Ivabradine augments high-frequency dynamic gain of the heart rate response to low- and moderate-intensity vagal nerve stimulation under β-blockade
Ivabradine augments high-frequency dynamic gain of the heart rate response to low- and moderate-intensity vagal nerve stimulation under β-blockade
复制标题
伊伐布雷定增强β-阻滞下低强度和中等强度迷走神经刺激的心率反应的高频动态增益
DOI：
10.1152/ajpheart.00057.2021
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发表时间：
2021
影响因子：
4.8
通讯作者：
Sugimachi Masaru
中科院分区：
文献类型：
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作者：
Kawada Toru;Yamamoto Hiromi;Uemura Kazunori;Hayama Yohsuke;Nishikawa Takuya;Zheng Can;Li Meihua;Miyamoto Tadayoshi;Sugimachi Masaru
我们先前的研究表明，静脉给予伊伐布雷定（IVA）可增强对中等强度迷走神经刺激（VNS）的动态心率（HR）反应。考虑到拮抗作用增强，结果有些矛盾;即，增强的拮抗作用表明，通过细胞内环磷酸腺苷（cAMP）的积累激活超极化激活的环核苷酸门控（HCN）通道增强了对VNS的HR反应，而IVA抑制HCN通道也增强了对VNS的HR反应。为了消除增强拮抗作用的可能影响，我们检查了IVA对β-阻滞下HR的动态迷走神经控制的影响。在麻醉大鼠（n= 7）中，根据0和10 Hz（V0-10）之间、0和20 Hz（V0-20）之间和0和40 Hz（V0-40）之间的二进制白色噪声信号刺激右侧迷走神经10 min。估计了VNS到HR的传递函数。在β-阻断下静脉注射普萘洛尔（2 mg/kg）、静脉注射IVA（2 mg/kg）不增加V0-10（0.53 ± 0.10vs.1.74 ± 0.40beats/min/Hz，P< 0.01）和V0-20（0.79 ± 0.14vs.2.06 ± 0.47beats/min/Hz，P< 0.001）的渐近低频增益，但增加了渐近高频增益。这些变化是在交感神经背景紧张的最小影响下观察到的，可能反映了IVA后乙酰胆碱敏感性钾通道（IK，ACh）通路的贡献增加，因为通过IK，ACh通路的HR控制比cAMP介导的通路更快，并且在更高的频率范围内起作用。交感神经效应、迷走神经效应和IVA之间的相互作用可以发生在心率（HR）的控制中。为了消除交感神经效应，我们在麻醉大鼠中估计了在β-阻滞下从迷走神经刺激到HR的传递函数。IVA增强了低强度和中等强度迷走神经刺激期间的高频动态增益。解除IVA后乙酰胆碱敏感性钾通道的超极化效应可能是一个潜在的机制。
Our previous study indicated that intravenously administered ivabradine (IVA) augmented the dynamic heart rate (HR) response to moderate-intensity vagal nerve stimulation (VNS). Considering an accentuated antagonism, the results were somewhat paradoxical; i.e., the accentuated antagonism indicates that an activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels via the accumulation of intracellular cyclic adenosine monophosphate (cAMP) augments the HR response to VNS, whereas the inhibition of HCN channels by IVA also augmented the HR response to VNS. To remove the possible influence from the accentuated antagonism, we examined the effects of IVA on the dynamic vagal control of HR under β-blockade. In anesthetized rats (n= 7), the right vagal nerve was stimulated for 10 min according to binary white noise signals between 0 and 10 Hz (V0–10), between 0 and 20 Hz (V0–20), and between 0 and 40 Hz (V0–40). The transfer function from VNS to HR was estimated. Under β-blockade (propranolol, 2 mg/kg iv), IVA (2 mg/kg iv) did not augment the asymptotic low-frequency gain but increased the asymptotic high-frequency gain in V0–10(0.53 ± 0.10 vs. 1.74 ± 0.40 beats/min/Hz,P< 0.01) and V0–20(0.79 ± 0.14 vs. 2.06 ± 0.47 beats/min/Hz,P< 0.001). These changes, which were observed under a minimal influence from sympathetic background tone, may reflect an increased contribution of the acetylcholine-sensitive potassium channel (IK,ACh) pathway after IVA, because the HR control via theIK,AChpathway is faster and acts in the frequency range higher than the cAMP-mediated pathway.NEW & NOTEWORTHYSince ivabradine (IVA) inhibits hyperpolarization-activated cyclic nucleotide-gated channels, interactions among the sympathetic effect, vagal effect, and IVA can occur in the control of heart rate (HR). To remove the sympathetic effect, we estimated the transfer function from vagal nerve stimulation to HR under β-blockade in anesthetized rats. IVA augmented the high-frequency dynamic gain during low- and moderate-intensity vagal nerve stimulation. Untethering the hyperpolarizing effect of acetylcholine-sensitive potassium channels after IVA may be a possible underlying mechanism.