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

Abstract

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 ( ICa) 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 ICa-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 ICa (∼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.