The Role of Hydrogen Sulfide in the Pathophysiology and Therapeutic Modulation of Hypertension: A Scoping Review

Hydrogen sulfide (H₂S) is an endogenous gasotransmitter involved in vascular regulation, endothelial signaling, oxidative balance, and inflammatory pathways relevant to blood pressure control. Experimental and clinical evidence suggest that reduced H₂S bioavailability contributes to hypertension and associated vascular dysfunction. This study aimed to map and synthesize the breadth of mechanistic, preclinical, and clinical evidence on the role of H₂S in the pathophysiology and therapeutic modulation of hypertension. This scoping review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guideline. A comprehensive search of PubMed was conducted for English-language publications from January 1, 2001, to July 31, 2025, with a final update on August 10, 2025. Supplementary sources included Google Scholar (first 300 relevance-ranked results screened) and ClinicalTrials.gov. Prespecified Boolean strategies were used to identify mechanistic studies, animal experiments, human observational studies, interventional trials, and relevant secondary literature. Data were charted using a standardized extraction framework. A total of 873 records were identified. After removing 223 duplicates, 650 unique records underwent title/abstract screening; 69 full texts were assessed; and 39 sources were included. Mechanistic and preclinical data consistently demonstrated that reduced H₂S signaling leads to endothelial dysfunction, oxidative stress, vascular remodeling, and elevated blood pressure, while H₂S supplementation improves vascular tone. Human observational studies showed lower circulating H₂S levels and impaired H₂S-mediated vasodilation in hypertensive populations. Interventional trials using H₂S-enhancing strategies, particularly aged garlic extract and early H₂S prodrugs, reported modest reductions in blood pressure and arterial stiffness, although clinical evidence remains limited and heterogeneous. Existing literature supports a biologically plausible role for H₂S in hypertension and suggests that H₂S-enhancing interventions may offer therapeutic benefit. However, translation to clinical practice is hindered by small sample sizes, heterogeneity of study designs, and lack of standardized H₂S measurement. Future research should prioritize validated biomarkers and adequately powered clinical trials.