EFFECTS OF DEVELOPMENT AND THYROID-HORMONE ON K-EXPRESSION IN RAT VENTRICLE( CURRENTS AND K+ CHANNEL GENE)

1. In rat heart, three K+ channel genes that encode inactivating trans ient outward (I-TO)-like currents are expressed. During development th e predominant K+ channel mRNA species switches from Kv1.4 to Kv4.2 and Kv4.3. However, no functional correlate of this isoform switch has be en reported. We investigated action potential characteristics and I-TO in cultured neonatal rat ventricular myocytes and adult rat hearts. W e further examined whether the changes in K+ channel gene expression a nd the associated electrophysiology that occurs during development cou ld be induced by thyroid hormone. 2. In myocytes isolated from right v entricle of adult rat heart, action potential duration was short and i ndependent 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 curre nt remaining at the end of a 500 ms pulse (I-SUS) was 6.2 +/- 0.5 pA p F(-1) (n = 19). 3. In contrast to adult cells, action potential durati on was prolonged and was markedly rate dependent in cultured neonatal rat ventricular myocytes. The current density of I-TO measured in cult ured ventricular myocytes from 1- to 2-day-old rats was 10.1 +/- 1.5 p A pF(-1) (n = 17). The recovery from inactivation for I-TO was best de scribed by the sum of two exponentials (tau(fast) = 64.3 +/- 8.8 ms, 5 4.4 +/- 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 in activation 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 independe nt 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 i nactivation 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 con trol 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 Kv 4.3 without changes in Kv4.2 mRNA levels. 6. The findings of the prese nt study indicate that postnatal development involves a shortening of action potential duration and an increase in the density of I-TO. Furt hermore, we show that development is also associated with a loss of ac tion potential rate dependence, and an acceleration in the rate of rec overy of I-TO. We propose that these functional effects occur as a con sequence of the previously reported developmental Kv1.4 to Kv4.2/Kv4.3 isoform switch. In cultured neonatal myocytes, T-3 induced many of th e electrophysiological and molecular changes that normally occur durin g postnatal development, suggesting that this hormone may play an impo rtant role in postnatal electrophysiological development.