ENDOTHELIN MECHANISMS IN ALTERED THYROID STATES IN THE RAT

Endothelin (ET) and its receptor characteristics were studied in hyper- and hypo-thyroid states in the rats. Hyperthyroidism was induced by daily administration of thyroxine (0.1 mg/kg i.p.) for 8 weeks, while hypothyroidism was induced by daily administration of methimazole (10 mg/kg i.p.) for 8 weeks. The chronic administration of thyroxine to rats decreased their rate of gain of body weight, increased serum T3 and T4 concentration, blood pressure and heart rate. The chronic administration of methimazole decreased the rate of gain of body weight, serum T3 and T4 concentration, blood pressure and heart rate as compared to vehicle-treated control. Plasma ET-1 levels were found to be similar in control and methimazole-treated rats, while the levels were found to be significantly (P < 0.002) increased in thyroxine-treated rats as compared to control rats. Binding studies showed that [I-125]ET-1 bound to a single, high affinity binding site in the cerebral cortex, hypothalamus and pituitary. The density (B(max)) and the affinity (K(d)) of [I-125]ET-1 binding in the cerebral cortex and hypothalamus were found to be similar in control, methimazole- and thyroxine-treated rats. The pituitary of thyroxine-treated rats showed a decrease in the binding (34.3% decrease in the density) of [I-125]ET-1 as compared to control rats. No difference was observed in the binding of [I-125]ET-1 to pituitary membranes from control and methimazole-treated rats. Competition studies showed that the IC50 and K(i) values of ET-3 for [I-125]ET-1 binding were about 8 to 11 times higher than ET-1 in cerebral cortex, hypothalamus and pituitary. In cerebral cortex and hypothalamus, the lC50 and K(i) values of ET-1 and ET-3 for [I-125]ET-1 binding were found to be similar in control, methimazole- and thyroxine-treated rats. In pituitary, the IC50 and K(i) values of ET-3 for [I-125]ET-1 binding were found to be similar in control, methimazole- and thyroxine-treated group. However, the IC50 and K(i) values of ET-1 for [I-125]ET-1 binding in pituitary membranes were found to be significantly (P < 0.0005) higher in thyroxine as compared to control and methimazole-treated rats, the values were similar in control and methimazole-treated rats. It could be possible that hyperthyroidism stimulates the production of ET-1 leading to higher plasma ET-1 concentration, which in turn produces down-regulation of ET(A) receptors in the pituitary of hyperthyroid rats. It is concluded that ET mechanisms may be involved in thyroid dysfunction.