An evolutionary perspective on endothelial cardiovascular control in vertebrates and its functions

• Grant number: 23/01267-2
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2023
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Physiology - Compared Physiology
• Agreement: CNPq
• Principal Investigator: Gilberto de Nucci
• Grantee: Gilberto de Nucci
• 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
• Associated scholarship(s): 23/15165-7 - Development of Liquid Chromatography methods coupled to Tandem Mass Spectrometry (LC-MS/MS) for monitoring the metabolites of new catecholamines, BP.JD

Abstract

Nitric oxide (NO), is commonly produced within the endothelial cells and is argued to possess potent vasodilatory effects. NO may induce nitration of catecholamine neurotransmitters, resulting in corresponding 6-nitroderivatives. Recently, the 6-nitroderivatives were demonstrated to affect vascular tone and cardiac chronotropy and inotropy. Additionally, a new family of catecholamines, also from endothelial origin, have been identified by the research group led by prof. Gilberto De Nucci, at the University of Campinas. These novel catecholamines are being suggested to play a pivotal role in the cardiovascular system regulation. These suggestions are supported by a series of in vitro experiments showing i) a complete inhibition of vasomotion in arterial rings denuded from the endothelium and subjected to electrical field stimulation (EFS), and ii) a positive chronotropic effect of 6-nitrodopamine in isolated rat atrium, estimated to be 100-fold more potent than adrenaline and noradrenaline, and 10,000-fold more potent than dopamine. Finally, the suggestion that the endothelium may secrete acetylcholine and catecholamines demand an urgent reappraisal of the role of the endothelium in the regulation of the cardiovascular system. In this proposal, I intend to investigate the role of the endothelium and the ensuing novel catecholamines on the cardiovascular system from an evolutionary and functional perspective. Using Nile tilapias (Oreochromis niloticus), I intend to unravel the putative functional role of the 6-nitrodopamine in cardiovascular regulation during acute hypoxia, and to identify putative catecholamines formed in the different vascular beds. Measurements of in vivo arterial pressure and heart rate of fish chronically exposed to L-NAME under normoxia and acute hypoxia will test if 6-nitroderivatives are relevant to the cardiovascular responses to hypoxia. These will be complemented by in vitro studies of vascular regulation in the myograph, and cardiac chronotropy/inotropy using Langendorff preparations, and measure of catecholamines using mass spectrometry. Using the novel experimental model of decerebrate rattlesnakes (Crotalus durissus), I will measure the hemodynamics of the pulmonary circulation to analyze its dependency on the vagal regulation and endothelium-derived production of acetylcholine. In vitro myography and EFS will be utilized to identify the specific muscarinic receptors responsible for the cholinergic vasoconstrictions observed in reptiles. Finally, using cornsnakes (Panterophis guttatus) I intend to identify the catecholamines produced in various vascular beds using mass spectrometry. I will also utilize in vivo and in vitro measurements to identify the responses of those vascular beds to the injection of different catecholamines. The project will count with the collaboration of prof. Cléo A. C. Leite (UFSCar) and prof. Tobias Wang (Aarhus University - Denmark). (AU)