Mechanism of myricetin stimulation of vascular L-type Ca2+ current

An in-depth analysis of the mechanism of the L-type Ca2+ current [I-Ca(L)] stimulation induced by myricetin was performed in rat tail artery myocytes using the whole-cell patch-clamp method. Myricetin increased I-Ca(L) in a frequency-, concentration, and voltage-dependent manner. At holding potentials (V-h) of -50 and -90 mV, the pEC(50) values were 4.9 +/- 0.1 and 4.2 +/- 0.1, respectively; the latter corresponded to the drug-apparent dissociation constant for resting channels, K-R, of 67.6 mu M. Myricetin shifted the maximum of the current-voltage relationship by 10 mV in the hyperpolarizing direction but did not modify the threshold for I-Ca(L) or the T-type Ca2+ current. The Ca2+ channel blockers nifedipine, verapamil, and diltiazem antagonized I-Ca(L) in the presence of myricetin. Myricetin increased the time to peak of I-Ca(L) in a voltage- and concentration-dependent manner. Washout reverted myricetin effect on both current kinetics and amplitude at V-h of -90 mV while reverting only current kinetics at V-h of -50 mV. At the latter V-h, myricetin shifted the voltage dependence of inactivation and activation curves to more negative potentials by 6.4 and 13.0 mV, respectively, in the mid-potential of the curves. At V-h of -90 mV, myricetin shifted, in a concentration-dependent manner, the voltage dependence of the inactivation curve to more negative potentials with an apparent dissociation constant for inactivated channels (K-I) of 13.8 mu M. Myricetin induced a frequency- and V-h-dependent block of I-Ca(L). In conclusion, myricetin behaves as an L-type Ca2+ channel agonist that stabilizes the channel in its inactivated state.