Bursting of cardiac sodium channels after acute exposure to 3,5,3′-triiodo-L-thyronine

Physiological concentrations of 3,5,3′-triiodo-L-thyronine (T₃) acutely increased burst-mode gating of Na⁺ channels in rabbit ventricular myocytes. Bursting was measured as the ratio of long events to the total number of events multiplied by 100 (%LE); a long event was defined as a set of openings or a single opening with a total duration greater than or equal to five times the control mean open time (MOT) for cell-attached patches. In the cell-attached configuration, adding either 5 or 50 nM T₃ to the pipette increased the %LE. %LE had a biphasic voltage dependence and peaked at -50 mV, although the largest percentage change from control occurred between -30 and -40 mV. Neither unitary conductance nor the overall MOT was altered by T₃-induced bursting. However, the MOT of openings within bursts increased, implying a kinetically distinct mode of channel gating during bursts. Long events sometimes were grouped into runs, but the more usual pattern suggested that modal shifts occurred in ≈1 second. Similar behavior was observed with triiodothyroacetic acid, a T₃ analogue that does not elicit protein synthesis. To investigate involvement of soluble second messengers, cell-attached recordings were made with and without T₃ in the bath. Placed outside the pipette, 50 and 100 nM T₃ failed to alter MOT, unitary current, or %LE. Na⁺ channel gating also was unaffected by patch excision and by exposing the cytoplasmic face of inside-out patches to 50 nM T₃. Nevertheless, excision to the inside-out configuration with 5 nM T₃ in the pipette dramatically increased the %LE and lengthened MOT. These results suggest that T₃ induced Na⁺ channel bursting by an extranuclear mechanism that requires proximity of T₃ to the extracellular face of the Na⁺ channel. Furthermore, T₃ was not membrane permeant on the time scale of these experiments. Na⁺ channel bursting may contribute to the propensity for arrhythmias in hyperthyroidism and to the positive inotropic effect of acute T₃ administration in the stunned and ischemic myocardium.