Downregulation of KCNQ channels in the CeA contributes to elevated sympathetic outflow in hypertension

Abstract

Elevation of sympathetic outflow is associated with many hypertensive conditions. The central nucleus of amygdala (CeA) is crucial in the regulation of emotion, pain, and cardiovascular functions. The M‐channel is a non‐inactivating voltage‐dependent K+ channel stabilizing the membrane potential and mainly consists of heterotetrameric Kv7.2 and Kv7.3 subunits. However, the role of M channels in the CeA in heightened sympathetic vasomotor tone in hypertension remain unknown. Microinjecting of the specific M‐channel blocker XE‐991 into the CeA significantly increased arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) but did not alter heart rate (HR) in anesthetized Wistar Kyoto rats (WKY) rats. In spontaneously hypertensive rats (SHRs), microinjection of the same dose of XE‐991 into the CeA had no effect on ABP, RSNA, or HR in SHRs. On the other hand, microinjection of the M‐channel opener QO‐58 into the CeA decreased ABP and RSNA in WKY rats but failed to alter these cardiovascular variables in SHRs. The protein and mRNA levels of Kv7.2 and Kv7.3 in the CeA were significantly lower in SHRs than in WKY rats. Lowering ABP via celiac ganglionectomy in SHRs did not altered the expression levels of Kv7.2 and Kv7.3 in the CeA. In a brain slice preparation, the basal firing activity of labeled CeA‐RVLM projection neurons was significantly greater in SHRs than in WKY rats. Blocking M‐currents with XE‐991 increased both spontaneous and current injection‐evoked firing rate of CeA‐RVLM projection neurons in WKY rats but had no such effect in SHRs. Also, the M‐currents triggered by a membrane depolarization in CeA‐RVLM neurons were significantly smaller in SHRs than in WKY rats. These data suggest that M‐channel activity is impaired and leads to hyperactivity of CeA‐RVLM projection neurons, which contributes to elevated sympathetic vasomotor activity in hypertension.Support or Funding Information SupportThis study was supported by NIH grant HL139523 and HL142133.