An exaggerated exercise pressor reflex (EPR) causes excessive sympatho-excitation and exercise intolerance during physical activity in the chronic heart failure (CHF) state. Muscle afferent sensitization contributes to the genesis of the exaggerated EPR in CHF. However, the cellular mechanisms underlying muscle afferent sensitization in CHF remain unclear. Considering that voltage-gated potassium (Kv) channels critically regulate afferent neuronal excitability, we examined the potential role of Kv channels in mediating the sensitized EPR in male CHF rats. Real time RT-PCR and western blotting experiments demonstrate that both mRNA and protein expressions of multiple Kv channel isoforms (Kv1.4, Kv3.4, Kv4.2 and Kv4.3) were downregulated in lumbar DRGs of CHF rats compared to sham rats. Immunofluorescence data demonstrates significant decreased Kv channel staining in both NF200-positive and IB4-positive lumbar DRG neurons in CHF rats compared to sham rats. Data from patch clamp experiments demonstrate that the total Kv current, especially I_A, was dramatically decreased in medium-sized IB4-negative muscle afferent neurons (a subpopulation containing mostly Aδ neurons) from CHF rats compared to sham rats, indicating a potential functional loss of Kv channels in muscle afferent Aδ neurons. In in vivo experiments, adenoviral overexpression of Kv4.3 in lumbar DRGs for one week attenuated the exaggerated EPR induced by muscle static contraction and the mechanoreflex by passive stretch without affecting the blunted cardiovascular response to hindlimb arterial injection of capsaicin in CHF rats. These data suggest that Kv channel dysfunction in DRGs play a critical role in mediating the exaggerated EPR and muscle afferent sensitization in CHF.

中文翻译：

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背根神经节的电压门控钾通道功能障碍导致慢性心力衰竭大鼠运动加压反射过度

在慢性心力衰竭 (CHF) 状态下的体力活动期间，过度的运动加压反射 (EPR) 会导致过度的交感神经兴奋和运动不耐受。肌肉传入致敏有助于 CHF 中过度 EPR 的发生。然而，CHF 中肌肉传入致敏的细胞机制仍不清楚。考虑到电压门控钾 (Kv) 通道严格调节传入神经元的兴奋性，我们检查了 Kv 通道在介导雄性 CHF 大鼠致敏 EPR 中的潜在作用。实时 RT-PCR 和蛋白质印迹实验表明，与假手术大鼠相比，CHF 大鼠腰椎 DRGs 中多种 Kv 通道亚型（Kv1.4、Kv3.4、Kv4.2 和 Kv4.3）的 mRNA 和蛋白质表达均下调. 免疫荧光数据表明，与假手术大鼠相比，CHF 大鼠的 NF200 阳性和 IB4 阳性腰椎 DRG 神经元的 Kv 通道染色显着降低。来自膜片钳实验的数据表明，总 Kv 电流，尤其是 I与假手术大鼠相比，来自 CHF 大鼠的中型 IB4 阴性肌肉传入神经元（主要包含 Aδ 神经元的亚群）显着降低，表明肌肉传入 Aδ 神经元中 Kv 通道的潜在功能丧失_。在体内实验中，Kv4.3 在腰椎 DRGs 中的腺病毒过表达 1 周减弱了肌肉静态收缩引起的过度 EPR 和被动拉伸引起的机械反射，而不影响 CHF 大鼠对后肢动脉注射辣椒素的心血管反应迟钝。这些数据表明，DRG 中的 Kv 通道功能障碍在介导 CHF 中过度的 EPR 和肌肉传入致敏中起关键作用。