Document Detail

Ca2+ clock malfunction in a canine model of pacing-induced heart failure.
MedLine Citation:
PMID:  20889842     Owner:  NLM     Status:  MEDLINE    
The mechanisms of sinoatrial node (SAN) dysfunction in heart failure (HF) remain unclear. We hypothesized that impaired rhythmic spontaneous sarcoplasmic reticulum Ca(2+) release (Ca(2+) clock) plays an important role in SAN dysfunction in HF. HF was induced in canine hearts by rapid ventricular pacing. The location of pacemaking sites was determined in vivo using computerized electrical mapping in acute open-chest preparations (normal, n = 3; and HF, n = 4). Isoproterenol (Iso, 0.2 μg·kg(-1)·min(-1)) infusion increased heart rate and shifted the pacemaking site to the superior SAN in all normal hearts. However, in failing hearts, Iso did not induce superior shift of the pacemaking site despite heart rate acceleration. Simultaneous optical recording of intracellular Ca(2+) and membrane potential was performed in Langendorff-perfused isolated right atrium (RA) preparations from normal (n = 7) and failing hearts (n = 6). Iso increased sinus rate, enhanced late diastolic Ca(2+) elevation (LDCAE), and shifted the pacemaking sites to the superior SAN in all normal but in none of the HF RAs. Caffeine (2 ml, 20 mmol/l) caused LDCAE and increased heart rate in four normal RAs but in none of the three HF RAs. Iso induced ectopic beats from lower crista terminalis in five of six HF RAs. These ectopic beats were suppressed by ZD-7288, a specific pacemaker current (I(f)) blocker. We conclude that HF results in the suppression of Ca(2+) clock, resulting in the unresponsiveness of superior SAN to Iso and caffeine. HF also increases the ectopic pacemaking activity by activating the I(f) at the latent pacemaking sites in lower crista terminalis.
Tetsuji Shinohara; Hyung-Wook Park; Seongwook Han; Mark J Shen; Mitsunori Maruyama; Daehyeok Kim; Peng-Sheng Chen; Shien-Fong Lin
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-10-01
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  299     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-03     Completed Date:  2011-01-13     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1805-11     Citation Subset:  IM    
Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
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MeSH Terms
Adrenergic beta-Agonists / pharmacology
Caffeine / pharmacology
Calcium Signaling* / drug effects
Cardiac Pacing, Artificial*
Circadian Clocks* / drug effects
Disease Models, Animal
Electrophysiologic Techniques, Cardiac
Heart Failure / etiology,  metabolism*,  physiopathology
Heart Rate* / drug effects
Isoproterenol / pharmacology
Membrane Potentials
Pyrimidines / pharmacology
Sarcoplasmic Reticulum / metabolism
Sinoatrial Node / drug effects,  metabolism*,  physiopathology
Time Factors
Grant Support
Reg. No./Substance:
0/Adrenergic beta-Agonists; 0/Pyrimidines; 133059-99-1/ICI D2788; 58-08-2/Caffeine; 7683-59-2/Isoproterenol

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