Pathophysiological aspects of the interaction between endogenous natriuretic factors and digoxin-like substances as different functional systems of central nervous system regulation: a systematic review

Background: Endogenous natriuretic factors (ENFs) and digitalis-like substances (DLS) are key endogenous regulators influencing the central nervous system (CNS) through distinct molecular mechanisms. ENFs, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), primarily regulate water-salt balance and vascular tone through guanylate cyclase receptor activation, while DLS, including endogenous ouabain and marinobufagenin, modulate Na-K-ATPase activity, affecting neuronal excitability and intracellular signaling cascades. Objective: To conduct a comprehensive systematic analysis of ENFs and DLS as functionally distinct CNS regulatory systems, evaluating their molecular mechanisms, clinical significance, and therapeutic potential. Methods: A systematic search was conducted in PubMed/MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library databases from 1957 to 2025. Search terms included: "endogenous natriuretic factors", "digitalis-like substances", "central nervous system regulation", "Na-K-ATPase inhibition", "ouabain-like compounds", "marinobufagenin". Study selection followed PRISMA 2020 guidelines with independent screening by two reviewers. Quality assessment used Cochrane RoB 2.0 for RCTs and Newcastle-Ottawa Scale for observational studies. Results: From 1,247 identified publications, 89 studies met inclusion criteria (n=15,847 participants). ENFs affect the CNS via cGMP-dependent mechanisms, reducing sympathetic activity by 20-35% and modulating neurotransmission through NPR-A, NPR-B, and NPR-C receptors. DLS activate Src-kinase cascades through selective inhibition of Na-K-ATPase α-subunits, influencing circadian rhythms and cognitive functions. In pathological conditions, characteristic imbalances were observed: DLS levels increased 1.5-2.8-fold in essential hypertension and depression, while ENF activity decreased 25-40% in neurodegenerative diseases. Conclusions: ENFs and DLS function as independent but interconnected regulatory systems with significant therapeutic potential. Understanding their distinct mechanisms opens new avenues for developing personalized treatment strategies for neurological disorders.