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1 Masonic Medical Research Laboratory, Utica, New York, United States
2 Mol. Pharmacol. and Biol. Chem., Northwestern University, Chicago, Illinois, United States
3 Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica,, New York, 13501-1787, United States
4 Medicine (Cardiology), Northwestern University, Chicago, Illinois, United States
* To whom correspondence should be addressed. E-mail: jcordeiro{at}mmrl.edu.
Background: Previous studies indicate that action potential duration (APD) alternans is initiated in the endocardial and midmyocardial regions rather than epicardium (ENDO, MID and EPI) in the canine left ventricle. This study examines regional differences in the rate-dependence of Ca2+ transient characteristics under conditions that give rise to APD and associated T wave alternans. The role of the sarcoplasmic reticulum (SR) was further evaluated by studying Ca2+ transient characteristics in myocytes isolated from neonates, where an organized SR is poorly developed. Methods: All studies were performed in cells and tissues isolated from the canine left ventricle. Isolated canine ENDO, MID and EPI left ventricular (LV) myocytes were either field stimulated or voltage clamped and Ca2+ transients measured by confocal microscopy. Results: In LV wedge preparations, increasing the basic cycle length (BCL) from 800 to 250 msec caused alternans to appear mainly in the ENDO and MID region; alternans were not observed in EPI under these conditions. Ca2+ transient alternans developed in response to rapid pacing, appearing in EPI cells at shorter BCL as compared to MID and ENDO cells (BCL=428±17 vs. 517±29 and 514±21, respectively, p<0.05). Further increases in pacing rate resulted in the appearance of subcellular alternans of Ca2+ transient amplitude, which also appeared in EPI at shorter BCL than in ENDO and MID cells. Ca2+ transient alternans was not observed in neonate myocytes. Conclusions: 1) There are distinct regional differences in the vulnerability to rate-dependent Ca2+ alternans in dog LV that may be related to regional differences in SR function and Ca2+ cycling; 2) the development of subcellular Ca2+ alternans suggests the presence of intracellular heterogeneities in Ca2+ cycling; 3) the failure of neonatal cells to develop Ca2+ alternans provides further support that SR Ca2+ cycling is a major component in the development of these phenomena.
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