title: I(f) and SR Ca(2+) release both contribute to pacemaker activity in canine sinoatrial node cells.
abstract: Increasing evidence suggests that cardiac pacemaking is the result of two sinoatrial node (SAN) cell mechanisms: a 'voltage clock' and a Ca(2+) dependent process, or 'Ca(2+) clock.' The voltage clock initiates action potentials (APs) by SAN cell membrane potential depolarization from inward currents, of which the pacemaker current (I(f)) is thought to be particularly important. A Ca(2+) dependent process triggers APs when sarcoplasmic reticulum (SR) Ca(2+) release activates inward current carried by the forward mode of the electrogenic Na(+)/Ca(2+) exchanger (NCX). However, these mechanisms have mostly been defined in rodents or rabbits, but are unexplored in single SAN cells from larger animals. Here, we used patch-clamp and confocal microscope techniques to explore the roles of the voltage and Ca(2+) clock mechanisms in canine SAN pacemaker cells. We found that ZD7288, a selective I(f) antagonist, significantly reduced basal automaticity and induced irregular, arrhythmia-like activity in canine SAN cells. In addition, ZD7288 impaired but did not eliminate the SAN cell rate acceleration by isoproterenol. In contrast, ryanodine significantly reduced the SAN cell acceleration by isoproterenol, while ryanodine reduction of basal automaticity was modest ( approximately 14%) and did not reach statistical significance. Importantly, pretreatment with ryanodine eliminated SR Ca(2+) release, but did not affect basal or isoproterenol-enhanced I(f). Taken together, these results indicate that voltage and Ca(2+) dependent automaticity mechanisms coexist in canine SAN cells, and suggest that I(f) and SR Ca(2+) release cooperate to determine baseline and catecholamine-dependent automaticity in isolated dog SAN cells.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Gao
authors.forename: Biyi
authors.initials: B
authors.lastname: Chen
authors.forename: Mei-Ling A
authors.initials: ML
authors.lastname: Joiner
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Wu
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Guan
authors.forename: Olha M
authors.initials: OM
authors.lastname: Koval
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Chaudhary
authors.forename: Shane R
authors.initials: SR
authors.lastname: Cunha
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: James B
authors.initials: JB
authors.lastname: Martins
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Song
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000502:physiology*; D004285:Dogs; D005260:Female; D006321:Heart; D007545:Isoproterenol / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism; D010138:Pacemaker, Artificial; D012433:Ryanodine / Q000378:metabolism / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012849:Sinoatrial Node / Q000166:cytology / Q000378:metabolism / Q000502:physiology
chemical_list: D012433:Ryanodine; D007545:Isoproterenol; D002118:Calcium