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

Figures

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  FIGURE 1. Typical time series of vagal nerve stimulation (VNS), heart rate (HR), and arterial pressure (AP) under conditions of control (CNT), blockade of muscarinic potassium channels by tertiapin‐Q (TQ), and TQ plus ivabradine (TQ + IVA) in one rat. The VNS trials were performed with binary white noise signals between 0–10 Hz (V0–10), 0–20 Hz (V0–20), and 0–40 Hz (V0–40). The VNS commands were identical among the CNT, TQ, and TQ + IVA conditions. For the VNS command and HR plots, 10‐Hz resampled signals are depicted. For the AP plots, the gray and black lines indicate 100‐Hz resampled and 2‐Hz moving average signals, respectively. For the transfer function (TF) analysis, the data were processed from 2 min after the initiation of the VNS. bpm: beats/min

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  FIGURE 2. Results of multiple regression analysis on prestimulation heart rate (HR) (a), prestimulation arterial pressure (AP) (b), delta HR (c), and AP during vagal nerve stimulation (VNS) (d). Delta HR was calculated as the difference between HR during VNS and prestimulation. CNT: control (circles); TQ: tertiapin‐Q (up‐pointing triangles); TQ +IVA: TQ plus ivabradine (down‐pointing triangles). Data points represent mean ± SE values (n = 8 rats). The dotted lines were drawn based on Equation 4 using the estimated coefficients for each parameter (Table 1). CNT data points: D TQ = 0 and D IVA = 0 (the black dotted lines); TQ data points: D TQ = 1 and D IVA = 0 (the blue dotted lines); TQ + IVA data points: D TQ = 1 and D IVA = 1 (the red dotted lines). adj r 2: adjusted r 2 value of multiple regressions; bpm: beats/min

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  FIGURE 3. (a) Group‐averaged transfer functions from vagal nerve stimulation (VNS) to heart rate (HR) and the corresponding coherence functions estimated under conditions of control (CNT), tertiapin‐Q (TQ), and TQ plus ivabradine (TQ + IVA). The VNS trials were performed with binary white noise signals between 0–10 Hz (V0–10), 0–20 Hz (V0–20), and 0–40 Hz (V0–40). Coh: coherence. (b) Group‐averaged step responses calculated from the transfer functions. The step response represents the HR response to a unit increase in the VNS. The solid and dashed lines indicate the means ± SE values (n = 8 rats). bpm: beats/min

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  FIGURE 4. Results of multiple regression analysis on transfer function parameters (a–d) and step response parameters (e–g). CNT: control (circles); TQ: tertiapin‐Q (up‐pointing triangles); TQ +IVA: TQ plus ivabradine (down‐pointing triangles); VNS: vagal nerve stimulation; K: asymptotic low frequency (LF) gain; f C: corner frequency; L: dead time; R: high frequency (HF) gain ratio; S 50: steady‐state response; S 1: initial response at 1 s; S 1/S 50: ratio of S 1 to S 50. Data points represent mean ± SE values (n = 8 rats). The dotted lines were drawn based on Equation 4 using the estimated coefficients for each parameter (Table 2). CNT data points: D TQ = 0 and D IVA = 0 (the black dotted lines); TQ data points: D TQ = 1 and D IVA = 0 (the blue dotted lines); TQ +IVA data points: D TQ = 1 and D IVA = 1 (the red dotted lines). adj r 2: adjusted r 2 value of multiple regression; bpm: beats/min. In panel (h), the effect of IVA alone on the HF gain ratio is shown based on previously obtained data (Kawada, Yamamoto, et al., 2019). CNT* (circles) and IVA* (squares) represent the data obtained under the conditions of control and IVA alone (n = 7 rats). The dotted lines were drawn based on…