Abstract
L-type Ca(2+) current (I (CaL)) is a key regulatory and functional element during early embryonic cardiomyogenesis. As the embryonic heart underlies hormonal modulation, e.g. catecholamines, we aimed at studying effects of beta-adrenergic stimulation on I (CaL) densities and inactivation kinetics during murine heart development. I (CaL) was recorded applying the whole-cell patch-clamp technique in ventricular myocytes of early embryonic (EDS, E9.5-11.5) and late developmental, fetal (LDS, E16.5-18.5) stages as well as adult cardiomyocytes. To distinguish between Ca(2+)-(CDI) and voltage-dependent inactivation (VDI), Ca(2+) was replaced with Ba(2+) in the extracellular recording solution. The beta-adrenergic signaling pathway was simulated by applying isoproterenol (Iso). Basal current densities showed an increase of I (CaL) during development (EDS: -9.61 +/- 1.97 pA/pF, n = 9; LDS: -13.2 +/- 4.26 pA/pF, n = 12; adult: -16.1 +/- 4.63 pA/pF, n = 5). Iso (1 microM) enhanced I (CaL) density with low effects at EDS (17.1 +/- 3.58%, n = 8, P > 0.05) but strong effects at LDS (74.1 +/- 3.77%, n = 8, P < 0.01) and in adults (90.6 +/- 7.01%, n = 6, P < 0.001). The current availability was significantly higher at LDS as compared to EDS and elevated after application of Iso. In the presence of Ca(2+), the fast phase of I (CaL) inactivation (tau(f)) was significantly enhanced by Iso at LDS. The slow phase of inactivation (tau(s)) was unaltered at both developmental stages. However, VDI was significantly reduced under Iso in LDS and adult cardiomyocytes. These results imply that beta-adrenergic modulation becomes of importance especially during fetal heart development. CDI and VDI of I (CaL) are modulated by beta-adrenergic stimulation in fetal but not in early embryonic mouse cardiomyocytes. Furthermore our data suggest important changes of the L-type Ca(2+) channel protein, and/or maturation of the Ca(2+)-induced Ca(2+) release (CICR) machinery.
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