Abstract 809: Chronic Testosterone Deficiency Increases Late Inward Sodium Current in Ventricular Myocytes from Aging Male C57BL/6 Mice

Abstract

Clinical studies suggest that testosterone modulates the electrical activity of the heart and that low testosterone promotes cardiac arrhythmias. Here we investigated cellular mechanisms involved in the electrophysiological effects of chronic testosterone deficiency on the heart in aging male mice. Male C57BL/6 mice were subjected to either a gonadectomy (GDX) or a sham surgery at 1 month of age and then aged to 16-18 months. Ventricular myocytes were isolated and transmembrane voltage plus ionic currents were recorded with microelectrodes (20-25 MΩ; current clamp & discontinuous single electrode voltage clamp; 37 o C). Cells were paced at 2 and 4 Hz. Action potential duration at 90% repolarization (APD 90 ) was prolonged by GDX (57.9 ± 1.7 vs 108.2 ± 14.1 msec; p<0.05), while APD 50 and resting membrane potential were unchanged. We next determined whether an increase in late inward sodium current (I Na-L ) contributed to the increase in APD 90 in GDX cells. Voltage clamp studies showed that I Na-L was significantly larger in GDX cells compared to sham cells (-0.70 ± 0.16 vs -1.53 ± 0.27 pA/pF; p<0.05). When myocytes were superfused with the I Na-L antagonist ranolazine (10 μM), the increase in APD 90 was blocked in cells from GDX mice, so that APD 90 no longer differed between the two groups. By contrast, ranolazine had no effect on either APD 50 or resting membrane potential. Ranolazine also blocked the increase in I Na-L in cells from GDX mice. Prolongation of the action potential in GDX myocytes was associated with a significant increase in the incidence of early afterdepolarizations (EADs) when compared to sham controls. EADs were also inhibited by ranolazine. These data demonstrate that long-term GDX prolongs APD 90 at least in part by increasing the magnitude of I Na-L . These findings also suggest that an increase in I Na-L may promote arrhythmias in older men with low circulating testosterone levels.