JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pennock, G. D.
Right arrow Articles by Morkin, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pennock, G. D.
Right arrow Articles by Morkin, E.

Identification of simple substituted phenols with thyromimetic activity: cardiac effects of 3,5-diiodo-4-hydroxyphenylpropionic acid

GD Pennock, JJ Milavetz, TE Raya, JJ Bahl, S Goldman and E Morkin

Department of Cardiology, Tucson Veterans Administration Medical Center, Arizona.

To define the minimal structural requirements for cardiac activity of thyroid hormone analogs, a series of substituted phenols were screened for their ability to bind bacterially expressed thyroid hormone receptors. Compounds with binding activity then were tested for their ability to induce expression of alpha-myosin heavy chain mRNA in primary cultures of fetal rat cardiomyocytes, a sensitive marker for potential inotropic activity. 3,5-Diiodo-4-hydroxyphenylpropionic acid (DIHPA) was found to bind specifically to bacterially expressed alpha-1 and beta-1 thyroid hormone receptors (Kaff approximately 1 to 2 x 10(5) M-1) and to induce alpha-myosin heavy chain (EC50 approximately 5 x 10(- 7)). To assess the effects of DIHPA on cardiac performance in vivo, hemodynamic measurements were made in three groups of hypothyroid rats treated for 5 days with s.c. doses of DIHPA (15 mg/100 g), L-thyroxine (T4, 1.5 micrograms/100 g) or saline. Compared to controls, DIHPA and T4 produced increases in heart rate, left ventricular +dP/dtmax, - dP/dtmax, and isovolumic relaxation. In isometric papillary muscles preparations, DIHPA and T4 shortened time-to-peak tension and time-from- peak tension to 50% decline as compared with saline-treated controls. Muscles from both drug-treatment groups showed similar responses to graded doses of isoproterenol (10(-8) to 10(-3) M) and to variations in Ca++ concentration of the muscle bath (0.3125 to 3.75 x 10(-3) M). Thus, DIHPA is a novel thyromimetic compound with effects on myocardial function similar to those observed with T4.

Volume 268, Issue 1, pp. 216-223, 01/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
C. Adamson, N. Maitra, J. Bahl, K. Greer, S. Klewer, J. Hoying, and E. Morkin
Regulation of Gene Expression in Cardiomyocytes by Thyroid Hormone and Thyroid Hormone Analogs 3,5-Diiodothyropropionic Acid and CGS 23425 [N-[3,5-Dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)-phenyl]-oxamic Acid]
J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 164 - 171.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1994 by the American Society for Pharmacology and Experimental Therapeutics.