Evaluation of the action of 6-nitrodopamine on the cardiovascular system in eNOS, nNOS and iNOS knockout mice

• Grant number: 23/03503-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): April 01, 2023
• Effective date (End): December 31, 2024
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Gilberto de Nucci
• Grantee: Larissa Bueno Andrade
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 19/16805-4 - Evaluation of the pathophysiological role of endothelial catecholamines, AP.TEM

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 tonus, cardiac chronotropism and inotropism through their release from adrenergic terminals, and with action on a and b adrenergic receptors. Using mass spectrometry, we identified 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, indicating that dopamine of endothelial origin has the potential to modulate vascular reactivity. We also identified the release of a new catecholamine, 6-nitrodopamine (6-ND), from human tissues (umbilical arteries and vein; peripheral arteries and veins such as popliteal, femoral; human vas deferens) and from vascular tissues of animals (thoracic duct, femoral, renal, carotid, coronary and pulmonary artery of Sus domesticus; aorta of Chelonoidis carbonaria; aorta of Panterophis guttatus, aorta and pulmonary artery of Callithrix sp), atrium and ventricles of Rattus norvegicus, black C57BL/6 mouse and of Sus domesticus and of vas deferens from Rattus norvegicus. The release of 6-ND is reduced with previous 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, acting through antagonism of D2-like 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 a specific receptor for 6-ND, which is blocked by tricyclic antidepressants, a-adrenergic antagonists and b-adrenergic antagonists. At the moment, we do not know if this action of 6-ND is due to itself, or to a possible metabolism of the same in 6-nitronoradrenaline (6-NN) and 6-nitroadrenaline (6-NA).Therefore, the objectives of this project are the following:Use of iNOS, nNOS and eNOS knockout mice to identify the source of 6-ND released from atria, ventricles and vessels.