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.