title: Differential effects of ivabradine and ryanodine on pacemaker activity in canine sinus node and purkinje fibers.
abstract: BACKGROUND
  It is generally accepted that at least 2 major mechanisms contribute to sinus node (SN) pacemaking: a membrane voltage (mainly I(f) ) clock and a calcium (Ca) clock (localized submembrane sarcoplasmic reticulum Ca(2+) release during late diastolic depolarization). The aim of this study was to compare the contributions of each mechanism to pacemaker activity in SN and Purkinje fibers (PFs) exhibiting normal or abnormal automaticity.
  
  
  RESULTS
  Conventional microelectrodes were used to record action potentials in isolated spontaneously beating canine SN and free running PF in control and in the presence of 0.1 μM isoproterenol. Ryanodine (0.1-3 μM) and ivabradine (3 μM) were used to inhibit sarcoplasmic reticulum Ca(2+) release or I(f), respectively. To induce automaticity at low membrane potentials, PFs were superfused with BaCl(2). In SN, ivabradine reduced the rate whereas ryanodine had no effect. Isoproterenol significantly accelerated automatic rate, which was decreased by ivabradine and ryanodine. In normally polarized PFs, ryanodine had no effects on the automatic rate in the absence or presence of isoproterenol, whereas ivabradine inhibited both control and isoproterenol-accelerated automaticity. In PF depolarized with BaCl(2), ivabradine decreased BaCl(2) -induced automatic rate while ryanodine had no effect.
  
  
  CONCLUSIONS
  In canine SN, I(f) contributes to both basal automaticity and β-adrenergic-induced rate acceleration while the ryanodine-inhibited Ca clock appears more involved in β-adrenergic regulation of pacemaker rate. In PF, normal automaticity depends mainly on I(f). Inhibition of basal potassium conductance results in high automatic rates at depolarized membrane potentials with SN-like responses to inhibition of membrane and Ca clocks.
authors.affiliation: Department of Pharmacology, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Sosunov
authors.forename: Evgeny P
authors.initials: EP
authors.lastname: Anyukhovsky
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology*; D001683:Biological Clocks / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D000077550:Ivabradine; D008839:Microelectrodes; D010477:Perfusion; D010507:Periodicity; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011690:Purkinje Fibers / Q000187:drug effects* / Q000378:metabolism; D012433:Ryanodine / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D012849:Sinoatrial Node / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
chemical_list: D000318:Adrenergic beta-Agonists; D000889:Anti-Arrhythmia Agents; D001552:Benzazepines; D026902:Potassium Channel Blockers; D012433:Ryanodine; D000077550:Ivabradine; D007545:Isoproterenol; D011188:Potassium; D002118:Calcium