Interpreting the serotonin blood pressure paradox: An updated integrative framework for hypertension

Abstract Background Serotonin (5-hydroxytryptamine) contributes to cardiovascular regulation through central and peripheral mechanisms, yet its reported effects on vascular tone, autonomic control, platelet function, renal physiology and arterial pressure are often opposing. We use the term ‘serotonin blood pressure paradox’ as an author-defined descriptive construct for these context-dependent observations rather than as a distinct clinical entity or single mechanism. Methods A structured narrative search of PubMed/MEDLINE, Scopus, Web of Science and Google Scholar was updated till 19 August 2026. Relevant data were selected with priority given to human studies, narratively extracted and synthesised according to evidence context; animal and in vitro studies addressed mechanisms insufficiently characterised clinically. Results Serotonergic cardiovascular effects are best interpreted within a distributed regulatory network involving autonomic pathways, vascular receptors, platelet serotonin handling and the serotonin transporter, endothelial and renal physiology, gut microbiota, serotonylation and genetic background. Their direction varies across biological compartment, context and time. Human evidence supports several vascular, platelet, renal, genetic and pharmacological associations, whereas microbiota-dependent mechanisms and serotonylation in systemic hypertension remain supported mainly by experimental or translational data. Circulating serotonin measurements are additionally limited by substantial pre-analytical variability. Conclusions The paradox is better understood as context-dependent serotonergic cardiovascular regulation than as a contradiction requiring a single mechanistic resolution. The proposed framework is interpretative and hypothesis-generating; current evidence does not establish serotonin as a dominant causal pathway, validated biomarker or specific therapeutic target in systemic arterial hypertension.