AUTHOR=Scridon Alina , Halaţiu Vasile Bogdan , Balan Alkora Ioana , Cozac Dan Alexandru , Moldovan Valeriu , Bănescu Claudia , Perian Marcel , Şerban Răzvan Constantin 

TITLE=Long-Term Effects of Ivabradine on Cardiac Vagal Parasympathetic Function in Normal Rats

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.596956

DOI=10.3389/fphar.2021.596956

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> The complex interactions that exist between the pacemaker current, <italic>I</italic><sub>f</sub>, and the parasympathetic nervous system could significantly influence the course of patients undergoing chronic therapy with the <italic>I</italic><sub>f</sub> blocker ivabradine. We thus aimed to assess the effects of chronic ivabradine therapy on autonomic modulation and on the cardiovascular response to <italic>in situ</italic> and <italic>in vitro</italic> parasympathetic stimulation. The right atrial expression of HCN genes, encoding proteins for <italic>I</italic><sub>f</sub>, was also evaluated.</p><p><bold>Methods:</bold> Sympathetic and parasympathetic heart rate variability parameters and right atrial <italic>HCN</italic>(1-4) RNA levels were analyzed in 6 Control and 10 ivabradine-treated male Wistar rats (IVA; 3 weeks, 10 mg/kg/day). The heart rate (HR) and systolic blood pressure (SBP) responses to <italic>in situ</italic> electrical stimulation of the vagus nerve (2–20 Hz) were assessed in 6 additional Control and 10 IVA rats. The spontaneous sinus node discharge rate (SNDR) response to <italic>in vitro</italic> cholinergic receptors stimulation using carbamylcholine (10<sup>−9</sup>–10<sup>−6</sup> mol/L) was also assessed in these later rats.</p><p><bold>Results:</bold> Ivabradine significantly increased vagal modulation and shifted the sympatho-vagal balance toward vagal dominance. In Control, <italic>in situ</italic> vagus nerve stimulation induced progressive decrease in both the SBP (<italic>p</italic> = 0.0001) and the HR (<italic>p</italic>&lt; 0.0001). Meanwhile, in IVA, vagal stimulation had no effect on the HR (<italic>p</italic> = 0.16) and induced a significantly lower drop in SBP (<italic>p</italic>&lt; 0.05). IVA also displayed a significantly lower SNDR drop in response to carbamylcholine (<italic>p</italic>&lt; 0.01) and significantly higher right atrial <italic>HCN4</italic> expression (<italic>p</italic> = 0.02).</p><p><bold>Conclusion:</bold> Chronic ivabradine administration enhanced vagal modulation in healthy rats. In addition, ivabradine reduced the HR response to direct muscarinic receptors stimulation, canceled the cardioinhibitory response and blunted the hemodynamic response to <italic>in situ</italic> vagal stimulation. These data bring new insights into the mechanisms of ivabradine-related atrial proarrhythmia and suggest that long-term <italic>I</italic><sub>f</sub> blockade may protect against excessive bradycardia induced by acute vagal activation.</p>