I(f) and SR Ca(2+) release both contribute to pacemaker activity in canine sinoatrial node cells.
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.
Gao
Zhan
Z
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
Chen
Biyi
B
Joiner
Mei-Ling A
ML
Wu
Yuejin
Y
Guan
Xiaoqun
X
Koval
Olha M
OM
Chaudhary
Ashok K
AK
Cunha
Shane R
SR
Mohler
Peter J
PJ
Martins
James B
JB
Song
Long-Sheng
LS
Anderson
Mark E
ME
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
D012433:Ryanodine; D007545:Isoproterenol; D002118:Calcium