Intravenous ivabradine augments the dynamic heart rate response to moderate vagal nerve stimulation in anesthetized rats

Abstract

Ivabradine is a selective bradycardic agent that reduces the heart rate (HR) by inhibiting the hyperpolarization-activated cyclic nucleotide-gated channels. Although its cardiovascular effect is thought to be minimal except for inducing bradycardia, ivabradine could interact with cardiovascular regulation by the autonomic nervous system. We tested whether ivabradine modifies dynamic characteristics of peripheral vagal HR control. In anesthetized Wistar-Kyoto rats ( n = 7), the right vagal nerve was sectioned and stimulated for 10 min according to a binary white noise sequence with a switching interval of 500 ms. The efferent vagal nerve stimulation (VNS) trials were performed using three different rates (10, 20, and 40 Hz), and were designated as V0–10, V0–20, and V0–40, respectively. The transfer function from the VNS to the HR was estimated before and after the intravenous administration of ivabradine (2 mg/kg). Ivabradine increased the asymptotic dynamic gain in V0–20 [from 3.88 (1.78–5.79) to 6.62 (3.12–8.31) beats·min−1·Hz−1, P < 0.01, median (range)] but not in V0–10 or V0–40. Ivabradine increased the corner frequency in V0–10 [from 0.032 (0.026–0.041) to 0.064 (0.029–0.090) Hz, P < 0.01] and V0–20 [from 0.040 (0.037–0.056) to 0.068 (0.051–0.100) Hz, P < 0.01] but not in V0–40. In conclusion, ivabradine augmented the dynamic HR response to moderate VNS. At high VNS, however, ivabradine did not significantly augment the dynamic HR response, possibly because ivabradine reduced the baseline HR and limited the range for the bradycardic response to high VNS. NEW & NOTEWORTHY Ivabradine is considered to be a pure bradycardic agent that has little effect on cardiovascular function except inducing bradycardia. The present study demonstrated that ivabradine interacts with the dynamic vagal heart rate control in a manner that augments the heart rate response to moderate-intensity efferent vagal nerve stimulation.