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J Thorac Cardiovasc Surg 1995;110:1369-1380
© 1995 Mosby, Inc.
SURGERY FOR ACQUIRED HEART DISEASE |
Charleston, S.C.
Supported by National Institutes of Health grant HL 45004 (F. G. S.), Established Investigator Award of the American Heart Association (F. G. S.), Nina S. Brainwald Research Fellowship of the Thoraic Suergery Foundation for Research and Education (J. D. W.), and Medical University of South Carolina Postdoctoral Research Fellowship Award (J. D. W.)
Address for reprints: Francis G. Spinale, MD, PhD, Division of Cardiothoracic Surgery, Medical University of South Carolina, 171 Ashley Ave., CSB 418, Charleston, SC 29425.
Abstract
Administration of 3,5,3'-triiodo-L-thyronine (T3) has recently been suggested to acutely improve left ventricular performance. However, the cellular and molecular mechanisms responsible for this improvement in left ventricular function with T3 remained unknown. Accordingly, the present study examined the direct effects of T3 administration on myocyte contractile function and the sarcolemmal systems that might potentially contribute to these effects. In isolated porcine left ventricular myocytes (n= 81), velocity of shortening increased in the presence of 80 pmol/L T3 compared with that in untreated myocytes (117.0± 5.0 versus 77.3± 3.3µm/sec, p < 0.05). In a separate series of experiments (n= 29), myocyte velocity of shortening increased in the presence of both T3and ß-adrenergic receptor stimulation (25 nmol/L isoproterenol) to greater than that with ß-adrenergic receptor stimulation alone (274.3± 16.9 versus 203.7± 16.2µm/sec, p < 0.05). Cyclic adenosine monophosphate generation was next examined in isolated myocyte preparations (n= 9). In the presence of T3, no significant increase in cyclic-adenosine monophosphate generation was observed 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 T3and ß-adrenergic receptor stimulation, cyclic-adenosine monophosphate generation increased significantly to greater than that with ß-adrenergic receptor stimulation alone (224.4 ± 61.1 versus 120.1± 35.5 fmoles/myocyte, p < 0.05). Because cyclic-adenosine monophosphate modulates intracellular Ca+2 processes, L-type Ca+2 channel current (patch clamp methods; -picoamp/picofarad, n= 15) and peak intracellular Ca+2 levels (fura 2 ionic measurement, n= 47) were next measured. In the presence of T3, a shift in the activation voltage at peak L-type Ca+2 channel current was observed from baseline (5.5 usmn;1.4 versus 9.0± 1.0 mV, p < 0.05). Furthermore, in the presence of both T3and ß-adrenergic receptor stimulation, peak L-type Ca+2 channel current (8.9± 0.7 versus 6.3± 1.0 mV, p < 0.05) and peak intracellular Ca+2 levels (189.9± 8.4 versus 171.7± 8.3 nmol/L, < 0.05) increased compared with values obtained with ß-adrenergic receptor stimulation alone. Important findings from the present study were twofold: (1) T3 improved myocyte contractile processes through a cyclic-adenosine monophosphate–independent mechanism and (2) T3potentiated the effects of ß-adrenergic receptor stimulation transduction by increasing cyclic-adenosine monophosphate production, L-type Ca+2 channel current, and Ca+2 availability to the myocyte contractile apparatus. Thus T3may provide a clinically useful adjunct to ß-adrenergic agonist therapy. (J THORAC CARDIOVASC SURG 1995;110:1369-80)
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