In order to compare the effect of 3,5,3'-triiodothyroacetic acid (TRIAC) with those of triiodothyronine (T3) and thyroxine (T4), severely hypothyroid rats (n=56) were infused over 13 days with 1, 2 or 4 nmol/100 g body weight (BW) per day of T3 or 2, 4 or 8 nmol/100 g BW per day of T4 or TRIAC. The 8 nmol/100 g BW per day of T4 or TRIAC induced the same increase in resting metabolic rate, yet 4 nmol/100 g BW per day of T3 was more potent (P < 0.05). For inhibiting serum TSH levels, 2 nmol/100 g BW per day of TRIAC were significantly less active than 2 nmol/100 g BW per day of T4 or 1 nmol/100 g BW per day of T3 (TRIAC, serum TSH 35.5 +/- 5.7; T3 2.58 +/- 0.91; T4 2.12 +/- 0.59 ng/ml). At higher doses serum TSH and beta-TSH mRNA were unmeasurable. Using serum T3 levels as covariate, the action of T3 and T4 was identical on cardiac monodeiodinase type 1 (5'D1) activity and hepatic malic enzyme (Me) mRNA levels and similar for hepatic 5'D1 activity. The effect of TRIAC was compared with T3 by using increasing doses of 1, 2 and 4 nmol/100 g BW per day of T3 and 2, 4 and 8 nmol/100 g BW per day of TRIAC. ANOVA indicated that there was no major difference between the effects of the hormones since with increasing doses the response of hepatic 5'D1 mRNA levels and enzyme activity and Me mRNA remained parallel. However, when studying the effect on cardiac 5'D1 activity there was not only a difference for type of treatment (T3 > TRIAC) but this difference became greater with each increment in dose. Interestingly there was also only a small effect of TRIAC on increase in heart weight compared with T3 and T4. Brain cortex monodeiodinase type 2 (5'D2) was mainly inhibited by T4 infusions. Monodeiodinase type 3 (5'D3) was stimulated by T4, less so by TRIAC and least by T3, expressing probably the local T3 and TRIAC concentrations. In conclusion, despite apparently similar effects of TRIAC and T3 and T4 on hepatic parameters of thyroid hormone action, TRIAC differs considerably in terms of its effects on cardiac 5'D1 activity and possibly on other fundamental effects of thyroid hormones on the heart since heart weight increased significantly less with TRIAC than with T3 or T4.