Sympathoexcitation in chronic heart failure: Ang II induced inhibition of voltage‐gated K + channel, an in vivo and in vitro study

Abstract

We have reported that elevated central Ang II plays a critical role in sympathoexcitation of chronic heart failure (CHF) by stimulating up-regulated AT1 receptors in rostral ventrolateral medulla (RVLM). However, the link between enhanced Ang II signaling and electrophysiological characteristics of neurons in RVLM remains unclear. In the present experiments, we first screened for potentially altered genes in the brainstem of rats with CHF that relate membrane conductance in neurons using the Rat Genome 230 2.0 Array GeneChip. We found that Kv 4.3 gene was significantly down-regulated in the CHF rats (-2.1 ± 0.2 times, P < 0.05, n = 3). Second, we used real-time PCR and Western blot further to confirm this down regulation of Kv 4.3 in the RVLM of CHF rats (mRNA: 1.3 ± 0.1 to 0.7 ± 0.1, P < 0.05; protein: 2.0 ± 0.1 to 0.9 ± 0.1, P < 0.05). Finally, we used a neuronal cell line (CATH.a neurons) to explore the effect of Ang II on Kv 4.3. We found that Ang II treatment (1) down-regulated the mRNA (0.4 ± 0.1 to 0.2 ± 0.1, P < 0.05) and protein (1.5 ± 0.2 to 0.6 ± 0.1, P < 0.05) of Kv 4.3; (2) decreased the K+ peak current (Ik: 289.6 ± 31.5 to 143.3 ± 8.9 pA, P < 0.05); and (3) up-regulated the mRNA (0.7 ± 0.1 to 1.8 ± 0.2, P < 0.05) and protein (0.8 ± 0.1 to 1.5 ± 0.2, P < 0.05) of the AT1 receptor. We conclude that the sympathoexcitation of CHF may be due to, in part, the effect of Ang II down-regulating the Kv 4.3 expression and decreasing Ik, and thereby increasing the excitability of neurons in the RVLM, via the enhanced AT1 receptor expression. (Supported by NIH grant HL PO-1 62222).