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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 294/2/C516    most recent 00417.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Huang, J. Articles by Tibbits, G. F. Search for Related Content PubMed PubMed Citation Articles by Huang, J. Articles by Tibbits, G. F.

MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Ontogeny of Ca²⁺-induced Ca²⁺ release in rabbit ventricular myocytes

¹Cardiac Membrane Research Laboratory, Simon Fraser University, Burnaby, British Columbia, Canada; ²Cardiovascular Sciences, Child and Family Research Institute, Vancouver, British Columbia, Canada; and ³Laboratorio de Fisiología Celular, Servei de Cardiología, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Submitted 12 September 2007 ; accepted in final form 3 December 2007

It is commonly accepted that L-type Ca²⁺ channel-mediated Ca²⁺-induced Ca²⁺ release (CICR) is the dominant mode of excitation-contraction (E-C) coupling in the adult mammalian heart and that there is no appreciable CICR in neonates. However, we have observed that cell contraction in the neonatal heart was significantly decreased after sarcoplasmic reticulum (SR) Ca²⁺ depletion with caffeine. Therefore, the present study investigated the developmental changes of CICR in rabbit ventricular myocytes at 3, 10, 20, and 56 days of age. We found that the inhibitory effect of the L-type Ca²⁺ current (I_Ca) inhibitor nifedipine (Nif; 15 µM) caused an increasingly larger reduction of Ca²⁺ transients on depolarization in older age groups [from 15% in 3-day-old (3d) myocytes to 90% in 56-day-old (56d) myocytes]. The remaining Ca²⁺ transient in the presence of Nif in younger age groups was eliminated by the inhibition of Na⁺/Ca²⁺ exchanger (NCX) with the subsequent addition of 10 µM KB-R7943 (KB-R). Furthermore, Ca²⁺ transients were significantly reduced in magnitude after the depletion of SR Ca²⁺ with caffeine in all age groups, although the effect was significantly greater in the older age groups (from 40% in 3d myocytes up to 70% in 56d myocytes). This SR Ca²⁺-sensitive Ca²⁺ transient in the earliest developmental stage was insensitive to Nif but was sensitive to the subsequent addition of KB-R, indicating the presence of NCX-mediated CICR that decreased significantly with age (from 37% in 3d myocytes to 0.5% in 56d myocytes). In contrast, the I_Ca-mediated CICR increased significantly with age (from 10% in 3d myocytes to 70% in 56d myocytes). The CICR gain as estimated by the integral of the CICR Ca²⁺ transient divided by the integral of its Ca²⁺ transient trigger was smaller when mediated by NCX (1.0 for 3d myocytes) than when mediated by I_Ca (3.0 for 56d myocytes). We conclude that the lower-efficiency NCX-mediated CICR is a predominant mode of CICR in the earliest developmental stages that gradually decreases as the more efficient L-type Ca²⁺ channel-mediated CICR increases in prominence with ontogeny.

excitation-contraction coupling; Na⁺/Ca²⁺ exchanger; L-type Ca²⁺ channels; sarcoplasmic reticulum