Antiarrhythmic effect of IKr activation in a cellular model of LQT3.
BACKGROUND
Long QT syndrome type 3 (LQT3) is an inherited cardiac disorder caused by gain-of-function mutations in the cardiac voltage-gated sodium channel, Na(v)1.5. LQT3 is associated with the polymorphic ventricular tachycardia torsades de pointes (TdP), which can lead to syncope and sudden cardiac death. The sea anemone toxin ATX-II has been shown to inhibit the inactivation of Na(v)1.5, thereby closely mimicking the underlying cause of LQT3 in patients.


OBJECTIVE
The hypothesis for this study was that activation of the I(Kr) current could counteract the proarrhythmic effects of ATX-II.


METHODS
Two different activators of I(Kr), NS3623 and mallotoxin (MTX), were used in patch clamp studies of ventricular cardiac myocytes acutely isolated from guinea pig to test the effects of selective I(Kr) activation alone and in the presence of ATX-II. Action potentials were elicited at 1 Hz by current injection and the cells were kept at 32 degrees C to 35 degrees C.


RESULTS
NS3623 significantly shortened action potential duration at 90% repolarization (APD(90)) compared with controls in a dose-dependent manner. Furthermore, it reduced triangulation, which is potentially antiarrhythmic. Application of ATX-II (10 nM) was proarrhythmic, causing a profound increase of APD(90) as well as early afterdepolarizations and increased beat-to-beat variability. Two independent I(Kr) activators attenuated the proarrhythmic effects of ATX-II. NS3623 did not affect the late sodium current (I(NaL)) in the presence of ATX-II. Thus, the antiarrhythmic effect of NS3623 is likely to be caused by selective I(Kr) activation.


CONCLUSIONS
The present data show the antiarrhythmic potential of selective I(Kr) activation in a cellular model of the LQT3 syndrome.
Diness
Jonas Goldin
JG
NeuroSearch A/S, Ballerup, Denmark.
Hansen
Rie Schultz
RS
Nissen
Jakob Dahl
JD
Jespersen
Thomas
T
Grunnet
Morten
M
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D018118:Chloride Channels; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015640:Ion Channel Gating / Q000502:physiology*; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology*
D018118:Chloride Channels; D062554:NAV1.5 Voltage-Gated Sodium Channel; C423868:NS 3623; D010671:Phenylurea Compounds; D015221:Potassium Channels; D015222:Sodium Channels; D013777:Tetrazoles