title: Pacemaker current inhibition in experimental human cardiac sympathetic activation: a double-blind, randomized, crossover study.
abstract: Hyperpolarization-activated, cyclic nucleotide-gated 4 (HCN4) channels 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.
authors: 1] Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany [2] Experimental Clinical Research Center, Charité Medical Faculty and Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors: C
authors: C
authors: Schroeder
authors: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors: K
authors: K
authors: Heusser
authors: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors: A A
authors: AA
authors: Zoerner
authors: Institute for Biostatistics, Hannover Medical School, Hannover, Germany.
authors: A
authors: A
authors: Großhennig
authors: Institute for Biostatistics, Hannover Medical School, Hannover, Germany.
authors: D
authors: D
authors: Wenzel
authors: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors: M
authors: M
authors: May
authors: Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: F C G J
authors: FC
authors: Sweep
authors: Experimental Clinical Research Center, Charité Medical Faculty and Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors: H
authors: H
authors: Mehling
authors: Experimental Clinical Research Center, Charité Medical Faculty and Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors: F C
authors: FC
authors: Luft
authors: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors: J
authors: J
authors: Tank
authors: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors: J
authors: J
authors: Jordan
mesh_terms: D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000328:Adult; D001552:Benzazepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D023381:Endpoint Determination; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000037:antagonists & inhibitors; D000077550:Ivabradine; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009124:Muscle Proteins / Q000037:antagonists & inhibitors; D009638:Norepinephrine / Q000378:metabolism; D054971:Orthostatic Intolerance / Q000503:physiopathology; D010138:Pacemaker, Artificial; D015221:Potassium Channels; D000077593:Reboxetine; D013318:Stroke Volume / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000502:physiology*; D013575:Syncope / Q000503:physiopathology; D055815:Young Adult
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000319:Adrenergic beta-Antagonists; D001552:Benzazepines; D002316:Cardiotonic Agents; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009025:Morpholines; D009124:Muscle Proteins; D015221:Potassium Channels; D000077550:Ivabradine; D000077593:Reboxetine; D008790:Metoprolol; D009638:Norepinephrine