REDUCTION OF THE TRANSIENT OUTWARD POTASSIUM CURRENT IN CANINE X-LINKED MUSCULAR-DYSTROPHY

Background The xmd dog develops a cardiomyopathy similar to that seen in Duchenne muscular dystrophy patients. In both the canine and human diseases, ECG abnormalities may precede the development of overt cardiac pathological lesions. The purpose of this study was to determine whether specific cellular electrical abnormalities occur in dystrophic ventricular tissue. Methods and Results Action potentials were recorded in epicardial tissue strips obtained from normal and xmd dogs. Phase 1 amplitude was increased from 86.8+/-2.7 mV in normal dogs to 94.3+/-1.8 mV in xmd dogs (mean+/-SEM; P<.05). The 4-aminopyridine-sensitive transient outward potassium current (I-to), as recorded in isolated epicardial myocytes using the whole-cell patch-clamp technique, was reduced in xmd dogs compared with age-matched normal dogs. Cell capacitance also was reduced significantly in xmd compared with normal cells, as was the current density (3.6+/-0.3 versus 5.4+/-0.8 pA/pF, respectively). No differences were observed in the time constants of current decay or in the kinetics of recovery from inactivation between groups. The slope factor (k) of steady-state inactivation was significantly greater in xmd compared with normal cells (7.2+/-0.9 versus 5.4+/-0.5, respectively), whereas the V-1/2 of inactivation did not differ (-38.2+/-2.4 versus -36.8+/-1.6 mV, respectively). Conclusions These data indicate that the magnitude of I-to is reduced in dystrophic epicardial myocytes, resulting in an increase in phase 1 amplitude. The reduction of I-to may alter the balance of inward and outward currents in dystrophic myocardium and thereby contribute to the development of cardiac pathology.