Mechanisms of excitation-contraction (EC) coupling and relaxation in mammalian ventricular myocytes undergo major changes during postnatal development (1,2). In mature myocardial cells, influx of calcium via L-type calcium channels triggers the intracellular release of calcium from the sarcoplasmic reticulum (SR), leading to activation of the contractile proteins (3). In contrast, calcium-induced calcium release plays a minor role in the neonatal rabbit heart. Neonatal myocytes are much more dependent on calcium influx across the sarcolemma through the sodium-calcium exchanger (NCX) and/or calcium channels as the source(s) of activator calcium for contraction. (1,2,4,5) It was demonstrated previously that NCX protein expression and functional NCX activity were highest in late fetal and early neonatal rabbits and declined postnatally to adult levels by 2-3 wk of age (6,7). These observations are consistent with more recent studies suggesting that the major source of calcium influx in neonatal myocytes is through the NCX (5,8). In contrast, L-type calcium current (I Ca ) density is relatively small in immature rabbit myocytes, and I Ca may not contribute significantly to calcium influx in newborns (5,9). Indeed, when I Ca is blocked and the SR is disabled experimentally, NCX is sufficient for normal contraction and relaxation in neonatal myocytes (4,8).Despite the observations that newborn myocytes rely predominately on NCX for contraction and that I Ca may play a relatively minor role in triggering SR calcium release, newborns are exquisitely sensitive to the negative inotropic effects of calcium channel blockers (10). Previous studies using voltage-clamp techniques provide some insights into this apparent paradox.
The Na+-Ca2+ exchanger (NCX) is up-regulated in the neonatal rabbit heart. Because the duration of membrane depolarization is an important determinant of calcium entry via NCX, pharmacological agents that lengthen the action potential (AP) may significantly increase the amount of activator calcium in newborns. We tested this potentially novel therapeutic strategy by using action potential voltage clamp steps or using dofetilide, a blocker of IKr, to prolong the action potential duration (APD). The effects of changing APD on calcium transients were determined in ventricular myocytes at different developmental stages: newborn (1-4 days), juvenile (9-10 days), and adult ventricular myocytes (35 degrees C; 1 Hz). Calcium transient amplitude in neonatal myocytes increased substantially with clamping with longer APs. In contrast, exposure to dofetilide (0.1, 1, and 10 microM) under current clamp conditions increased APD in a concentration-dependent manner but had no significant effect on calcium transient amplitude in either neonates or adults. When the AP was held constant under voltage clamp conditions, dofetilide decreased the calcium transient amplitude in neonates. This effect is likely related to inhibition of sodium-calcium exchanger and L-type Ca2+ currents (ICa), as observed in separate experiments. These results suggest that dofetilide has a paradoxical effect on APD and calcium transients in the newborn heart.
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