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Pacemaker current inhibition in experimental human cardiac sympathetic activation: a double-blind, randomized, crossover study

Item Type:Article
Title:Pacemaker current inhibition in experimental human cardiac sympathetic activation: a double-blind, randomized, crossover study
Creators Name:Schroeder, C. and Heusser, K. and Zoerner, A.A. and Großhennig, A. and Wenzel, D. and May, M. and Sweep, F.C.G.J. and Mehling, H. and Luft, F.C. and Tank, J. and Jordan, J.
Abstract:Hyperpolarization-activated cyclic nucleotide-gated 4 channels (HCN4) comprise the final pathway for autonomic heart rate (HR) regulation. We hypothesized that HCN4 inhibition could reverse autonomic imbalance in a human model of cardiac sympathetic activation. Nineteen healthy men ingested oral metoprolol+reboxetine, ivabradine+reboxetine, or placebo+reboxetine in a double-blind, randomized, crossover fashion. We assessed HR, blood pressure (BP), stroke volume, and cardiac output during rest and profound orthostatic stress. HR variability, BP variability, and baroreflex sensitivity were analyzed. Metoprolol, but not ivabradine, decreased resting HR and BP. Ivabradine attenuated the HR increase to orthostatic stress, albeit to a lesser extent than metoprolol. Stroke volume and cardiac output at a given HR were significantly lower with metoprolol. Unlike metoprolol, ivabradine did not affect HR variability, BP variability, or baroreflex sensitivity. Ivabradine attenuates sympathetic influences on HR at the sinus node level, leaving myocardial sympathetic activation unopposed. Reversal of parasympathetic dysfunction by ivabradine appears limited.
Keywords:Adrenergic Uptake Inhibitors, Adrenergic beta-Antagonists, Artificial Pacemaker, Benzazepines, Blood Pressure, Cardiotonic Agents, Cross-Over Studies, Double-Blind Method, Endpoint Determination, Heart, Heart Rate, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Metoprolol, Morpholines, Muscle Proteins, Norepinephrine, Orthostatic Intolerance, Potassium Channels, Stroke Volume, Sympathetic Nervous System, Syncope
Source:Clinical Pharmacology and Therapeutics
ISSN:0009-9236
Publisher:Nature Publishing Group (U.S.A.)
Volume:95
Number:6
Page Range:601-607
Date:June 2014
Official Publication:https://doi.org/10.1038/clpt.2014.25
PubMed:View item in PubMed

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