Delayed rectifier K currents have reduced amplitudes and altered kinetics in myocytes from infarcted canine ventricle.

OBJECTIVE The rapid (I(Kr)) and slow (I(Ks)) components of delayed rectifier currents play an important role in determining the cardiac action potential configuration. Abnormalities in their function may contribute to arrhythmogenesis under pathological conditions. We studied the effects of myocardial infarction on I(Kr) and I(Ks) in canine ventricular myocytes and their molecular basis. METHODS Infarct zone myocytes (IZs) were isolated from a thin layer of surviving epicardium overlying an infarct 5 days after a total occlusion of the left anterior descending (LAD) coronary artery. Normal myocytes (NZs) were isolated from the corresponding region of control hearts for comparison. Currents were recorded under the whole-cell patch clamp conditions. RESULTS Both I(Kr) and I(Ks) current densities were reduced in IZs versus NZs. Kinetic analysis further suggests an acceleration of I(Kr) activation and I(Ks) deactivation. RNase protection assays were used to quantify the mRNA levels of I(Kr) and I(Ks) channel subunits (dERG, dIsK and dKvLQT1) in tissue immediately adjacent to the region where myocytes were isolated. mRNA levels of all three subunits were reduced 2 days after LAD occlusion (by 48+/-9%, 68+/-5%, and 45+/-4% for dERG, dIsK and dKvLQT1, respectively, n=8 each). By day 5, the dKvLQT1 message returned to control while those of dERG and dIsK remained reduced (by 52+/-7% and 76+/-6%, respectively). CONCLUSIONS The decrease in I(Kr) and I(Ks) amplitudes and changes in their kinetics in infarcted tissue might be due to a decrease in functional channels and/or changes in their subunit composition. Heterogeneous changes in I(Kr) and I(Ks) in infarcted hearts may impact on the effects of varying heart rate or neurohumoral modulation on repolarization.

[1]  P. Ursell,et al.  Structural and Electrophysiological Changes in the Epicardial Border Zone of Canine Myocardial Infarcts during Infarct Healing , 1985, Circulation research.

[2]  B. Fermini,et al.  Rapid and slow components of delayed rectifier current in human atrial myocytes. , 1994, Cardiovascular research.

[3]  M. Sanguinetti,et al.  Isoproterenol antagonizes prolongation of refractory period by the class III antiarrhythmic agent E-4031 in guinea pig myocytes. Mechanism of action. , 1991, Circulation research.

[4]  G. Tseng,et al.  Azimilide (NE‐10064) Can Prolong or Shorten the Action Potential Duration in Canine Ventricular Myocytes: , 1997, Journal of cardiovascular electrophysiology.

[5]  P. Boyden,et al.  Abnormal Electrical Properties of Myocytes From Chronically Infarcted Canine Heart: Alterations in &OV0312;max and the Transient Outward Current , 1992, Circulation.

[6]  P. Pennefather,et al.  Gating of IsK expressed in Xenopus oocytes depends on the amount of mRNA injected , 1994, The Journal of general physiology.

[7]  M. Janse,et al.  Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. , 1989, Physiological reviews.

[8]  Glenn I. Fishman,et al.  A minK–HERG complex regulates the cardiac potassium current IKr , 1997, Nature.

[9]  W. Giles,et al.  Inhibition of transient outward K+ current by DHP Ca2+ antagonists and agonists in rabbit cardiac myocytes. , 1991, The American journal of physiology.

[10]  M. Sanguinetti,et al.  A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel , 1995, Cell.

[11]  M. Keating,et al.  MiRP1 Forms IKr Potassium Channels with HERG and Is Associated with Cardiac Arrhythmia , 1999, Cell.

[12]  L. Kaczmarek,et al.  Modulation by cAMP of a slowly activating potassium channel expressed in Xenopus oocytes , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[13]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[14]  M. Sanguinetti,et al.  Coassembly of KVLQT1 and minK (IsK) proteins to form cardiac IKS potassium channel , 1996, Nature.

[15]  G. Gintant,et al.  Two components of delayed rectifier current in canine atrium and ventricle. Does IKs play a role in the reverse rate dependence of class III agents? , 1996, Circulation research.

[16]  D. Roden,et al.  Replacement by homologous recombination of the minK gene with lacZ reveals restriction of minK expression to the mouse cardiac conduction system. , 1999, Circulation research.

[17]  S Nattel,et al.  Evidence for two components of delayed rectifier K+ current in human ventricular myocytes. , 1996, Circulation research.

[18]  Jacques Barhanin,et al.  KvLQT1 and IsK (minK) proteins associate to form the IKS cardiac potassium current , 1996, Nature.

[19]  W. Stühmer,et al.  The role of the IsK protein in the specific pharmacological properties of the IKs channel complex , 1997, British journal of pharmacology.

[20]  C. Antzelevitch,et al.  Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell. , 1995, Circulation research.

[21]  S Nattel,et al.  Transient outward and delayed rectifier currents in canine atrium: properties and role of isolation methods. , 1996, The American journal of physiology.