Three Different Bradycardic Agents, Zatebradine, Diltiazem and Propranolol, Distinctly Modify Heart Rate Variability and QT-Interval Variability

Abstract

Zatebradine, diltiazem and propranolol are all antiarrhythmic agents, and all induce bradycardia, but each is known to have a different initial molecular mechanism: zatebradine is a channel blocker of the hyperpolarization-activated inward current (I_f ); diltiazem is a blocker of the L-type Ca²⁺ channel (I_CaL), and propranolol is a β-blocker. To further investigate the mechanisms underlying their clinical effects, we studied their effects on heart rate variability (HRV) and QT-interval variability (QTV). To this end, guinea pigs were treated with either zatebradine (1.5 mg/kg, i.p.), diltiazem (40 mg/kg, i.p.) or propranolol (20 mg/kg, i.p.). A dose of each agent that decreased HR by 20–22% was used in this study. HRV and QTV were analyzed by a fast Fourier and/or a wavelet transform algorithm. Zatebradine, an I_f channel blocker, had no significant effect on HRV and QTV. Diltiazem, a non-dihydropyridine I_CaL blocker, increased high frequency (HF) power and decreased the power ratio of the low frequency (LF) range to the HF range (L/H) in HRV, and increased QTV. Propranolol, a non-selective β-antagonist, decreased LF power and L/H ratios in HRV, and appreciably reduced QTV. These differences in pharmacological action may help us better understand the antiarrhythmic and/or proarrhythmic actions of these agents when they are used clinically for reducing HR.

Mechanisms Underlying Interactions Between Low-Frequency Oscillations and Beat-to-Beat Variability of Celullar Ventricular Repolarization in Response to Sympathetic Stimulation: Implications for Arrhythmogenesis

“…The mechanisms underlying the interactions between BVR and LF patterning of APD in response to sympathetic provocation (SP) and its potential link to arrhythmogenesis remain to be investigated. Regarding BVR, a growing number of studies, both experimental and computational, have provided evidence on the role of ion channel stochasticity and Ca 2+ cycling variations as underlying mechanisms of temporal variability at different scales, covering from isolated cells (Lemay et al, 2011; Pueyo et al, 2011, 2016a; Antoons et al, 2015; Kistamas et al, 2015; Nánási et al, 2017) to coupled cells / tissue (Zaniboni et al, 2000; Pueyo et al, 2011; Lemay et al, 2011; Magyar et al, 2015; Nánási et al, 2017) to whole heart (Yamabe et al, 2007; Baumert et al, 2016). Furthermore, the action of adrenergic stimulation in modulating those BVR mechanisms and facilitating arrhythmia initiation by the formation of afterdepolarizations and triggered activity has been reported in single cells (Johnson et al, 2010, 2013; Heijman et al, 2013; Szentandrássy et al, 2015; Hegyi et al, 2018) and in the whole heart (Gallacher et al, 2007).…”

Ivabradine Ameliorates Cardiac Diastolic Dysfunction in Diabetic Mice Independent of Heart Rate Reduction

“…Ivabradine (20 mg/kg/d) administration significantly reduced the HR, but did not have hypoglycemic or weight loss effects (Figures 5A-C). On the basis of previous publications (Stieber et al, 2006;Yamabe et al, 2007), we administered 5, 10, or 20 mg/kg/day zatebradine and determined the effects on the HR of the mice. We found that 10 mg/kg/day zatebradine had the same HR-reducing effect as 20 mg/kg/day ivabradine FIGURE 6 | Ivabradine reduces JNK and p38 MAPK activation and inhibits diabetes-induced CF proliferation and activation in vivo (A) Left ventricular fibroblasts isolated from mice treated with ivabradine at the indicated dose.…”

Enhanced BDNF Actions Following Acute Hypoxia Facilitate HIF-1α-Dependent Upregulation of Cav3-T-Type Ca2+ Channels in Rat Cardiomyocytes

“…Unfortunately, we could not provide enough data to illustrate these two contrary views. Because several classes of ion channels including the T-type Ca 2+ channels, most are the Cav3.1 and less are the Cav3.2 but not the Cav3.3 [ 6 ], contribute to pacemaker activity in the heart [ 31 , 32 , 33 ], the upregulation of Cav3-T-type Ca 2+ channels by BDNF lend support to the view that BDNF contributes to cardiac pacing activities. Interestingly, BDNF increases T-type Ca 2+ channel current as a short-term effect in sensory neurons via PI3K pathway [ 34 ], whereas the T-type Ca 2+ channel was not stimulated by BDNF in chick nodose neurons [ 35 , 36 ].…”