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(Circulation Research. 1999;85:415-427.)
© 1999 American Heart Association, Inc.

Cellular Biology

Subcellular [Ca²⁺]_i Gradients During Excitation-Contraction Coupling in Newborn Rabbit Ventricular Myocytes

Peter S. Haddock, William A. Coetzee, Emily Cho, Lisa Porter, Hideki Katoh, Donald M. Bers, M. Saleet Jafri, Michael Artman

From the Departments of ¹Pediatrics (P.S.H., W.A.C., E.C., L.P., M.A.) and Physiology and Neuroscience (W.A.C., M.A.), New York University Medical Center, New York, NY; Department of Physiology (H.K., D.M.B.), Loyola University School of Medicine, Maywood, Ill; and Department of Biomedical Engineering (M.S.J.), The Johns Hopkins University School of Medicine, Baltimore, Md.

Correspondence to Michael Artman, MD, Pediatric Cardiology, Suite 9-V, NYU Medical Center, 530 First Ave, New York, NY 10016. E-mail michael.artman{at}med.nyu.edu

Abstract—The central role of T-tubule and sarcoplasmic reticulum (SR) diadic junctions in excitation-contraction (EC) coupling in adult (AD) ventricular myocytes suggests that their absence in newborn (NB) cells may manifest as an altered EC coupling phenotype. We used confocal microscopy to compare fluo-3 [Ca²⁺]_i transients in the subsarcolemmal space and cell center of field-stimulated NB and AD rabbit ventricular myocytes. Peak systolic [Ca²⁺]_i occurred sooner and was higher in the subsarcolemmal space compared with the cell center in NB myocytes. In AD myocytes, [Ca²⁺]_i rose and declined with similar profiles at the cell center and subsarcolemmal space. Disabling the SR (10 µmol/L thapsigargin) slowed the rate of rise and decline of Ca²⁺ in AD myocytes but did not alter Ca²⁺ transient kinetics in NB myocytes. In contrast to adults, localized SR Ca²⁺ release events ("Ca²⁺ sparks") occurred predominantly at the cell periphery of NB myocytes. Immunolabeling experiments demonstrated overlapping distributions of the Na⁺-Ca²⁺ exchanger and ryanodine receptors (RyR2) in AD myocytes. In contrast, RyR2s were spatially separated from the sarcolemma in NB myocytes. Confocal sarcolemmal imaging of di-8-ANEPPS–treated myocytes confirmed an extensive T-tubule network in AD cells, and that T-tubules are absent in NB myocytes. A mathematical model of subcellular Ca²⁺ dynamics predicts that Ca²⁺ flux via the Na⁺-Ca²⁺ exchanger during an action potential can account for the subsarcolemmal Ca²⁺ gradients in NB myocytes. Spatial separation of sarcolemmal Ca²⁺ entry from SR Ca²⁺ release channels may minimize the role of SR Ca²⁺ release during normal EC coupling in NB ventricular myocytes.

Key Words: Ca²⁺ • development • T-tubule • excitation-contraction coupling • modeling

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