Characterization of mice with a combined suppression of I(to) and I(K,slow)

Am J Physiol Heart Circ Physiol. 2001 Sep;281(3):H1201-9. doi: 10.1152/ajpheart.2001.281.3.H1201.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 4-Aminopyridine / pharmacology
  • Action Potentials / physiology
  • Animals
  • Carbohydrate Epimerases
  • Cell Separation
  • Crosses, Genetic
  • Electrocardiography, Ambulatory
  • Electrophysiologic Techniques, Cardiac
  • Female
  • Gene Expression
  • Genes, Dominant
  • Heart Ventricles / cytology
  • Heart Ventricles / drug effects
  • Kv1.1 Potassium Channel
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myocardium / cytology
  • Myocardium / metabolism*
  • Patch-Clamp Techniques
  • Potassium / metabolism
  • Potassium Channels / deficiency*
  • Potassium Channels / genetics
  • Potassium Channels, Voltage-Gated*
  • Shal Potassium Channels
  • Tachycardia / genetics
  • Tachycardia / physiopathology*
  • Time Factors
  • Transgenes
  • Ventricular Function*

Substances

  • Kcna1 protein, mouse
  • Kcnd2 protein, mouse
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Shal Potassium Channels
  • Kv1.1 Potassium Channel
  • 4-Aminopyridine
  • Carbohydrate Epimerases
  • aldose 1-epimerase
  • Potassium