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 (I_Na,L) in this remodeling. C57BL/6 mice had a gonadectomy (GDX) or sham surgery (1 mo) and were aged to 22-28 mo. 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 with sham myocytes (APD₉₀, 96.9 ± 3.2 vs. 55.4 ± 2.0 ms; P < 0.001). I_Na,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 I_Na,L antagonist ranolazine (10 µM), I_Na,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 Na_V1.8 blocker A-803467 (30 nM) also reduced I_Na,L, decreased APD and abolished triggered activity in GDX cells. Scn5a (Na_V1.5) and Scn10a (Na_V1.8) mRNA was increased in GDX ventricles, but only Na_V1.8 protein abundance was increased in GDX compared with 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 Na_V1.8- and Na_V1.5-associated currents, which may explain the increase in arrhythmias.NEW & NOTEWORTHY Older men with low testosterone levels are at increased risk of developing cardiac arrhythmias. We found aged mice chronically exposed to low testosterone had more arrhythmias and ventricular myocytes had prolonged repolarization, abnormal electrical activity, larger late sodium currents, and increased expression of Na_V1.8 sodium channels. Drugs that inhibit late sodium current or Na_V1.8 channels abolished abnormal electrical activity and shortened repolarization. This suggests the late sodium current may be a novel target to treat arrhythmias in older testosterone-deficient men.

Keywords: arrhythmia; gonadectomy; sex hormones.