Heterogeneity of the early outward current in ventricular cells isolated from normal and hypertrophied rat hearts

Abstract

1. The nature, magnitude and kinetics of the 4-aminopyridine-sensitive early outward current (Ito) were analysed in isolated ventricular myocytes from the septum, the apex and the left ventricular free wall of rat ventricles using the whole-cell voltage clamp method. The modulatory effect of pressure overload-induced cardiac hypertrophy on the regional variations of Ito was assessed in each topographical class of cells. 2. Voltage clamp experiments were performed at room temperature (20-25 degrees C) in the absence of Na+ on both sides of the membrane and in the presence of 3 mM CoCl2. Ito was studied from a holding potential of -80 mV and determined by subtraction of total outward currents elicited by the same protocols in the presence of 3 mM 4-aminopyridine (4-AP) from those obtained in its absence. 3. In normal hearts, membrane passive properties were very similar in each topographical class of cells. Our results confirmed that the predominant early outward current in rat ventricular cells was 4-AP-sensitive, time and voltage dependent, and demonstrated that the magnitude of the current varied on a regional basis: current density of Ito in left ventricular free wall cells (30.1 +/- 9.2 pA/pF at +60 mV) was larger than in apex cells (20.2 +/- 1.7 pA/pF) or in septum cells (11.9 +/- 3.3 pA/pF). We noticed a larger variability in data from left ventricular free wall compared with other regions. 4. No shift in steady-state voltage dependence of Ito activation and inactivation was found. However, the maximal computed chord conductances were (in microS/pF): 0.18 +/- 0.07 for left ventricular free wall cells, 0.13 +/- 0.02 for apex cells, and 0.08 +/- 0.02 for septum cells. These findings might reflect a differential distribution in functional channel densities. 5. No difference in voltage-dependent Ito activation kinetics was present with respect to topography. However, inactivation time constants in septum were longer than those of both other groups. 6. Left ventricular hypertrophy was induced by abdominal aortic constriction and its effects compared to the findings from normal rats. Hypertrophied cells had similar resting potentials but higher capacitance values than normal cells. Although Ito magnitude appeared not to be modified, the current density-voltage curves were slightly shifted to more positive potentials and significantly decreased as compared to normal cells (in pA/pF, at +60 mV): 8.4 +/- 5.0 in the left free wall group, 11.6 +/- 2.0 in the apex group, and 3.8 +/- 1.5 in the septum group.(ABSTRACT TRUNCATED AT 400 WORDS)