title: Abnormalities of the thyroid hormone negative feedback regulation of TSH secretion in spontaneously hypertensive rats.
abstract: Spontaneously hypertensive rats (SHR) are characterized by several neuroendocrine abnormalities including a chronic hypersecretion of thyrotropin (TSH) of unknown etiology. We hypothesized that the inappropriately high TSH secretion in SHR may be the result of an impaired thyroid hormone negative feedback regulation of hypothalamic thyrotropin-releasing hormone (TRH) and/or pituitary TSH production. To test this hypothesis, SHR or their normotensive Wistar-Kyoto (WKY) controls were treated with either methimazole (0.02% in drinking water) to induce hypothyroidism or administered L-thyroxine (T4) at a dose of 0.8 or 2.0 micrograms/100 g body weight/day to induce hyperthyroidism. All treatments were continued for 14 days after which animals were killed under low stress conditions. TSH concentrations in plasma and anterior pituitary tissue were 2-fold higher (P less than 0.01) in euthyroid SHR compared to WKY control rats while thyroid hormone (T3 and T4) levels were in the normal range. Hypothyroidism induced by either methimazole or thyroidectomy caused a significant (P less than 0.01) rise of plasma TSH levels in both WKY and SHR rats. However, relative to the TSH concentrations in control animals, the increase of plasma TSH in SHR was significantly blunted (P less than 0.01) in comparison to the WKY group. Hypothyroidism caused a significant depletion of TRH in stalk-median eminence (SME) tissue in both groups of rats. However, no differences between SHR and WKY rats were observed. The administration of thyroid hormone caused a dose dependent suppression of plasma TSH levels in both strains of rats. However, at both doses tested plasma TSH concentrations in SHR rats were significantly less suppressed (P less than 0.05) than those in WKY animals. Under in vitro conditions basal and potassium induced TRH release from SMEs derived from SHR was significantly (P less than 0.05) higher than that from WKY rats, whether expressed in absolute terms or as percent of content. These findings suggest that the thyroid hormone negative feedback regulation of TSH secretion may be impaired in SHR rats. Our data do not allow conclusions as to whether defects in the regulation of TSH production are located exclusively at the hypothalamic level. Since the overproduction of hypothalamic TRH and hypophysial TSH should lead to an increased thyroid hormone biosynthesis other defects in the hypothalamus-pituitary-thyroid-axis may contribute to the abnormal regulation of TSH secretion in SHR rats.
authors.affiliation: Department of Medicine, Brown University/Rhode Island Hospital, Providence 02903.
authors.forename: T O
authors.initials: TO
authors.lastname: Bruhn
authors.forename: I M
authors.initials: IM
authors.lastname: Jackson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005246:Feedback; D006973:Hypertension / Q000150:complications / Q000378:metabolism*; D007037:Hypothyroidism / Q000139:chemically induced / Q000150:complications / Q000378:metabolism; D008297:Male; D008473:Median Eminence / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D011863:Radioimmunoassay; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013972:Thyrotropin / Q000097:blood / Q000378:metabolism*; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism*; D013974:Thyroxine / Q000494:pharmacology
chemical_list: D011498:Protein Precursors; C069493:prepro-thyrotropin releasing hormone (25-50); D013973:Thyrotropin-Releasing Hormone; D013972:Thyrotropin; D013974:Thyroxine