Endocrine Abstracts

Thyroid hormone resistance (THR) is associated with elevated FT4 and FT3 with inappropriately high TSH levels. T3 action is mediated by two types of thyroid hormone receptor, encoded by alpha and beta genes. We evaluated the endothelial function of a THR transgenic mouse model with a targeted mutation in the thyroid hormone beta receptor gene ex vivo.

Isometric tension of aortic rings of 10 mice of each genotype (TRb^PV/PV, TRb^PV/+) were compared with controls (TRb^+/+) after being mounted in Krebs’ buffer in a myograph. After resting a dose response to contraction with phenylephrine [PE] (half log increments from 10⁻⁹ to 10⁻⁶ M) was measured. After maximal contraction, relaxation to acetylcholine [ACH] (10⁻⁹ to 10⁻⁵M) was measured and a further dose relaxation response to sodium nitroprusside [SNP] (10⁻⁹ to 10⁻⁶) was performed.

A difference in the peak contraction obtained with PE (P=ns) was found between genotypes. The average relaxation to ACH (an endothelium dependent relaxation) was lower in TRb^PV/PV (62.1%) compared to both TRb^PV/+(70.6%; P<0.01) and TRb^+/+(74.9%; P<0.001). Relaxation to SNP, (endothelium independent smooth muscle relaxation) differed between TRb^PV/PV and TRb^PV/+(105%, 130% P<0.01).

The EC₅₀ (concentration required to achieve 50% relaxation) to ACH was higher (1.1×10⁻⁶ P<0.05) in TRb^PV/PV compared to TRb^PV/+ or TRb^+/+(1.2×10⁻⁷, 1.1×¹⁰⁻⁷ P=ns). In contrast in TRb^PV/PV mice in response to SNP 10⁻⁹ to 10⁻⁵ EC₅₀ was not different between genotypes. T4 levels were 10 fold higher in TRb^PV/PV c.f. TRb^+/+ and TSH levels 110 fold higher in the same genotypes.

The impaired vascular response of THR may be partly due to the beta mutation though the role of T4 and TSH levels needs further exploration.