Chronic Testosterone Deficiency Increases Late Inward Sodium Current and Promotes Triggered Activity in Ventricular Myocytes from Aging Male Mice.

Abstract

Clinical studies suggest low testosterone levels are associated with cardiac arrhythmias, especially in later life. We investigated whether chronic exposure to low circulating testosterone promoted maladaptive electrical remodeling in ventricular myocytes from aging male mice and determined the role of late inward sodium current (INa-L) in this remodeling. C57BL/6 mice had a gonadectomy (GDX) or sham surgery (1-month) and were aged to 22-28-months. Ventricular myocytes were isolated; transmembrane voltage and currents were recorded (37°C). Action potential duration at 70 and 90% repolarization (APD70 and APD90) was prolonged in GDX compared to sham myocytes (APD90: 96.9±3.2 vs 55.4±2.0 ms; p<0.001). INa-L was also larger in GDX than sham (-2.4±0.4 vs -1.2±0.2 pA/pF; p=0.002). When cells were exposed to the INa-L antagonist ranolazine (10 µM), INa-L declined in GDX cells (-1.9±0.5 vs -0.4±0.2 pA/pF; p<0.001) and APD90 was reduced (96.3±14.8 vs 49.2±9.4 ms; p=0.001). GDX cells had more triggered activity (early/delayed afterdepolarizations, EADs/DADs) and spontaneous activity than sham. EADs were inhibited by ranolazine in GDX cells. The selective NaV1.8 blocker A-803467 (30 nM) also reduced INa-L, decreased APD and abolished triggered activity in GDX cells. Scn5a (NaV1.5) and Scn10a (NaV1.8) mRNA was increased in GDX ventricles, but only NaV1.8 protein abundance was increased in GDX compared to sham. In vivo studies showed QT prolongation and more arrhythmias in GDX mice. Thus, triggered activity in ventricular myocytes from aging male mice with long-term testosterone deficiency arises from APD prolongation mediated by larger NaV1.8- and NaV1.5-associated currents, which may explain the increase in arrhythmias.