Characterization of mice with a combined suppression of I(to) and I(K,slow).
Cardiac-specific expression of a truncated Kv1.1 polypeptide (Kv1DN) attenuates the slow inactivating outward K(+) current (I(K,slow)), increases action potential duration (APD) and Q-T intervals, and induces spontaneous ventricular arrhythmias. Expression of the pore mutant of Kv4.2 (Kv4DN) eliminates the fast component of the transient outward current (I(to)) and prolongs APDs and Q-T intervals markedly; however, no arrhythmias are seen in Kv4DN mice, suggesting that APD and Q-T prolongation are not per se proarrhythmic. To test this hypothesis, the Kv1DN and Kv4DN lines were crossbred to produce animals (Kv1/Kv4DN) expressing both transgenes in an identical genetic background. Whole cell voltage-clamp recordings from left ventricular apex cells confirmed that in Kv1/Kv4DN left ventricular apex cells, both components (fast and slow) of I(to) and the 4-aminopyridine-sensitive component of I(K,slow) are eliminated, resulting in marked APD prolongation compared with wild-type, Kv1DN, or Kv4DN cells. Telemetric electrocardiogram monitoring (n = 10 mice/group) revealed a significant prolongation of Q-Tc and P-R intervals in Kv1/Kv4DN animals compared with Kv1DN or Kv4DN animals. Spontaneous arrhythmias were observed mainly in Kv1DN mice. Thus the attenuation of fast I(to) in addition to I(K,slow) in Kv1/Kv4DN mice causes significant prolongation of APD and Q-T intervals and attenuation of spontaneous arrhythmias.
Brunner
M
M
Cardiovascular Research Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Guo
W
W
Mitchell
G F
GF
Buckett
P D
PD
Nerbonne
J M
JM
Koren
G
G
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002238:Carbohydrate Epimerases; D002469:Cell Separation; D003433:Crosses, Genetic; D015716:Electrocardiography, Ambulatory; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D015870:Gene Expression; D005799:Genes, Dominant; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D051662:Kv1.1 Potassium Channel; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000172:deficiency* / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D051672:Shal Potassium Channels; D013610:Tachycardia / Q000235:genetics / Q000503:physiopathology*; D013997:Time Factors; D019076:Transgenes; D016276:Ventricular Function
C496947:Kcna1 protein, mouse; C497019:Kcnd2 protein, mouse; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051672:Shal Potassium Channels; D051662:Kv1.1 Potassium Channel; D015761:4-Aminopyridine; D002238:Carbohydrate Epimerases; C019646:aldose 1-epimerase; D011188:Potassium