3,3′-O-dimethylquercetin: A bi-functional vasodilator isolated from green propolis of the Caatinga Mimosa tenuiflora.

In the search for novel, bi-functional compounds acting as Ca V 1.2 channel blockers and K+ channel stimulators, which represent an effective therapy for hypertension, 3,3′- O -dimethylquercetin was isolated for the first time from Brazilian Caatinga green propolis. Its effects were investigated through electrophysiological, functional, and computational approaches. In rat tail artery myocytes, 3,3′- O -dimethylquercetin blocked Ba2+ currents through Ca V 1.2 channels (I Ba1.2) in a concentration-dependent manner, with the inhibition being reversed upon washout. The compound also shifted the voltage dependence of the steady-state inactivation curve to more negative potentials without affecting the slope of the inactivation and activation curves. Furthermore, the flavonoid stimulated K Ca 1.1 channel currents (I KCa1.1). In silico simulations provided additional evidence for the binding of 3,3′- O -dimethylquercetin to K Ca 1.1 and Ca V 1.2 channels and elucidated its mechanism of action. In depolarized rat tail artery rings, the flavonoid induced a concentration-dependent relaxation. Moreover, in rat aorta rings its antispasmodic effect was inversely related to the transmembrane K+ gradient. In conclusion, 3,3′- O -dimethylquercetin demonstrates effective in vitro vasodilatory properties, encouraging the exploration of its scaffold to develop novel derivatives for potential use in the treatment of hypertension. [Display omitted] [ABSTRACT FROM AUTHOR]