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

Abstract

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. (Circulation Research 1993;73:301-313) KEY WoRDs * thyroid hormone * triiodothyroacetic acid * sodium currents * modal gating modulation F or some time, thyroid hormone has been known to alter cardiac electrophysiological properties. Chronic hyperthyroidism shortens the action potential duration",2 and increases the whole-cell Ca 2 and K' currents.3 These effects seem to be independent of the modulation of the autonomic nervous system by hyperthyroidism.14 Thyroid hormone's action generally is thought to require protein synthesis. However, recent evidence suggests that 3,5,3'-triiodo-L-thyronine (T3) has specific cardiac membrane binding sites and can acutely influence the sarcolemmal Ca2-ATPase,5 adenylate cyclase,6 the number of -and a-adrenergic receptors,7 and 2-deoxyglucose transport.8 Studies on plasma membrane T3 receptors and the extranuclear effects of T3 were reviewed recently by Segal.9In contrast to the abbreviation of action potential duration in chronic hyperthyroidism,1'2 acute exposure to...

Thyroid hormone regulates Na+currents in cultured hippocampal neurons from postnatal rats

“…As previous studies had shown T3 concentrations close to the total, not the free T3 concentration found in serum to effect neurons in cell culture (Honegger & Lenoir 1980 ;Atterwill et al 1984 ;Brodie & Sampson 1989 ;Harris et al 1991 ;Dudley & Baumgarten 1993), we used a similar concentration to obtain pronounced effects. Hippocampal neurons grown in either the absence or presence of 5.2 nM T3 for 2-12 days in culture showed no major differences in morphological appearance (figure 1).…”

“…Chopra 1991 for review). Recent investigations have demonstrated effects of T3 on the synthesis of Na + channels in skeletal myotubes (Brodie & Sampson 1989), and direct effects on the gating of Na + channels in cardiac myocytes have been described (Harris et al 1991 ;Dudley & Baumgarten 1993). Likewise, effects of T3 on Ca# + channels have been demonstrated in heart and skeletal muscle (e.g.…”

Thyroid Hormone Effects on Sensory Perception, Mental Speed, Neuronal Excitability and Ion Channel Regulation

“…Patch clamp recordings revealed that in heart cells from neonatal rats (185,186) and in cat atrial myocytes (187), acute applications of 5-20 nM T3 increased voltage activated sodium currents. Single channel recordings revealed that the application of 5-50 nM T3 induced bursting of Na + -channels in rabbit ventricular myocytes (188). Later studies showed, that T3 increases the sodium channel open probability by binding directly inside the membrane and that the interaction with a pertussis toxin sensitive G-protein greatly enhances this effect (189).…”

Slowing of the Inactivation of Cardiac Voltage-Dependent Sodium Channels by the Amiodarone Derivative 2-Methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015)

“…6A, right), enhanced the negative shift of the inactivation curve, and further slowed the recovery from inactivation. Because, on the one hand, KB like amiodarone may share some receptors with thyroid hormones, and on the other hand these hormones have been reported to slow I Na inactivation (Craelius et al, 1990;Harris et al, 1991;Dudley and Baumgarten, 1993), we also examined the effect of T 3 and of its analog DITPA and their interaction with KB. T 3 at physiological concentrations (10 pM-1 nM; n cells ϭ 3) did not affect I Na .…”

“…In the present study, we report marked acute effects of KB on the inactivation of Na ϩ channels. These effects were unexpected based on those known for amiodarone (Follmer et al, 1987;Kohlhardt and Fichtner, 1988;Kodama et al, 1999;Maltsev et al, 2001), but a few studies have reported similar effects with high concentrations of thyroid hormones (Craelius et al, 1990;Harris et al, 1991;Dudley and Baumgarten, 1993).…”