the vas deferens duct in rats, BP.IC - associated scholarships

Abstract

The endothelium is an organ capable of regulating vascular tone through the release of endothelium-derived relaxing factors such as nitric oxide, prostacyclin, etc., or endothelium-derived contracting factors as endothelins, prostanoid. In addition, the current physiological concept poses that such regulation can also occur through the release of exclusively neural-derived catecholamines. Our group has demonstrated in tissues isolated from reptiles that the endothelium is also a source of catecholamines, since the contraction of the snake aorta induced by electrical field stimulation (EFS) is abolished by adrenergic antagonists and by removing the endothelium. As described in this project, the pathophysiology role of endothelial catecholamines in humans will be evaluated by in vitro pharmacological tests, using human arteries, veins and cardiac tissue, and a through pharmacological clinical trials. The observation that the endothelium could be a source of catecholamines was supported by the identification of the enzyme tyrosine hydroxylase in the snake endothelium by immunohistochemistry. Accidentally, this observation was also extended for human endothelial cells. As described in the project, the physiological and pathophysiological role of endothelial catecholamines in humans is being evaluated through in vitro pharmacological approaches using human arteries and veins, and an in vivo pharmacological approach through clinical trials. It also aims to support the observations obtained in pharmacological tests in vitro and in vivo with a morphological substrate through the identification and possible quantification of the metabolic pathway of catecholamines by immunohistochemistry, fluorescence in situ hybridization (FISH) and by RNA in situ hybridization assay (RNA-ISH) with RNA Scope® technology. It is expected that the information collected will demonstrate the physiological and pathophysiological relevance of endothelial catecholamines in humans and will determine its importance in relation to neural adrenergic control. It will also be investigated whether the endothelium has the ability to synthesize and release other vasoactive amines, such as serotonin and histamine. (AU)

Scientific publications

(26)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BRITTO-JUNIOR, JOSE; LIMA, ANTONIO TIAGO; FUGUHARA, VIVIAN; MONICA, FABIOLA Z. Z.; ANTUNES, EDSON; DE NUCCI, GILBERTO. Investigation on the positive chronotropic action of 6-nitrodopamine in the rat isolated atria. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, v. N/A, p. 12-pg., 2023-01-31. (19/16805-4, 17/15175-1, 21/13593-6, 21/14414-8, 22/07737-8)

BRITTO-JUNIOR, JOSE; DE OLIVEIRA, MARIANA GONCALVES; GATI, CAROLINA DOS REIS; CAMPOS, RAFAEL; MORAES, MANOEL ODORICO; MORAES, MARIA ELISABETE A.; MONICA, FABIOLA Z.; ANTUNES, EDSON; DE NUCCI, GILBERTO. 6-NitroDopamine is an endogenous modulator of rat heart chronotropism. Life Sciences, v. 307, p. 10-pg., 2022-08-17. (18/09765-3, 19/16805-4, 17/15175-1)

BRITTO-JUNIOR, JOSE; CAMPOS, RAFAEL; PEIXOTO, MATHEUS; LIMA, ANTONIO TIAGO; JACINTHO, FELIPE FERNANDES; MONICA, FABIOLA Z.; MORENO, RONILSON AGNALDO; ANTUNES, EDSON; DE NUCCI, GILBERTO. 6-Nitrodopamine is an endogenous selective dopamine receptor antagonist in Chelonoidis carbonaria aorta. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY, v. 260, p. 7-pg., 2022-07-07. (19/16805-4, 17/15175-1, 18/24971-9, 21/13593-6)

ANTUNES, NATALICIA DE JESUS; COOMBES, GEMMA; DA CUNHA, KELLY FRANCISCO; MOREIRA, FERNANDA DE LIMA; PILON, ALAN C.; LOPES, NORBERTO PEPORINE; DA COSTA, JOSE LUIZ; KIPPER, KARIN; COUCHMAN, LEWIS; JOHNSTON, ATHOLL; et al. In vitro metabolism of the new antifungal dapaconazole using liver microsomes. DRUG METABOLISM AND PHARMACOKINETICS, v. 47, p. 10-pg., 2022-11-09. (19/16805-4, 16/22506-1)

BRITTO, JOSE; DO PRADO, GUSTAVO L. PEREIRA; CHIAVEGATTO, SILVANA; CUNHA, FERNANDO; MORAES, MANOEL ODORICO; MORAES, MARIA ELISABETE A.; MONICA, FABIOLA Z.; ANTUNES, EDSON; DE NUCCI, GILBERTO. The importance of the endothelial nitric oxide synthase on the release of 6-nitrodopamine from mouse isolated atria and ventricles and their role on chronotropism. NITRIC OXIDE-BIOLOGY AND CHEMISTRY, v. 138, p. 8-pg., 2023-06-12. (17/15175-1, 19/16805-4, 21/14414-8)

MENDES, GUSTAVO D.; LOTUFO, CLAUDINEY CHELI; BOSIO-GUIMARAES, RENAN ARTHUR; DE CASTRO, HELESON ALVES; BABADOPULOS, TAINAH; RIBAS FREITAS, ANDRE RICARDO; ANTUNES, NATALICIA DE JESUS; DE NUCCI, GILBERTO. Comparative bioavailability study with two sodium valproate tablet formulations administered under fasting conditions in healthy subjects. INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, v. 60, n. 5, p. 10-pg., 2022-05-01. (19/16805-4)

BRITTO-JUNIOR, JOSE; GUIMARAES, RENAN ARTHUR BOSIO; OLIVEIRA, DENIS LIMA; LIMA, ANTONIO TIAGO; QUIRINO, GILBERTO; STOCCO, GABRIEL AUGUSTO DE OLIVEIRA; URAMOTO, EDSON HIROSHI SALGADO; FREGONESI, ADRIANO; ANTUNES, EDSON; DE NUCCI, GILBERTO. Alpha₁-adrenergic blockers selectively antagonize the contractions induced by 6-nitrodopamine in the human vas deferens. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, v. 397, n. 5, p. 12-pg., 2023-11-01. (17/15175-1, 19/16805-4, 21/13593-6, 22/08022-2, 21/14414-8)

LIMA, ANTONIO TIAGO; BRITTO-JUNIOR, JOSE; MORAES, MANOEL ODORICO; MORAES, MARIA ELISABETE A.; FREGONESI, ADRIANO; MONICA, FABIOLA Z.; ANTUNES, EDSON; DE NUCCI, GILBERTO. 6-Nitrodopamine is an endogenous mediator of the rabbit corpus cavernosum relaxation. ANDROLOGY, v. 12, n. 6, p. 10-pg., 2023-12-29. (21/14414-8, 17/15175-1, 19/16805-4, 21/13593-6)

OLIVEIRA, DENIS LIMA; CARDOSO, VINICIUS FRANCISCO; BRITTO-JUNIOR, JOSE; FUGUHARA, VIVIAN; FRECENTESE, FRANCESCO; SPARACO, ROSA; SANTAGADA, VINCENZO; CALIENDO, GIUSEPPE; PUPO, ANDRE SAMPAIO; ANTUNES, EDSON; et al. The negative chronotropic effects of (±)-propranolol and (±)-4-NO₂-propranolol in the rat isolated right atrium are due to blockade of the 6-nitrodopamine receptor. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, v. N/A, p. 12-pg., 2024-10-09. (21/14414-8, 22/07737-8, 17/15175-1, 19/16805-4)

ZATZ, ROBERTO; DE NUCCI, GILBERTO. Endothelium-Derived Dopamine and 6-Nitrodopamine in the Cardiovascular System. PHYSIOLOGY, v. 39, n. 1, p. 16-pg., 2024-01-24. (23/01376-6, 19/16805-4)

BRITTO-JUNIOR, JOSE; DA SILVA-FILHO, WALTER PINTO; AMORIM, AMANDA CONSULIN; CAMPOS, RAFAEL; MORAES, MANOEL ODORICO; MORAES, MARIA ELISABETE A.; FREGONESI, ADRIANO; MONICA, FABIOLA Z.; ANTUNES, EDSON; DE NUCCI, GILBERTO. 6-nitrodopamine is a major endogenous modulator of human vas deferens contractility. ANDROLOGY, v. 10, n. 8, p. 8-pg., 2022-08-17. (19/16805-4, 17/15175-1)

LIMA, ANTONIO TIAGO; JABBOUR, SAMI; BRITTO-JUNIOR, JOSE; DE CARVALHO, DEMETRIO MARTINHO RAMOS; FREGONESI, ADRIANO; MARIANO, FERNANDA V.; DE SOUZA, VALERIA BARBOSA; SCHENKA, ANDRE ALMEIDA; ANTUNES, EDSON; DE NUCCI, GILBERTO. 6-Nitrodopamine potentiates catecholamine-induced contractions of human isolated vas deferens. FASEB BIOADVANCES, v. 7, n. 2, p. 9-pg., 2025-01-15. (19/16805-4, 17/15175-1, 21/13593-6, 21/14414-8, 21/13726-6)

BRITTO-JUNIOR, JOSE; LIMA, ANTONIO TIAGO; CAMPOS, RAFAEL; GIAO, ALEXANDRE ASTURIANO; MENDES, GUSTAVO DUARTE; SILVA, LUIZA P. FERREIRA-NOVAES P.; FREGONESI, ADRIANO; PUPO, ANDRE SAMPAIO; ANTUNES, EDSON; DE NUCCI, GILBERTO. 6-Nitrodopamine potentiates contractions of rat isolated vas deferens induced by noradrenaline, adrenaline, dopamine and electric field stimulation. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, v. N/A, p. 16-pg., 2023-04-04. (21/14414-8, 17/15175-1, 19/16805-4, 22/08232-7, 22/06644-6, 21/13593-6)

SPARACO, ROSA; SCOGNAMIGLIO, ANTONIA; CORVINO, ANGELA; CALIENDO, GIUSEPPE; FIORINO, FERDINANDO; MAGLI, ELISA; PERISSUTTI, ELISA; SANTAGADA, VINCENZO; SEVERINO, BEATRICE; LUCIANO, PAOLO; et al. Synthesis, Chiral Resolution and Enantiomers Absolute Configuration of 4-Nitropropranolol and 7-Nitropropranolol. Molecules, v. 28, n. 1, p. 15-pg., 2023-01-01. (19/16805-4)

LIMA, ANTONIO TIAGO; AMORIM, AMANDA CONSULIN; BRITTO-JUNIOR, JOSE; CAMPITELLI, RAQUEL RIOS; FREGONESI, ADRIANO; MONICA, FABIOLA Z.; ANTUNES, EDSON; DE NUCCI, GILBERTO. beta(1)- and beta(1)/beta(2)-adrenergic receptor antagonists block 6-nitrodopamine-induced contractions of the rat isolated epididymal vas deferens. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, v. 395, n. 10, p. 12-pg., 2022-07-08. (21/14120-4, 19/16805-4, 17/15175-1, 21/13593-6)

BRITTO-JUNIOR, JOSE; XIMENES, LUIZ; RIBEIRO, ANDRE; FREGONESI, ADRIANO; CAMPOS, RAFAEL; KIGUTI, LUIZ RICARDO DE ALMEIDA; MONICA, FABIOLA Z.; ANTUNES, EDSON; DE NUCCI, GILBERTO. 6-Nitrodopamine is an endogenous mediator of rat isolated epididymal vas deferens contractions induced by electric-field stimulation. European Journal of Pharmacology, v. 911, NOV 15 2021. (17/15175-1, 19/16805-4)

NASH, CHARLES ELLIOT SERPELLONE; ANTUNES, NATALICIA J.; COELHO-SILVA, WEVERTON C.; CAMPOS, RAFAEL; DE NUCCI, GILBERTO. Quantification of cyclic AMP and cyclic GMP levels in Krebs-Henseleit solution by LC-MS/MS: Application in washed platelet aggregation samples. JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, v. 1211, p. 8-pg., 2022-10-07. (19/16805-4)

J. BRITTO-JÚNIOR; A.T. LIMA; J.S. SANTOS-XAVIER; P. GONZALEZ; F.Z. MÓNICA; R. CAMPOS; V.B. DE SOUZA; A.A. SCHENKA; E. ANTUNES; G. DE NUCCI. Relaxation of thoracic aorta and pulmonary artery rings of marmosets (Callithrix spp.) by endothelium-derived 6-nitrodopamine. Brazilian Journal of Medical and Biological Research, v. 56, 2023-04-07. (17/15175-1, 21/14414-8, 21/13726-6, 21/13593-6, 19/16805-4)

BRITTO-JUNIOR, JOSE; RIBEIRO, ANDRE; XIMENES, LUIZ; LIMA, ANTONIO TIAGO; JACINTHO, FELIPE FERNANDES; FREGONESI, ADRIANO; MONICA, FABIOLA Z.; ANTUNES, EDSON; DE NUCCI, GILBERTO. lpha1-adrenergic antagonists block 6-nitrodopamine contractions on the rat isolated epididymal vas deferen. European Journal of Pharmacology, v. 915, JAN 15 2022. (18/24971-9, 17/15175-1, 19/16805-4)

BRITTO-JUNIOR, JOSE; LIMA, ANTONIO TIAGO; OLIVEIRA, DENIS LIMA; MARIANO, FERNANDA, V; DE SOUZA, VALERIA BARBOSA; SCHENKA, ANDRE ALMEIDA; PETERSON, LARRYN W.; SLOT, MARIA SKOVBJERG; FJORD, REBECCA; WANG, TOBIAS; et al. 6-Cyanodopamine as an endogenous modulator of heart chronotropism and inotropism. Life Sciences, v. 366, p. 13-pg., 2025-02-24. (21/13726-6, 19/16805-4, 21/13593-6, 17/15175-1, 23/16075-1, 23/04217-6, 21/14414-8)

CAMPOS, RAFAEL; NIEDERAUER, ANA JULIA SCHMIDT; BRITTO-JUNIOR, JOSE; DE SOUZA, VALERIA B.; SCHENKA, ANDRE A.; MONICA, FABIOLA Z.; MORAES, MANOEL ODORICO; MORAES, MARIA ELISABETE A.; ANTUNES, EDSON; DE NUCCI, GILBERTO. Basal release and relaxation responses to 6-nitrodopamine in swine carotid, coronary, femoral, and renal arteries. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY, v. 285, p. 13-pg., 2024-08-17. (21/13726-6, 22/08232-7, 17/15175-1, 19/16805-4, 21/14414-8, 23/15350-9, 23/14557-9)

DAL POZZO, CAROLINE FERNANDA SANCHES; MALDONADO JUNIOR, JOSE EDUARDO; BRITTO-JUNIOR, JOSE; BADIN, JOAO FELIPE AGOSTINI; DE SOUZA, VALERIA BARBOSA; SCHENKA, ANDRE ALMEIDA; PETERSON, LARRYN W.; FREGONESI, ADRIANO; ANTUNES, EDSON; DE NUCCI, GILBERTO. Basal release of 6-cyanodopamine from rat isolated vas deferens and its role on the tissue contractility. PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, v. 476, n. 8, p. 15-pg., 2024-07-04. (21/13726-6, 17/15175-1, 19/16805-4, 22/13062-3, 21/14414-8)

DE OLIVEIRA, MARIANA GONCALVES; BRITTO-JUNIOR, JOSE; DIAS, DOUGLAS RAFAEL MARTINS; PEREIRA, LUISE GABRIELA SANTOS; CHIAVEGATTO, SILVANA; HERMAWAN, IDAM; SHIMOKAWA, HIROAKI; TSUTSUI, MASATO; ANTUNES, EDSON; DE NUCCI, GILBERTO. Neurogenic-derived 6-nitrodopamine is the most potent endogenous modulator of the mouse urinary bladder relaxation. NITRIC OXIDE-BIOLOGY AND CHEMISTRY, v. 153, p. 8-pg., 2024-10-29. (17/06100-8, 21/14414-8, 23/09792-9, 19/16805-4)

LIMA, ANTONIO TIAGO; DOS SANTOS, ERIC XAVIER; BRITTO-JUNIOR, JOSE; DE SOUZA, VALERIA B.; SCHENKA, ANDRE A.; CAMPOS, RAFAEL; MORAES, MANOEL ODORICO; MORAES, MARIA ELISABETE A.; ANTUNES, EDSON; DE NUCCI, GILBERTO. Release of 6-nitrodopamine modulates vascular reactivity of Pantherophis guttatus aortic rings. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY, v. 262, p. 9-pg., 2022-12-01. (21/13593-6, 21/13726-6, 19/16805-4, 17/15175-1)

DE OLIVEIRA, LUIS FREDERICO GERBASE; BRITTO JUNIOR, JOSE; LIMA, ANTONIO TIAGO; MORAES, MANOEL ODORICO; MORAES, MARIA ELISABETE A.; DE SOUZA, VALERIA BARBOSA; SCHENKA, ANDRE ALMEIDA; MONICA, FABIOLA ZAKIA; DE NUCCI, GILBERTO. Release of 6-nitrodopamine from human popliteal artery and vein. Life Sciences, v. 326, p. 9-pg., 2023-05-31. (21/14414-8, 17/15175-1, 19/16805-4, 21/13593-6, 21/13726-6)

QUIRINO JUNIOR, GILBERTO; BRITTO-JUNIOR, JOSE; MAGALHAES, TAINAH BABADOPULOS; CAMPOS, RAFAEL; NYAMKONDIWA, KUDZAI L.; KLUGH, KAMERON L.; PETERSON, LARRYN W.; CORVINO, ANGELA; SPARACO, ROSA; FRECENTESE, FRANCESCO; et al. Measurement of 6-cyanodopamine, 6-nitrodopa, 6-nitrodopamine and 6-nitroadrenaline by LC-MS/MS in Krebs-Henseleit solution. Assessment of basal release from rabbit isolated right atrium and ventricles. BIOMEDICAL CHROMATOGRAPHY, v. N/A, p. 14-pg., 2023-07-10. (21/14414-8, 22/08022-2, 19/16805-4, 22/08232-7)