Comprehensive vasodilatory and antihypertensive effects of 3,7,3',4'-tetrahydroxyflavone (fisetin): Ex vivo and in vivo evidence.

Hypertension is a chronic condition characterised by persistently elevated arterial blood pressure and remains a major global health burden. Although many antihypertensive agents are clinically effective, treatment is often limited by poor adherence and adverse effects, underscoring the need for alternative or adjunctive therapies with favourable tolerability. Fisetin, a naturally occurring plant flavonol found in fruits and vegetables, has been reported to exert antihypertensive activity; however, the vascular mechanisms underlying its effects remain incompletely defined. This study investigated fisetin-induced vasorelaxation using isolated rat aortic rings and evaluated its antihypertensive efficacy in spontaneously hypertensive rats (SHRs). Fisetin produced concentration-dependent vasorelaxation through multiple mechanisms, including nitric oxide/soluble guanylate cyclase (NO/sGC) signalling, cyclooxygenase/prostacyclin-related pathways, G-protein-coupled receptor-mediated signalling, potassium channel activation, and calcium channel inhibition. Western blot analysis further supported activation of the Akt/eNOS pathway. Daily oral fisetin administration for 28 days significantly reduced systolic, diastolic, and mean arterial pressure in SHRs. No overt toxicity was observed based on body weight, haematological indices, or serum biochemical parameters. These findings suggest that fisetin is a promising candidate for further development as an antihypertensive adjunct targeting multiple vasodilatory pathways.