Ivabradine augments high-frequency dynamic gain of the heart rate response to low- and moderate-intensity vagal nerve stimulation under β-blockade

Abstract

Since 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.

Ivabradine increases the high frequency gain ratio in the vagal heart rate transfer function via an interaction with muscarinic potassium channels

“…The effect of IVA on the dynamic vagal control of HR was characterized by an increase in the HF gain ratio of the transfer function from VNS to HR, as described in our previous studies (Kawada, Yamamoto, et al, 2019 ; Kawada et al, 2021 ) and demonstrated in Figure 4h . In the present study, TQ decreased the HF gain ratio compared to controls (Figure 4d ), suggesting the involvement of I K,ACh in the determination of the HF gain ratio.…”

“…However, the effects of HCN channel blockade on the frequency‐dependent nature of the vagal control of HR are yet to be elucidated. We have previously shown that IVA increased the HF gain ratio of the transfer function from VNS to HR (Figure 4h ; Kawada, Yamamoto, et al, 2019 ; Kawada et al, 2021 ). On the other hand, in the present study, IVA in the presence of TQ was unable to increase the HF gain ratio compared to controls (Figure 4d ).…”

“…The following mathematical model (Equation 3 ) was used to describe the estimated transfer function from VNS to HR according to previous studies (Kawada et al, 2013 , 2021 ; Kawada, Yamamoto, et al, 2019 ): where j , imaginary unit; f , frequency (Hz); K , steady‐state gain (bpm/Hz), referred to as “asymptotic LF gain”; f C , corner frequency (Hz); R , fraction of the HF gain to K , referred to as “HF gain ratio”; and L , dead time (s).…”

“…In our previous study, IVA augmented the dynamic gain of the transfer function from VNS to HR during moderate‐intensity VNS (Kawada, Yamamoto, et al, 2019 ). This augmentation partly depended on sympathetic background tone because β‐blockade prevented the augmentation of the dynamic gain in the low frequency (LF, approximately 0.01–0.05 Hz) range (Kawada et al, 2021 ). On the other hand, β‐blockade did not prevent the augmentation of the dynamic gain in the high frequency (HF, approximately 0.5–1 Hz) range.…”