Ethnopharmacological insights into Sagrantino grape leaves: vasoactive phytocomplexes and extracellular vesicles from an underutilised agro-waste

Ethnopharmacological relevance: Grapevine leaves are traditionally used in Mediterranean and Middle Eastern ethnomedicine to treat circulatory disorders, inflammation, and venous insufficiency. However, cultivar-specific phytochemical profiles and their underlying vascular mechanisms remain poorly characterised. Aim of the study: To investigate the chemical composition and vascular activity of extracts and extracellular micro- and nanovesicles (EVs) derived from leaves of the Italian Vitis vinifera cv. Sagrantino. Materials and methods: Extracts were obtained using ultrasound-assisted extraction and Soxhlet methods with solvents of different polarity. Phytochemical profiling was performed by UHPLC-HRMS and 1H NMR. EVs were characterised by nanoparticle tracking analysis and transmission electron microscopy and analysed by NMR. Vascular effects were assessed ex vivo on rat aorta rings. Modulation of vascular smooth muscle CaV1.2 channels was evaluated by whole-cell patch-clamp recordings. Results: Extracts were rich in polyphenols, including flavonoid glycosides, gallotannins, ellagitannins, and cinnamic acid derivatives. All extracts induced concentration-dependent vasorelaxation in endothelium-intact aorta rings, whereas removal of the endothelium markedly reduced or reversed this effect, often leading to contraction. A hormetic response was observed at higher concentrations. Ultrasound-assisted hydroalcoholic extracts showed the strongest activity. EVs showed nanoscale morphology, contained polyphenols, sugars, fatty acids and amino acids, induced vasorelaxation, and inhibited CaV1.2 channel currents in a concentration-dependent manner. Conclusions: Sagrantino grapevine leaves represent an underutilised source of vasoactive compounds. Their vascular effects involve both endothelium-dependent mechanisms and direct inhibition of CaV1.2 channels. These findings provide mechanistic support for their traditional use and highlight their potential for sustainable cardiovascular applications within a circular bioeconomy framework.