title: Preserved Autonomic Cardiovascular Regulation With Cardiac Pacemaker Inhibition: A Crossover Trial Using High-Fidelity Cardiovascular Phenotyping.
abstract: BACKGROUND
  Sympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization-activated cyclic nucleotide-gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact.
  
  
  RESULTS
  We treated 21 healthy men with 2×7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9±8.1 to 58.4±6.2 beats per minute (P<0.001) with unaffected blood pressure and muscle sympathetic nerve activity. On ivabradine, cardiac and sympathetic baroreflex gains and blood pressure responses to vasoactive drugs were unchanged. Ivabradine aggravated bradycardia during baroreflex loading.
  
  
  CONCLUSIONS
  HCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact. Ivabradine could aggravate bradycardia during parasympathetic activation.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865917.
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany (K.H., J.T., J.B., C.S., M.M., J.J.).
authors.forename: Karsten
authors.initials: K
authors.lastname: Heusser
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany (K.H., J.T., J.B., C.S., M.M., J.J.).
authors.forename: Jens
authors.initials: J
authors.lastname: Tank
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany (K.H., J.T., J.B., C.S., M.M., J.J.).
authors.forename: Julia
authors.initials: J
authors.lastname: Brinkmann
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany (K.H., J.T., J.B., C.S., M.M., J.J.).
authors.forename: Christoph
authors.initials: C
authors.lastname: Schroeder
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany (K.H., J.T., J.B., C.S., M.M., J.J.).
authors.forename: Marcus
authors.initials: M
authors.lastname: May
authors.affiliation: Institute of Biostatistics, Hannover Medical School, Hannover, Germany (A.G., D.W.).
authors.forename: Anika
authors.initials: A
authors.lastname: Großhennig
authors.affiliation: Institute of Biostatistics, Hannover Medical School, Hannover, Germany (A.G., D.W.).
authors.forename: Daniela
authors.initials: D
authors.lastname: Wenzel
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Autonomic Dysfunction Service, Vanderbilt University, Nashville, TN (A.D.).
authors.forename: André
authors.initials: A
authors.lastname: Diedrich
authors.affiliation: Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands (F.J.S.).
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.affiliation: Experimental Clinical Research Center, Charité Medical Faculty and Max Delbrück Center for Molecular Medicine, Berlin, Germany (H.M., F.C.L.).
authors.forename: Heidrun
authors.initials: H
authors.lastname: Mehling
authors.affiliation: Experimental Clinical Research Center, Charité Medical Faculty and Max Delbrück Center for Molecular Medicine, Berlin, Germany (H.M., F.C.L.).
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany (K.H., J.T., J.B., C.S., M.M., J.J.).
authors.forename: Jens
authors.initials: J
authors.lastname: Jordan
mesh_terms: D000328:Adult; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000502:physiology; D017704:Baroreflex / Q000187:drug effects*; D001552:Benzazepines / Q000008:administration & dosage* / Q000009:adverse effects; D001683:Biological Clocks / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D001919:Bradycardia / Q000139:chemically induced / Q000503:physiopathology; D002317:Cardiovascular Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography; D005858:Germany; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077550:Ivabradine; D008297:Male; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018482:Muscle, Skeletal / Q000294:innervation; D015221:Potassium Channels / Q000378:metabolism; D012849:Sinoatrial Node / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D013997:Time Factors; D055815:Young Adult
chemical_list: D001552:Benzazepines; D002317:Cardiovascular Agents; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009124:Muscle Proteins; D015221:Potassium Channels; D000077550:Ivabradine
keywords: autonomic nervous system; baroreflex control; funny channel; heart rate; hemodynamics; inhibitor; microneurography; pharmacology; physiology; sinoatrial node