(+/-)-Naringenin as large conductance Ca(2+)-activated K+ (BKCa) channel opener in vascular smooth muscle cells

• Published in: British journal of pharmacology Vol. 149; no. 8; pp. 1013 - 1021
• Main Authors: Saponara, S, Testai, L, Iozzi, D, Martinotti, E, Martelli, A, Chericoni, S, Sgaragli, G, Fusi, F, Calderone, V
• Format: Journal Article
• Language: English
• Published: England 01.12.2006
• Subjects: Animals; Arteries - cytology; Arteries - drug effects; Arteries - metabolism; Calcium - metabolism; Cell Separation; Chelating Agents - pharmacology; Egtazic Acid - analogs & derivatives; Egtazic Acid - pharmacology; Electrophysiology; Flavanones - pharmacology; In Vitro Techniques; Kinetics; Male; Membrane Potentials - drug effects; Muscle Relaxation - drug effects; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - drug effects; Patch-Clamp Techniques; Potassium Channels, Calcium-Activated - agonists; Rats; Rats, Sprague-Dawley; Vasodilation - drug effects
• ISSN: 0007-1188
• DOI: 10.1038/sj.bjp.0706951

BACKGROUND AND PURPOSE. The aim of this study was to investigate, in vascular smooth muscle cells, the mechanical and electrophysiological effects of (+/-)-naringenin. Aorta ring preparations and single tail artery myocytes were employed for functional and patch-clamp experiments, respectively. (+/-)-Naringenin induced concentration-dependent relaxation in endothelium-denuded rat aortic rings pre-contracted 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 concentration-dependent 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 Ca(2+)-activated K(+) (BK(Ca)) currents in a concentration-dependent manner; this stimulation was iberiotoxin-sensitive and fully reversible upon drug wash-out. (+/-)-Naringenin accelerated the activation kinetics of BK(Ca) 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 BK(Ca) current was insensitive either to changes in the intracellular Ca(2+) concentration or to the presence, in the pipette solution, of the fast Ca(2+) chelator BAPTA. However, such stimulation was diminished when the K(+) gradient across the membrane was reduced. The vasorelaxant effect of the naturally-occurring flavonoid (+/-)-naringenin on endothelium-denuded vessels was due to the activation of BK(Ca) channels in myocytes.