In vitro and in vivo evaluation of nitrated derivatives of propranolol and atenolol

• Grant number: 23/13692-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2023
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Gilberto de Nucci
• Grantee: Flaviano Lorenzon
• 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

6-Nitrodopamine (6-ND) is released by the endothelium of human umbilical cord vessels, aortic rings of the tortoise Chelonoidis carbonarius and aortic rings of the snake Panterophis guttatus. In these vascular tissues, 6-ND is a potent vasodilator, acting as a highly selective antagonist for dopamine D2-like dopamine receptors. The synthesis/release of 6-ND is coupled to the synthesis of nitric oxide (NO), as it is significantly reduced when vascular tissues are pretreated with the nitric oxide synthase inhibitor, L-NAME. 6-ND is an endogenous mediator of contractility of the human vas deferens and rat vas deferens, acting on a specific 6-ND receptor, which is blocked by tricyclic antidepressants and a1 and b1 adrenergic receptor antagonists. In isolated rat atrium, 6-ND is 100 times more potent than norepinephrine and adrenaline, and 10,000 times more potent than dopamine, as a positive chronotropic agent. In this context, we recently synthesized two nitrated derivatives of propranolol; 4-nitro-propranolol and 7-nitro-propranolol. 4-nitro-propranolol acts as a specific inhibitor of the 6-ND receptor in the isolated atrium, as it has a negative chronotropic effect at concentrations that block the positive chronotropic effect of 6-ND, but does not affect the positive chronotropic effect induced by the classical catecholamines dopamine. , norepinephrine and adrenaline. Furthermore, its S enantiomer has a positive chronotropic effect, while the R enantiomer does not have a chronotropic effect, indicating high stereoselectivity of the 6-ND receptor in the isolated atrium. The objective of this project would be to further study the negative chronotropic effect of 4-nitro-propranolol, and investigate its inotropic effect, both in vitro and in vivo. Furthermore, we are in the process of synthesizing nitrated derivatives of atenolol, and as this supposed b1-adrenergic blocker is more commonly used clinically, we will verify the occurrence of nitrated derivatives of atenolol in patients who chronically take atenolol.