Cardiac hypertrophy and prolongation of the cardiac action potential are hallmark features of heart disease. We examined the molecular mechanisms and the functional consequences of this action potential prolongation on calcium handling in right ventricular myocytes obtained from rats 8 weeks following ligation of the left anterior descending coronary artery (post‐myocardial infarction (MI) myocytes). Compared with myocytes from sham‐operated rats (sham myocytes), post‐MI myocytes showed significant reductions in transient outward K+ current (Ito) density (sham 19·7 ± 1·1 pA pF−1versus post‐MI 11·0 ± 1·3 pA pF−1; means ± s.e.m.), inward rectifier K+ current density (sham ‐13·7 ± 0·6 pA pF−1versus post‐MI ‐10·3 ± 0·9 pA pF−1) and resting membrane potential (sham ‐84·4 ± 1·3 mV versus post‐MI ‐74·1 ± 2·6 mV). Depressed Ito amplitude correlated with significant reductions in Kv4.2 and Kv4.3 mRNA and Kv4.2 protein levels. Kv1.4 mRNA and protein levels were increased and coincided with the appearance of a slow component of recovery from inactivation for Ito. In current‐clamp recordings, post‐MI myocytes showed a significant increase in [Ca2+]i transient amplitude compared with sham myocytes. Using voltage‐clamp depolarizations, no intrinsic differences in Ca2+ handling by the sarcoplasmic reticulum or in L‐type Ca2+ channel density (ICa,L) were detected between the groups. Stimulation of post‐MI myocytes with an action potential derived from a sham myocyte reduced the [Ca2+] transient amplitude to the sham level and vice versa. The net Ca2+ influx per beat via ICa,L was increased about 2‐fold in myocytes stimulated with post‐MI action potentials compared with sham action potentials. Our findings demonstrate that reductions in K+ channel expression in post‐MI myocytes prolong action potential duration resulting in elevated Ca2+ influx and [Ca2+]i transients.

The aim of the present study was to assess differences in transient outward potassium current ( I to) between the right ventricular free wall and the interventricular septum of the adult rat ventricle and to evaluate the relative contributions of Kv4.2, Kv4.3, and Kv1.4 to I to in these regions. The results show that I to is composed of both rapidly and slowly recovering components in the right wall and septum. The fast component had a significantly higher density in the right free wall than in the septum, whereas the slow component did not differ between the two sites. Kv4.2mRNA and protein levels were also highest in the right wall and correlated with I to density, whereas Kv4.3 was expressed uniformly in these regions. The kinetics of the rapidly recovering component of I to in myocytes was similar to that recorded in tsa-201 cells expressing Kv4.2 and Kv4.3 channels. Kv1.4 mRNA and protein expression correlated well with the density of the slowly recovering I to, whereas the recovery kinetics of the slow component were identical to Kv1.4 expressed in tsa-201 cells. In conclusion, expression of Kv1.4, Kv4.2, and Kv4.3 differs between regions in rat hearts. Regionally specific differences in the genetic composition of I to can account for the region-specific properties of this current.

1. In rat heart, three K¤ channel genes that encode inactivating transient outward (ITO)-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 ITO 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 ITO was 21·5 ± 1·8 pA pF¢ (n = 21). Recovery from inactivation was best described by a single exponential (ôfast = 31·7 ± 2·7 ms, n = 13). The current remaining at the end of a 500 ms pulse (ISUS) was 6·2 ± 0·5 pA pF¢ (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 ITO measured in cultured ventricular myocytes from 1-to 2-day-old rats was 10·1 ± 1·5 pA pF¢ (n = 17). The recovery from inactivation for ITO was best described by the sum of two exponentials (ôfast = 64·3 ± 8·8 ms, 54·4 ± 10·2 %; ôslow = 8216 ± 2396 ms, 37·4 ± 7·9 %; n = 5). ISUS was 4·4 ± 0·6 pA pF¢ (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 (T3, 100 nÒ), action potential duration was abbreviated and independent of stimulation rate. Whilst T3 did not significantly increase ITO density (24·0 ± 2·9 pA pF¢; n = 21 in T3 treated cells cf. 20·1 ± 3·0 pA pF¢; n = 37 in untreated controls), the recovery from inactivation of ITO was accelerated (ôfast = 39·2 ± 3·6 ms, 82·2 ± 8·9 %, n = 9). T3 did however, increase ISUS current density (4·7 ± 0·77 pA pF¢; n = 37 and 7·0 ± 0·7 pA pF¢, n = 21, in control and T3 treated cells, respectively). 5. The effects of T3 (100 nÒ) 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 ITO. 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 ITO. We propose that these functional effects occur as a consequence of the previously reported developmental Kv1.4 to Kv4.2ÏKv4.3 isoform switch. In cultured neonatal myocytes, T3 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.