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Endocrinology Vol. 141, No. 9 3057-3064
Copyright © 2000 by The Endocrine Society

ARTICLES

The Thyroid Hormone Receptor-ß-Selective Agonist GC-1 Differentially Affects Plasma Lipids and Cardiac Activity1

Susanne U. Trost, Eric Swanson, Bernd Gloss, David B. Wang-Iverson, Hongjiang Zhang, Tanya Volodarsky, Gary J. Grover, John D. Baxter, Grazia Chiellini, Thomas S. Scanlan and Wolfgang H. Dillmann

Department of Medicine, University of California, San Diego, California 92093-0618; Bristol-Myers Squibb Co. (D.B.W.-I., H.Z., T.V., G.J.G.), Princeton, New Jersey 08543; and Metabolic Research Unit (J.D.B.) and Departments of Pharmaceutical Chemistry (G.C., T.S.S.) and Molecular and Cellular Pharmacology (G.C., T.S.S.), University of California, San Francisco, California 94143

Address all correspondence and requests for reprints to: Wolfgang H. Dillmann M.D., Department of Medicine, 9500 Gilman Drive (BSB 5063), La Jolla, California 92093-0618. E-mail: wdillmann{at}ucsd.edu

Thyroid hormones influence the function of many organs and mediate their diverse actions through two types of thyroid hormone receptors, TR{alpha} and TRß. Little is known about effects of ligands that preferentially interact with the two different TR subtypes. In the current study the comparison of the effects of the novel synthetic TRß-selective compound GC-1 with T3 at equimolar doses in hypothyroid mice revealed that GC-1 had better triglyceride-lowering and similar cholesterol-lowering effects than T3. T3, but not GC-1, increased heart rate and elevated messenger RNA levels coding for the If channel (HCN2), a cardiac pacemaker that was decreased in hypothyroid mice. T3 had a larger positive inotropic effect than GC-1. T3, but not GC-1, normalized heart and body weights and messenger RNAs of myosin heavy chain {alpha} and ß and the sarcoplasmic reticulum adenosine triphosphatase (Serca2). Additional dose-response studies in hypercholesteremic rats confirmed the preferential effect of GC-1 on TRß-mediated parameters by showing a much higher potency to influence cholesterol and TSH than heart rate. The preferred accumulation of GC-1 in the liver vs. the heart probably also contributes to its marked lipid-lowering effect vs. the absent effect on heart rate. These data indicate that GC-1 could represent a prototype for new drugs for the treatment of high lipid levels or obesity.




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