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The transduction mechanism(s) employed by 6-nitrodopamine and 6-cyanodopamine in human platelets and cultured cell lines

Grant number: 23/14557-9
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): March 25, 2024
Effective date (End): March 24, 2025
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Principal Investigator:Gilberto de Nucci
Grantee:José Britto Júnior
Supervisor: Albert Ferro
Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Research place: King's College London, England  
Associated to the scholarship:21/14414-8 - Evaluation of the action of nitro-catecholamines in the cardiovascular system, BP.PD

Abstract

Endothelial cells modulate vascular reactivity through the release of mediators such as nitric oxide and endothelin. The current dogma is that catecholamines modulate vascular tone, chronotropism and cardiac inotropism through their release from adrenergic terminals, and through their action on ±- and beta-adrenergic receptors. We identified, through mass spectrometry, the basal release of endothelium-dependent dopamine in human vascular tissues (arteries and umbilical vein, structures known for not having nerve endings) and in the aorta of Chelonoidis carbonaria, showing that dopamine of endothelial origin has modular potential. vascular reactivity. We also identified the release of a new catecholamine, 6-nitrodopamine (6-ND), from human tissues (umbilical arteries and veins; peripheral arteries and veins such as popliteal, femoral; human vas deferens) and from animal vascular tissues (thoracic duct, femoral, renal, carotid, coronary and pulmonary arteries of Sus domesticus; aorta of Chelonoidis carbonaria; aorta of Panterophis guttatus, aorta and pulmonary arteries of Callithrix sp), atrium and ventricles of Rattus norvegicus, black C57BL/6 mouse and Sus domesticus and of the vas deferens of Rattus norvegicus. The release of 6-ND is reduced with prior incubation of the tissue with the nitric oxide synthase inhibitor L-NAME, or when the tissue comes from animals (Rattus norvegicus) chronically treated with L-NAME. 6-ND has several actions on the cardiovascular system. It is a potent vasodilator, competing through the antagonism of D2 dopaminergic receptors, and one hundred times more potent than noradrenaline and adrenaline and ten thousand times more potent than dopamine as a chronotropic agent in the isolated atrium of Rattus norvegicus. It has a contractile effect on the vas deferens of Rattus norvegicus and humans, and this effect is through its interaction with the specific receptor for 6-ND, which is blocked by tricyclic antidepressants, a-adrenergic antagonists and Beta-adrenergic antagonists. Based on the experiments above, the objective would be to verify whether different cell lines present a basal release of 6-ND and other new catecholamines, such as 6-nitrodopa, 6-nitroadrenaline, 6-cyanodpamine and, if so, whether they present an increase in intracellular calcium. after stimulation with these new catecholamines.

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