Acute effects of thyroid hormone on inward rectifier potassium channel currents in guinea pig ventricular myocytes

Thyroid hormones play an important role in cardiac electrophysiology. However, the regulation of cardiac ionic channels by thyroid hormones is still unclear. To evaluate the acute effect of 3,3',5-triiode-L-thyronine (T3) on inward rectifier potassium channel (IK1) action potentials, whole-cell IK1 currents and steady-state single IK1 currents were recorded in guinea pig ventricular myocytes. Acute exposure of cells to T3 resulted in shortening of the action potential durations. This effect was initiated at 5-15 min and reached a stable plateau at 25 min. The amplitude of steady-state whole-cell IK1 was significantly increased by T3 at 1 nM to 1 microM concentration rage and with ED50 12 nM/liter. T3 (1 microM) increased IK1 by 68 +/- 7% at -40 mV and 52 +/- 9% at -100 mV. Similar effects were observed with triiodothyroacetic acid, an analogue of T3 that does not stimulate DNA transcription. The single IK1 open probability (Po) was increased 7 +/- 1% by 1 nM T3 (n = 9, P < 0.05) and 42 +/- 6% by 1 microM T3 at -40 mV (n = 18, P < 0.0001). However, the channel unit amplitude, time constants of open and fast-closed time were not changed. T3 shortened interburst duration at each membrane potential but did not change the burst behavior. To elucidate detailed mechanism, we assumed a three-state model (C1 <==> C2 <==> O) and calculated each rate constant. T3 significantly increased the rate constant, k+1, for the transition from the C1 to the C2 state at RP -40 mV (2.84 +/- 0.56 to 7.28 +/- 1.23 sec-1, P < 0.01), RP -20 mV (3.63 +/- 0.95 to 10.17 +/- 2.60 sec-1, P < 0.05) and RP (6.73 +/- 1.20 to 21.94 +/- 4.49 sec-1, P < 0.01). However, the other rate constants were not affected. These results demonstrate that T3 enhances IK1 with the increment in Po, which mainly results from shortening of interburst duration without any changes in burst behavior. Hence, the shortening of interburst duration is due to acceleration of the transition from the C1 to the C2 state. The enhanced IK1 by T3 might be one of the causes for shortened action potential duration in hyperthyroidism.