(+/-)-Naringenin as large conductance Ca2+-activated K+ (BKCa) channel opener in vascular smooth muscle cells

Background and purpose. The aim of this study was to investigate, in vascular smooth muscle cells, the mechanical and electrophysiological effects of (+/-) -naringenin. Experimental approach. Aorta ring preparations and single tail artery myocytes were employed for functional and patchclamp experiments, respectively. Key results. (+/-)- Naringenin induced concentration-dependent relaxation in endothelium-denuded rat aortic rings precontracted with either 20 mM KCl or noradrenaline (pIC(50) values of 4.74 and 4.68, respectively). Tetraethylammonium, iberiotoxin, 4-aminopyridine and 60 mM KCl antagonised (+/-)-naringenin-induced vasorelaxation, while glibenclamide did not produce any significant antagonism. Naringin [(+/-)-naringenin 7-beta-neohesperidoside] caused a concentrationdependent relaxation of rings pre-contracted with 20 mM KCl, although its potency and efficacy were significantly lower than those of (+/-)-naringenin. In rat tail artery myocytes, (+/-)-naringenin increased large conductance Ca2+-activated K+ (BKCa) currents in a concentration-dependent manner; this stimulation was iberiotoxin-sensitive and fully reversible upon drug wash-out. (+/-)-Naringenin accelerated the activation kinetics of BKCa current, shifted, by 22 mV, the voltage dependence of the activation curve to more negative potentials, and decreased the slope of activation. (+/-)-Naringenin-induced stimulation of BKCa current was insensitive either to changes in the intracellular Ca2+ concentration or to the presence, in the pipette solution, of the fast Ca2+ chelator BAPTA. However, such stimulation was diminished when the K+ gradient across the membrane was reduced. Conclusions and Implications. The vasorelaxant effect of the naturally-occurring flavonoid (+/-)-naringenin on endothelium-denuded vessels was due to the activation of BKCa channels in myocytes.