Induction of atrial ectopic beats with calcium release inhibition: Local hierarchy of automaticity in the right atrium.
BACKGROUND
Recent evidence indicates that spontaneous sarcoplasmic reticulum (SR) calcium (Ca) release underlies the mechanism of sinoatrial node (SAN) acceleration during beta-stimulation, indicating the importance of the Ca clock in SAN automaticity. Whether or not the same mechanism applies to atrial ectopic pacemakers (AEPs) remains unclear.


OBJECTIVE
The purpose of this study was to assess the mechanism of AEP.


METHODS
We simultaneously mapped intracellular calcium (Ca(i)) and membrane potential in 12 isolated canine right atria. The late diastolic Ca(i) elevation (LDCAE) was used to detect the Ca clock activity. Pharmacological interventions with isoproterenol (ISO), ryanodine, and ZD7288, a blocker of the I(f) membrane current, were performed.


RESULTS
Ryanodine, which inhibits SR Ca release, reduced LDCAE in SAN, resulting in an inferior shift of the pacemaking site. Cycle length increased significantly in a dose-dependent way. In the presence of 3 to 10 mumol/l of ryanodine, ISO infusion consistently induces AEPs from the lower crista terminalis. All ectopic beats continuing over 30 seconds were located at the lower crista terminalis. These AEPs were resistant to ryanodine treatment even at high doses. Subsequent blockade of I(f) inhibited the AEP and resulted in profound bradycardia.


CONCLUSIONS
Spontaneous SR Ca release underlies ISO-induced increase of superior SAN activity. As compared with SAN, the AEP is less dependent on the Ca clock and more dependent on the membrane clock for its automaticity. AEPs outside the SAN can effectively serve as backup pacemakers when the Ca clock functionality is reduced.
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Tetsuji
T
Shinohara
Boyoung
B
Joung
Daehyeok
D
Kim
Mitsunori
M
Maruyama
Hsiang-Ning
HN
Luk
Peng-Sheng
PS
Chen
Shien-Fong
SF
Lin
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D018880:Atrial Premature Complexes / Q000209:etiology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D004285:Dogs; D006325:Heart Atria / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology*; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D018570:Risk Assessment; D012307:Risk Factors; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D012849:Sinoatrial Node / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D020746:Calcium Channels, L-Type; D002316:Cardiotonic Agents; D011743:Pyrimidines; C082246:ICI D2788; D012433:Ryanodine; D007545:Isoproterenol; D002118:Calcium