LIDOCAINE BLOCK OF LQT-3 MUTANT HUMAN NA+ CHANNELS

In transiently transfected mammalian cells we have identified pharmaco logical consequences of a naturally occurring deletion mutation, Delta KPQ, of the human heart Na+ channel alpha subunit that previously has been linked to one form of the long QT syndrome, an inherited heart d isease. Our results show that the Class I-B antiarrhythmic agent lidoc aine blocks maintained inward current through and slows recovery from inactivation of Delta KPQ-encoded Na+ channels. Block is greater for m aintained than for peak current. Because incomplete inactivation of mu tant Na+ channels is now thought to underlie the prolonged ventricular action potential, which is the phenotype of this disease, and we find that the Delta KPQ mutation speeds the recovery from inactivation of drug-free mutant channels, our results provide evidence, for the first time, that clinically relevant dysfunctional properties of an ion cha nnel can be selectively targeted on the basis of the molecular propert ies conferred on the channel by an inherited genetic disorder.