Imbalanced K+ and Ca2+subthreshold interactions contribute to increased hypothalamic presympathetic neuronal excitability in hypertensive rats
Imbalanced K+ and Ca2+subthreshold interactions contribute to increased hypothalamic presympathetic neuronal excitability in hypertensive rats
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DOI：
10.1113/jphysiol.2010.198556
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发表时间：
2011-02-01
影响因子：
5.5
通讯作者：
Stern, J. E.
中科院分区：
文献类型：
--
作者：
Sonner, P. M.;Lee, S.;Stern, J. E.
非技术摘要尽管大脑介导的交感神经激活在高血压患者的发病率和死亡率中很重要，但所涉及的精确细胞机制仍然很大程度上未知。我们发现，在高血压大鼠的交感相关下丘脑神经元中，钾（I-A）和钙（I-T）通道介导的两个相反电流之间存在不平衡的相互作用。我们表明，这种不平衡有助于增强该神经元群体的膜兴奋性和放电活动。了解这些相反的离子通道在正常和疾病状态下如何相互作用，可以增加我们对导致高血压的潜在大脑机制的理解。我们在此研究了阈下电流 A 型钾 (I-A) 和 T 型钙 (I-T) 之间的相反相互作用是否影响下丘脑室旁核 (PVN) 交感前神经元的膜兴奋性 支配延髓头侧腹外侧 (RVLM)。此外，我们评估了这两个阈下电流之间的平衡变化是否导致高血压神经元活动增加。为此，我们从假手术大鼠和肾血管性高血压大鼠中鉴定出的 PVN-RVLM 神经元获得了同步电生理记录、共聚焦 Ca2+ 成像和单细胞 RT-PCR 样本。我们的结果表明，PVN-RVLM 神经元中存在 I-A 和 I-T，表现出重叠的电压依赖性和动力学特性。我们发现超极化膜电位下每个电流的相对优势决定了 PVN-RVLN 神经元是否表达低阈值尖峰（LTS）或瞬时向外整流（TOR）。此外，我们报告 I-A/I-T 平衡与个体神经元内 Kv4.3 和 Cav3.1 亚基 mRNA 的相对表达相关。 I-A 的药理学阻断导致 I-T 介导的 LTS 以及 LTS 介导的体细胞树突 Ca2+ 瞬变增强。在高血压大鼠中，我们发现 I-T/I-A 平衡向 I-T 主导方向转变，部分原因是 Kv4.3 减少和 Cav3.1 mRNA 亚基表达增强。不平衡的 I-T/I-A 关系导致高血压大鼠 LTS 增强、LTS 介导的体细胞树突 Ca2+ 瞬变以及放电活动增加。综上所述，我们的结果支持平衡的 I-T/I-A 相互作用影响 PVN-RVLM 神经元的膜兴奋性和 Ca2+ 动力学。此外，有利于 I-T 的不平衡关系导致高血压大鼠的神经元兴奋性和放电放电增强，从而构成了在这种疾病中观察到的特征性交感神经兴奋的可能机制。
Non-technical summaryDespite the importance of brain-mediated sympathetic activation in the morbidity and mortality of patients with high blood pressure, the precise cellular mechanisms involved remain largely unknown. We show that an imbalanced interaction between two opposing currents mediated by potassium (I-A) and calcium (I-T) channels occurs in sympathetic-related hypothalamic neurons in hypertensive rats. We show that this imbalance contributes to enhanced membrane excitability and firing activity in this neuronal population. Knowledge of how these opposing ion channels interact in normal and disease states increases our understanding of underlying brain mechanisms contributing to the high blood pressure condition.We investigated here whether an opposing interplay between the subthreshold currents A-type potassium (I-A) and T-type calcium (I-T) influences membrane excitability in presympathetic neurones of the hypothalamic paraventricular nucleus (PVN) that innervate the rostral ventrolateral medulla (RVLM). Moreover, we assessed whether a shift in the balance between these two subthreshold currents contributed to increased neuronal activity in hypertension. To this end, we obtained simultaneous electrophysiological recordings, confocal Ca2+ imaging, and single-cell RT-PCR samples from identified PVN-RVLM neurones in sham and renovascular hypertensive rats. Our results indicate that I-A and I-T, displaying overlapping voltage-dependent and kinetic properties, are present in PVN-RVLM neurones. We found that the relative predominance of each current at hyperpolarized membrane potentials dictates whether PVN-RVLN neurones express a low-threshold spike (LTS) or a transient outward rectification (TOR). Moreover, we report the I-A/I-T balance to be correlated with the relative expression of Kv4.3 and Cav3.1 subunit mRNA within individual neurones. Pharmacological blockade of I-A resulted in an enhanced I-T-mediated LTS, as well as LTS-mediated somatodendritic Ca2+ transients. In hypertensive rats, we found a shift in the I-T/I-A balance, towards an I-T predominance, due in part to a diminished Kv4.3 and enhanced Cav3.1 mRNA subunits expression. The imbalanced I-T/I-A relationship resulted in enhanced LTS, LTS-mediated somatodendritic Ca2+ transients, and increased firing activity in hypertensive rats. Taken together, our results support that a balanced I-T/I-A interaction influences membrane excitability and Ca2+ dynamics in PVN-RVLM neurones. Moreover, an imbalanced relationship favouring I-T results in enhanced neuronal excitability and firing discharge in hypertensive rats, constituting thus a likely mechanism contributing to the characteristic sympathoexcitation observed in this disease.