THE DIRECT EFFECTS OF 3,5,3'-TRIIODO-L-THYRONINE (T-3) ON MYOCYTE CONTRACTILE PROCESSES - INSIGHTS INTO MECHANISMS OF ACTION

Administration of 3,5,3'-triiodo-L-thyronine (T-3) has recently been s uggested to acutely improve left ventricular performance. However, the cellular and molecular mechanisms responsible for this improvement in left ventricular function with T-3 remained unknown. Accordingly, the present study examined the direct effects of T-3 administration on my ocyte contractile function and the sarcolemmal systems that might pote ntially contribute to these effects. In isolated porcine left ventricu lar myocytes (n = 81), velocity of shortening increased in the presenc e of 80 pmol/L T-3 compared with that in untreated myocytes (117.0 +/- 5.0 versus 77.3 +/- 3.3 mu m/sec, p < 0.05). In a separate series of experiments (n = 29), myocyte velocity of shortening increased in the presence of both T-3 and beta-adrenergic receptor stimulation (25 nmol /L, isoproterenol) to greater than that with beta-adrenergic receptor stimulation alone (274.3 +/- 16.9 versus 203.7 +/- 16.2 mu m/sec, p < 0.05). Cyclic adenosine monophosphate generation was next examined in isolated myocyte preparations (n = 9), In the presence of T-3, no sign ificant increase in cyclic-adenosine monophosphate generation was obse rved compared with that in untreated myocytes (39.1 +/- 8.3 versus 24. 7 +/- 5.8 fmols/myocyte, p = 0.17). However, in the presence of both T -3 and beta-adrenergic receptor stimulation, cyclic-adenosine monophos phate generation increased significantly to greater than that with bet a-adrenergic receptor stimulation alone (224.4 +/- 61.1 versus 120.1 /- 35.5 fmoles/myocyte, p < 0.05), Because cyclic-adenosine monophosph ate modulates intracellular Ca+2 processes, L-type Ca+2 channel curren t (patch clamp methods; -picoamp/picofarad, n = 15) and peak intracell ular Ca+2 levels (fura 2 ionic measurement, n = 47) were next measured , In the presence of T-3, a shift in the activation voltage at peak L- type Ca+2 channel current was observed from baseline (5.5 +/- 1.4 vers us 9.0 +/- 1.0 mV, p < 0.05). Furthermore, in the presence of both T-3 and beta-adrenergic receptor stimulation, peak L-type Ca+2 channel cu rrent (8.9 +/- 0.7 versus 6.3 +/- 1.0 mV, p < 0.05) and peak intracell ular Ca+2 levels (189.9 +/- 8.4 versus 171.7 +/- 8.3 nmol/L, p < 0.05) increased compared with values obtained with beta-adrenergic receptor stimulation alone. Important findings from the present study were two fold: (1) T-3 improved myocyte contractile processes through a cyclic- adenosine monophosphate-independent mechanism and (2) T-3 potentiated the effects of beta-adrenergic receptor stimulation transduction by in creasing cyclic-adenosine monophosphate production, L-type Ca+2 channe l current, and Ca+2 availability to the myocyte contractile apparatus. Thus T-3 may provide a clinically useful adjunct to beta-adrenergic a gonist therapy.