Abstract
A low resting heart rate (HR) would be of great benefit in cardiovascular diseases. Ivabradine—a novel selective inhibitor of hyperpolarization-activated cyclic nucleotide gated (HCN) channels- has emerged as a promising HR lowering drug. Its effects on the autonomic HR control are little known. This study assessed the effects of chronic treatment with ivabradine on the modulatory, reflex and tonic cardiovascular autonomic control and on the renal sympathetic nerve activity (RSNA). Male Wistar rats were divided in 2 groups, receiving intraperitoneal injections of vehicle (VEH) or ivabradine (IVA) during 7 or 8 consecutive days. Rats were submitted to vessels cannulation to perform arterial blood pressure (AP) and HR recordings in freely moving rats. Time series of resting pulse interval and systolic AP were used to measure cardiovascular variability parameters. We also assessed the baroreflex, chemoreflex and the Bezold-Jarish reflex sensitivities. To better evaluate the effects of ivabradine on the autonomic control of the heart, we performed sympathetic and vagal autonomic blockade. As expected, ivabradine-treated rats showed a lower resting (VEH: 362 ± 16 bpm vs. IVA: 260 ± 14 bpm, p = 0.0005) and intrinsic HR (VEH: 369 ± 9 bpm vs. IVA: 326 ± 11 bpm, p = 0.0146). However, the chronic treatment with ivabradine did not change normalized HR spectral parameters LF (nu) (VEH: 24.2 ± 4.6 vs. IVA: 29.8 ± 6.4; p > 0.05); HF (nu) (VEH: 75.1 ± 3.7 vs. IVA: 69.2 ± 5.8; p > 0.05), any cardiovascular reflexes, neither the tonic autonomic control of the HR (tonic sympathovagal index; VEH: 0.91± 0.02 vs. IVA: 0.88 ± 0.03, p = 0.3494). We performed the AP, HR and RSNA recordings in urethane-anesthetized rats. The chronic treatment with ivabradine reduced the resting HR (VEH: 364 ± 12 bpm vs. IVA: 207 ± 11 bpm, p < 0.0001), without affecting RSNA (VEH: 117 ± 16 vs. IVA: 120 ± 9 spikes/s, p = 0.9100) and mean arterial pressure (VEH: 70 ± 4 vs. IVA: 77 ± 6 mmHg, p = 0.3293). Our results suggest that, in health rats, the long-term treatment with ivabradine directly reduces the HR without changing the RSNA modulation and the reflex and tonic autonomic control of the heart.
Highlights
There is a clear association between increased resting heart rate and mortality rate, especially in patients suffering from cardiovascular disease (Fox et al, 2008; Verrier and Tan, 2009)
We evaluated the effects of chronic treatment with ivabradine—a “pure” heart rate (HR) lowering drug which selectively inhibits the pacemaker hyperpolarization-activated cyclic nucleotide gated (HCN) channels—on the autonomic control of the HR in rats
As no study has investigated this set of variables to date, our data provides new in vivo insights about the chronic effects of ivabradine on the cardiovascular autonomic system
Summary
There is a clear association between increased resting heart rate (rHR) and mortality rate, especially in patients suffering from cardiovascular disease (Fox et al, 2008; Verrier and Tan, 2009). A pure bradycardic agent might be useful in conditions in which beta-adrenergic blocker cannot be used due to their side effects In this regard, ivabradine—a novel selective inhibitor of HCN channels—has emerged as a promising “pure” heart rate (HR) lowering drug (DiFrancesco and Camm, 2004; Bucchi et al, 2006). In vitro studies have demonstrated that ivabradine blocks the HCN pore in a low-moderate concentration range (Bucchi et al, 2002; DiFrancesco, 2010) It greatly inhibits the hyperpolarization-active current (If) and reduces the firing rate of the sinoatrial node cells at small concentrations, without influencing other ion currents (calcium and potassium) (Bois et al, 1996). Improving our knowledge on the pharmacodynamics of this drug and providing substantial outcomes for the clinical usage of ivabradine as a cardiac medication
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