Role of 6-nitrodopamine and adenylyl cyclase on the acid secretion from the snake Crotalus durissus terrificus

• Grant number: 25/01520-5
• Support Opportunities: Research Grants - Visiting Researcher Grant - International
• Start date: September 01, 2025
• End date: August 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Autonomic Pharmacology
• Principal Investigator: Gilberto de Nucci
• Grantee: Gilberto de Nucci
• Visiting researcher: Tobias Wang
• Visiting researcher institution: Aarhus University, Denmark
• 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 a recently discovered endogenous catecholamine released from vascular tissues, the heart endothelium, and seminal vesicle epithelium. It is the predominant catecholamine released from isolated vascular tissues in both mammals and reptiles, and its release is significantly reduced by the nitric oxide (NO) synthase inhibitor N ¿ -nitro-L-arginine methyl ester (L-NAME). 6-ND is the most potent endogenous vasorelaxant in the rabbit isolated aorta, being over 1,000 times more potent than acetylcholine, and its vasorelaxation is unaffected by soluble guanylate cyclase (sGC) inhibition, suggesting a novel mechanism of NO-induced vasorelaxation. In the heart, 6-ND is the major catecholamine released from both atria and ventricles, and studies with knockout mice suggest that endothelial nitric oxide synthase (eNOS) is primarily responsible for its synthesis. Additionally, 6-ND has been identified as a key mediator of heart chronotropism and inotropism, potentiating the effects of classical catecholamines like noradrenaline, adrenaline, and dopamine. Its receptor in human cardiomyocytes is associated with cyclase-associated proteins CAP-1 and CAP-2, which modulate adenylyl cyclase activity. In contrast to mammals, where acid secretion in the stomach involves a complex cascade triggering proton pump translocation, snakes exhibit unique gastric acid regulation, with acid secretion shutting down post-digestion, raising questions about the role of adenylyl cyclase in gastric function in reptiles. Furthermore, studies on snake metabolism during digestion reveal a significant increase in the lactate-to-pyruvate ratio and a rise in mitochondrial respiration, indicating a metabolic shift during digestion that may differ from the mechanisms seen in mammals. These findings highlight the complexity of 6-ND's role in physiological processes across different species, including its potential involvement in metabolic regulation in snakes. (AU)