Abstract

The roots from Aconitum sp. plants have long been used in Chinese herbal medicine for treating pain and various heart conditions. The principal component of Aconitum remedies is usually aconitine, a site 2 neurotoxin that may induce severe neurological symptoms and cardiovascular collapse. SomeAconitum species also contain lappaconitine, the structure of which is remarkably similar to that of aconitine. In contrast to aconitine, a sodium channel agonist, lappaconitine reportedly blocks voltage-gated sodium channels in heart tissue. The results in the present study demonstrate that lappaconitine blocks cloned human heart (hH1) sodium channels under whole-cell, voltage-clamp conditions. Lappaconitine binding has several characteristics in common with the binding of site 2 neurotoxins, such as aconitine and batrachotoxin. For example, lappaconitine binds almost exclusively to open channels, but has little affect on resting or inactivated channels. Moreover, lappaconitine binding is inhibited by bupivacaine, a tertiary amine local anesthetic. Whereas site 2 neurotoxins often irreversibly modify channel kinetics, lappaconitine irreversibly blocks the channels. Finally, channels containing lysine substitutions within the local anesthetic receptor region at residues F1760 or N1765 are resistant to block by bupivacaine or lappaconitine. Given that site 2 neurotoxins and local anesthetics have nonidentical but overlapping binding regions, these data suggest that lappaconitine irreversibly blocks hH1 channels by binding to the site 2 receptor.