title: Modulation of sympathetic activity and heart rate variability by ivabradine.
abstract: OBJECTIVE
  Bradycardic agents are currently used in the treatment of angina and heart failure; direct information on their effects on cardiac sympathetic nerve activity (SNA) may be relevant to their chronic use. The present study evaluates the effect of pacemaker inhibition on SNA; direct nerve recordings and indirect autonomic indexes are compared.
  
  
  RESULTS
  Experiments were performed in 18 anaesthetized rats. SNA (direct nerve recording) and heart rate variability (HRV) indexes were evaluated in parallel. All parameters were recorded 10 min before to 60 min after administration of the If blocker ivabradine (IVA; 2 mg/kg, i.v.; n = 8) or vehicle (VEH; n = 5). IVA-induced RR interval (RR) prolongation (at 60 min +15.0 ± 7.1%, P < 0.01) was associated with decreased diastolic arterial pressure (DAP; -17.3 ± 8.4%, P < 0.05) and increased SNA (+51.1 ± 12.3%, P < 0.05). These effects were accompanied by increased RR variance (RRσ(2)), which showed strong positive correlation with RR. Frequency-domain HRV indexes (in normalized units) were unchanged by IVA. After baroreceptor reflexes had been eliminated by sino-aortic denervation (n = 5), similar IVA-induced RR prolongation (at 60 min +14.3 ± 5.9%, NS vs. intact) was associated with a larger DAP reduction (-30.9 ± 4.1%, P < 0.05 vs. intact), but failed to affect SNA.
  
  
  CONCLUSIONS
  (i) IVA-induced bradycardia was associated with increased SNA, resulting from baroreceptor unloading; if this applied to chronic IVA use in humans, it would be of relevance for therapeutic use of the drug. (ii) Whenever mean HR is concomitantly changed, time-domain HRV indexes should not be unequivocally interpreted in terms of autonomic balance.
authors.affiliation: Department of Biomedical and Clinical Sciences, L. Sacco Hospital, University of Milan, Milan, Italy IRCCS Fondazione Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy Biological Sciences Institute, Triangulo Mineiro Federal University, Uberaba, MG, Brazil.
authors.forename: Valdo Jose
authors.initials: VJ
authors.lastname: Dias da Silva
authors.affiliation: Department of Biomedical and Clinical Sciences, L. Sacco Hospital, University of Milan, Milan, Italy IRCCS Fondazione Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Tobaldini
authors.affiliation: Department of Biotechnology and Bioscience, University of Milan-Bicocca, P.za Della Scienza 2, Milan 20126, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rocchetti
authors.affiliation: Department of Biomedical and Clinical Sciences, L. Sacco Hospital, University of Milan, Milan, Italy IRCCS Fondazione Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Maddalena A
authors.initials: MA
authors.lastname: Wu
authors.affiliation: Division of Cardiology, San Luca Hospital, 'Istituto Auxologico Italiano' IRCCS, Milan, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Malfatto
authors.affiliation: Department of Biomedical and Clinical Sciences, L. Sacco Hospital, University of Milan, Milan, Italy IRCCS Fondazione Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Montano
authors.affiliation: Department of Biotechnology and Bioscience, University of Milan-Bicocca, P.za Della Scienza 2, Milan 20126, Italy antonio.zaza@unimib.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Zaza
mesh_terms: D000818:Animals; D017704:Baroreflex / Q000187:drug effects / Q000502:physiology; D001552:Benzazepines / Q000494:pharmacology*; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000294:innervation*; D006339:Heart Rate / Q000187:drug effects*; D000077550:Ivabradine; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000187:drug effects*
chemical_list: D001552:Benzazepines; D000077550:Ivabradine
keywords: Bradycardic agents; Heart rate variability; Ivabradine; Sympathetic nerve activity