Effects of development and thyroid hormone on K+ currents and K+ channel gene expression in rat ventricle

1. In rat heart, three K+ channel genes that encode inactivating transient outward (I-TO)-like currents are expressed. During development the predominant K+ channel mRNA species switches from Kv1.4 to Kv4.2 and Kv4.3. However, no functional correlate of this isoform switch has been reported. We investigated action potential characteristics and I-TO in cultured neonatal rat ventricular myocytes and adult rat hearts. We further examined whether the changes in K+ channel gene expression and the associated electrophysiology that occurs during development could be induced by thyroid hormone. 2. In myocytes isolated from right ventricle of adult rat heart, action potential duration was short and independent of rate of stimulation. The density of I-TO was 21.5 +/- 1.8 pA pF(-1) (n = 17). Recovery from inactivation was best described by a single exponential (tau(fast) = 31.7 +/- 2.7 ms, n = 13). The current remaining at the end of a 500 ms pulse (I-SUS) was 6.2 +/- 0.5 pA pF(-1) (n = 19). 3. In contrast to adult cells, action potential duration was prolonged and was markedly rate dependent in cultured neonatal rat ventricular myocytes. The current density of I-TO measured in cultured ventricular myocytes from 1- to 2-day-old rats was 10.1 +/- 1.5 pA pF(-1) (n = 17). The recovery from inactivation for I-TO was best described by the sum of two exponentials (tau(fast) = 64.3 +/- 8.8 ms, 54.4 +/- 10.2%; tau(slow) = 8216 +/- 2396 ms, 37.4 +/- 7.9%; n = 5). I-SUS was 4.4 +/- 0.6 pA pF(-1) (n = 17). Steady-state activation and inactivation were similar in adult and neonatal ventricular myocytes. 4. In neonatal myocytes treated with thyroid hormone, tri-iodothyronine (T-3, 100 nM), action potential duration was abbreviated and independent of stimulation rate. Whilst T-3 did not significantly increase I-TO density (24.0 +/- 2.9 pA pF(-1); n = 21 in T-3 treated cells cf. 20.1 +/- 3.0 pA pF(-1); n = 37 in untreated controls), the recovery from inactivation of I-TO was accelerated (tau(fast) = 39.2 +/- 3.6 ms, 82.2 +/- 8.9%, n = 9). T-3 did however, increase I-SUS current density (4.7 +/- 0.77 pA pF(-1); n = 37 and 7.0 +/- 0.7 pA pF(-1): n = 21, in control and T-3 treated cells, respectively). 5. The effects of T-3 (100 nM) were associated with a marked decrease in the expression of Kv1.4 at the mRNA and protein level, and an increase in the expression of Kv4.3 without changes in Kv4.2 mRNA levels. 6. The findings of the present study indicate that postnatal development involves a shortening of action potential duration and an increase in the density of I-TO. Furthermore, we show that development is also associated with a loss of action potential rate dependence, and an acceleration in the rate of recovery of I-TO. We propose that these functional effects occur as a consequence of the previously reported developmental Kv1.4 to Kv4.2/Kv4.3 isoform switch. In cultured neonatal myocytes, T-3 induced many of the electrophysiological and molecular changes that normally occur during postnatal development, suggesting that this hormone may play an important role in postnatal electrophysiological development.