Organ-specific effects of 3,5,3'-triiodothyroacetic acid in rats

Abstract

In order to compare the effect of 3,5,3 0 -triiodothyroacetic acid (TRIAC) with those of triiodothyronine (T 3 ) and thyroxine (T 4 ), severely hypothyroid rats (n ¼ 56) were infused over 13 days with 1, 2 or 4 nmol/100 g body weight (BW) per day of T 3 or 2, 4 or 8 nmol/100 g BW per day of T 4 or TRIAC. The 8 nmol/100 g BW per day of T 4 or TRIAC induced the same increase in resting metabolic rate, yet 4 nmol/100 g BW per day of T 3 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 T 4 or 1 nmol/100 g BW per day of T 3 (TRIAC, serum TSH 35.5 Ϯ 5.7; T 3 2.58 Ϯ0.91; T 4 2.12 Ϯ0 .59 ng/ml). At higher doses serum TSH and b-TSH mRNA were unmeasurable.Using serum T 3 levels as covariate, the action of T 3 and T 4 was identical on cardiac monodeiodinase type 1 (5 0 D1) activity and hepatic malic enzyme (Me) mRNA levels and similar for hepatic 5 0 D1 activity. The effect of TRIAC was compared with T 3 by using increasing doses of 1, 2 and 4 nmol/100 g BW per day of T 3 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 0 D1 mRNA levels and enzyme activity and Me mRNA remained parallel. However, when studying the effect on cardiac 5 0 D1 activity there was not only a difference for type of treatment (T 3 >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 T 3 and T 4 . Brain cortex monodeiodinase type 2 (5 0 D2) was mainly inhibited by T 4 infusions. Monodeiodinase type 3 (5 0 D3) was stimulated by T 4 , less so by TRIAC and least by T 3 , expressing probably the local T 3 and TRIAC concentrations.In conclusion, despite apparently similar effects of TRIAC and T 3 and T 4 on hepatic parameters of thyroid hormone action, TRIAC differs considerably in terms of its effects on cardiac 5 0 D1 activity and possibly on other fundamental effects of thyroid hormones on the heart since heart weight increased significantly less with TRIAC than with T 3 or T 4 .

Triiodothyroacetic acid in health and disease

“…Interestingly, Mirell and coworkers (Mirell et al 1989) found that TSH mRNA expression levels are unchanged 6 h after TA 3 administration, suggesting that the initial decline in serum TSH is not caused by alterations at transcriptional level, but rather points to direct inhibition of TSH secretion by TA 3 . In contrast, prolonged (>12 days) TA 3 administration to rats persistently suppressed pituitary TSH mRNA levels (Juge-Aubry et al 1995, Liang et al 1997, resulting in a dose-dependent decrease in serum T 3 and T 4 levels (Medina-Gomez et al 2008). Similar effects on TSH levels were found in mice treated with TA 4 , whereas no effects were observed on hypothalamic TRH mRNA expression (Horn et al 2013).…”

“…Nevertheless, the plasma clearance rate of TA 3 considerably exceeds the clearance rate of T 3 in humans (compiled data shown in Table 1). The clearance rate of TA 3 in rats is more similar to that of T 3 (Table 1; Gosling et al 1976, Liang et al 1997. In humans, the estimated plasma half-life of TA 3 is ~6 h and, thus, is markedly shorter than the half-life of T 3 (~24 h) (Table 1).…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…However, there is only moderate TRb selectivity in cell culture studies (298). In rats, tiratricol has been shown to have antidepressant effects (299), thermogenic effects in the BAT (300,301), and some degree of organ specificity due to its enhanced liver and skeleton effects and reduced cardiac effects (302). The use of tiratricol in a number of settings, including patients with TSH hypersecretion and athyrotic patients, reduced serum TSH (303-305) and lowered serum cholesterol levels without affecting heart rate but elevated biochemical markers of bone turnover (306,307).…”

Differences between the effects of thyroxine and tetraiodothyroacetic acid on TSH suppression and cardiac hypertrophy

“…It may be puzzling to find a smaller Triac to Tetrac serum ratio compared with the T 3 to T 4 ratio. We have published the metabolic clearance rate of Triac which, in the rat, does not differ from T 3 (28 ml/h per 100 g BW) (9). Using the present serum Triac levels, the above-mentioned MCR and the infusion rates of Tetrac, one can estimate the conversion rate.…”

“…In the rat, studies with Triac revealed differences with tri-iodothyronine (T 3 ) for cardiac hypertrophy and cardiac monodeiodinase type 1 activity (8,9). These differential peripheral sensitivities and actions of Triac might be used for clinical benefit.…”