© 1996 American Heart Association, Inc.
Articles |
Lidocaine Block of LQT-3 Mutant Human Na+ Channels
the Department of Physiology, University of Rochester (NY) School of Medicine.
Correspondence to Robert S. Kass, PhD, Department of Pharmacology, College of Physicians and Surgeons of Columbia Uni-versity, 630 W 168th St, New York, NY 10032. E-mail rsks@uhura.cc.rochester.edu.
In transiently transfected mammalian cells we have identified pharmacological consequences of a naturally occurring deletion mutation, 
KPQ, of the human heart Na+ channel 
subunit that previously has been linked to one form of the long QT syndrome, an inherited heart disease. Our results show that the Class IB antiarrhythmic agent lidocaine blocks maintained inward current through and slows recovery from inactivation of KPQ-encoded Na+ channels. Block is greater for maintained than for peak current. Because incomplete inactivation of mutant Na+ channels is now thought to underlie the prolonged ventricular action potential, which is the phenotype of this disease, and we find that the 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 channel can be selectively targeted on the basis of the molecular properties conferred on the channel by an inherited genetic disorder.
Key Words: long QT syndrome • molecular genetics • Na+ channel • lidocaine • congenital heart disease
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