ABSTRACT

The present work studied the effects of amiodarone (AMD) and iopanoic acid (IA) on the conversion of thyroxine (T₄) to tri-iodothyronine (T₃) by rat myocardium. In vivo: male Wistar rats weighing 200–250 g were injected i.p. with AMD (2·5 mg/100 g body weight per day for 12 days) or IA (5 mg/100 g body weight every 12 h for 72 h). Hearts were then removed and processed as in the in-vitro studies. In vitro: hearts were homogenized in Krebs–Ringer phosphate buffer (pH 7·4) and AMD (0·1 mmol/l) or IA (10 mmol/l) plus dithiothreitol (8 mmol/l) and 0·01 μCi [¹²⁵I]T₄ or [¹²⁵I]T₃ were added. After incubation for 2 h at 37 °C, radioactive compounds were identified by paper chromatography. Both AMD and IA given in vivo blocked T₄ to T₃ conversion significantly (P<0·005). When added in vitro, AMD failed to inhibit T₄ deiodination to T₃ whereas IA induced a significant (P<0·005) decrease in T₃ generation. Deiodination of [¹²⁵I]T₃ by heart homogenates was not altered by AMD or IA. While the expected increase in circulating T₄ (P< 0·001) and decrease in T₃ (P< 0·001) did occur after AMD or IA treatment, plasma TSH in AMD-treated rats was decreased (P<0·001), while in IA-treated animals it was increased (P< 0·001), thus indicating that AMD did not inhibit pituitary type-II 5′-monodeiodinase.

In summary, these data suggest that the hypometabolism induced by AMD in rat myocardium through a decrease in the supply of T₃ is not responsible for the anti-arrhythmic activity of this drug since IA, which is not an anti-arrhythmic compound, elicited the same effect on cardiac T₃. It follows that inhibition of 5′-deiodinase and the anti-arrhythmic activity of AMD are independent properties.

Journal of Endocrinology (1989) 121, 431–434

ABSTRACT

The effects of a physiological replacement dose of thyroxine (T₄) on the response of plasma TSH to TRH in hypothyroid rats were studied. Animals were treated with iopanoic acid (IOP; 5 mg/100 g body weight) or vehicle 24, 12 and 1·5 h before the experiment. Thereafter, 800 ng T₄/100 g body weight were administered i.v. and 20 min later 1 μg TRH/100 g body weight was injected i.v. In control rats the basal concentration of TSH was 1450 ± 300 (s.e.m.) mu./l. The plasma concentration of TSH 10 min after injection of TRH increased to 167 ± 14% of the mean basal value (P < 0·001). The injection of T₄ significantly (P < 0·05) reduced the TSH response to TRH in both IOP-treated (118 ± 15%) and vehicle-treated (108 ± 15%) rats compared with untreated controls. Tri-iodothyronine (T₃) was undetectable in the plasma of all rats, whereas the plasma concentration of T₄ was 121 ± 19 nmol/l in IOP-treated and 139 ± 23 nmol/l in vehicle-treated rats 30 min after injection of 800 ng T₄/100 g body weight. In pituitary cells of control rats, cytoplasmic radioactivity 30 min after injection of [¹²⁵I]T₄ was 1·28 ± 0·13 × 10⁻²% (76 ± 6% T₄ and 17 ± 3% T₃), whereas that in nuclei reached 0·42 ± 0·36 × 10⁻²% (51 ± 4% T₄ and 28 ± 3% T₃) of the injected dose. In IOP-treated rats there was an increase in total cytoplasmic radioactivity (P < 0·05), with a decreased proportion of [¹²⁵I]T₃ (0·12 ± 0·07%; P < 0·01), whereas nuclear T₃ was significantly (P < 0·005) lower than in controls (0·057 ± 0·025 vs 0·22 ± 0·022 pmol T₃/mg DNA). Administration of 25 μg unlabelled T₄ along with the tracer reduced cytoplasmic radioactivity in both control and IOP-treated rats (P < 0·05), without a detectable change in nuclear radioactivity. The results suggest that T₄, at a physiological replacement dose, possesses an intrinsic capacity to regulate secretion of TSH following administration of TRH to hypothyroid rats.

J. Endocr. (1987) 113, 349–354

ABSTRACT

The effects of histamine H₁- and H₂-receptor antagonists on the pituitary-thyroid axis were studied in normal and thyroxine (T₄)-treated rats. Acute administration (120 min before the test) of the H₂ antagonist cimetidine induced a significant (P<0·01) increase in the TSH response to TRH, whereas treatment with histamine (30 min before the test) or with the H₁-receptor blocker diphenhydramine (120 min before the test) was without effect. Treatment with cimetidine or ranitidine (another H₂-receptor antagonist) for 5 days induced a marked decrease in basal plasma TSH concentrations (P<0·01), with no changes in pituitary concentrations of TSH. Plasma prolactin concentrations were similarly decreased by cimetidine (P<0·01), though not by ranitidine. Neither antihistaminic altered pituitary prolactin concentrations. Despite decreasing basal concentrations of plasma TSH, cimetidine augmented the response to TRH above baseline values (P<0·01) in control rats as well as in animals with T₄-induced suppression of plasma TSH. Administration of cimetidine or ranitidine for 5 days was followed by a reduced concentration of plasma T₄ and tri-iodothyronine (T₃) (P<0·05 and P<0·01 respectively), perhaps as a result of the declining plasma TSH levels. These results provide the first evidence for the reduction of plasma TSH concentrations by H₂-receptor blockers, and may indicate that histamine can physiologically regulate TSH and prolactin secretion through H₂ receptors in the anterior pituitary. The results, however, do not disprove a central action of histamine, since the decreased plasma TSH concentrations in the presence of low plasma T₄ and T₃ concentrations, and also the decrease in plasma prolactin concentrations induced by cimetidine, suggest reduced hypothalamic stimulation.

J. Endocr. (1986) 111, 175–180

Abstract

The effect of in vivo administration of cadmium chloride on the pituitary-thyroidal axis was assessed in 200 g body weight Wistar rats. A dose of 2·5 mg/kg body weight was injected i.v. 24 h before the experiments were initiated. Plasma thyroxine (T₄) and tri-iodothyronine (T₃) concentrations in cadmium-treated rats were significantly (P<0·01) decreased, whereas plasma TSH failed to increase in response to low T₄ and T₃. However, the TSH response to TRH and the pituitary content of TSH in these rats were both normal. Cadmium induced a significant (P<0·01) decrease in 4-h thyroidal ¹³¹I uptake and in thyroid/plasma radioactivity ratio. The in vitro conversion of T₄ to T₃ in the pituitary was significantly (P<0·01) blocked by cadmium whereas there was no in vivo effect. Parameters of peripheral T₄ kinetics in cadmium-treated rats, such as metabolic clearance rate (P<0·01), fractional turnover rate (P<0·01), absolute disposal rate (P<0·05), urinary clearance (P<0·05) and faecal clearance (P<0·05), were all decreased by cadmium. The lack of response of TSH to low plasma T₄ and T₃ and the normal response to exogenous TRH in this and in other non-thyroidal illness syndromes produced by other pathologies suggest a decreased stimulation of pituitary thyrotrophs by endogenous TRH.

Journal of Endocrinology (1997) 154, 113–117

ABSTRACT

The effects of thyroxine (T₄) were studied on the concentration of oestrogen receptors in the anterior pituitary gland and hypothalamus of ovariectomized euthyroid and hypothyroid rats. A group of rats was made hypothyroid by the administration of I. Seven days after ovariectomy, animals were separated into five groups: I, euthyroid controls; II, hypothyroid controls; III, hypothyroid and injected with oestradiol benzoate (10 μg/day for 10 days); IV, hypothyroid and injected with T₄ (4 μg/day for 10 days) and V, hypothyroid and injected with both oestradiol and T₄ as described above. In group I, oestrogen receptor levels in pituitary cytosol were 44·4 ± 3·4 (s.d.) fmol/mg protein and in the nucleus 47·7 ± 4·0 fmol/mg DNA. In group II the respective values were 12·8 ± 1·7 fmol/mg protein (P <0·01) and 12·7 ± 1·7 fmol/mg DNA (P <0·01 compared with group I). In group III, cytosolic receptor concentrations decreased when compared with those in group II (P <0·05), whereas nuclear receptor concentrations rose significantly (P <0·01). Group IV had both pituitary cytosolic and nuclear receptors increased (P <0·01 compared with group II). In group V there were no changes in cytosolic receptor concentrations but a significant (P <0·01) rise in nuclear receptors as compared with group II. Hypothalamic oestrogen receptors in untreated hypothyroid rats (group II) were unchanged in the cytosol and diminished (P <0·01) in the nucleus in relation to euthyroid controls (group I). Thyroxine, but not oestrogen, was effective in increasing the concentration of cytosolic receptors (P <0·05). Neither hormone caused changes in nuclei. The results show that there is a pronounced decrease in pituitary and hypothalamic (nuclei) oestrogen receptors in untreated hypothyroid rats and that this decrease can be reversed by T₄ treatment.

J. Endocr. (1988) 119, 383–387

ABSTRACT

The effects of cadmium on 5′-deiodination of thyroxine (T₄) by rat liver and on the hepatic concentration of non-protein sulfhydryl groups (NPSH) were studied in Wistar rats of 200–250 g body weight. A group of ten rats was injected with cadmium chloride (300 μg/100 g body weight i.p.) daily for 4 days. Another group of six rats received, in addition, dithiothreitol (DTT; 1 mg/100 g body weight i.p.) daily for the same period. A group of eight normal untreated rats served as control. T₄ deiodination was also determined in aliquots of liver from untreated rats, with cadmium (2 or 5 mmol/l) and with or without DTT (0, 2·5, 5 or 10 mmol/l) plus 1 μCi ¹²⁵I-labelled T₄. Hepatic NPSH were measured by a colorimetric method employing dithioldinitrobenzoic acid. Homogenates were incubated for 90 min at 37 °C and chromatographed in a tertiary amyl alcohol: hexane: ammonia (2 mol/l) (10: 1: 12) system. Cadmium-injected rats showed a significant (P <0·01) decrease in T₄ deiodination and in the generation of ¹²⁵I (P <0·01) and tri-iodothyronine (T₃) (P <0·02). NPSH were also decreased (P <0·02). Administration of DTT restored T₄ deiodination and NPSH to normal. In-vitro addition of cadmium or DTT to normal rat liver homogenates induced similar effects on the degradation of T₄. Serum concentrations of T₄ (P <0·01) and T₃ (P <0·01) declined significantly in cadmium-injected rats, whereas DTT administration failed to normalize serum hormone levels. The data suggest that cadmium may have decreased 5′-deiodinating activity through binding to sulfhydryl groups of 5′-deiodinase as it does in other enzymes. The effects on serum T₄ concentrations may be unrelated to those on 5′-deiodinase.

Journal of Endocrinology (1993) 138, 219–224

Abstract

We have assessed the relative contribution of the thyroid hormones and noradrenaline (NA) on the calorigenic function of brown adipose tissue (BAT) as indicated by GDP binding and O₂ consumption of BAT mitochondria. Male Wistar rats of 200 g body weight were made hypothyroid with ¹³¹I. Groups of animals were injected s.c., in divided doses, daily for 10 days, with thyroxine (2 μg/100 g body weight) or tri-iodothyronine (T₃; 0·3 μg/100 g body weight). Animals were used 7 days after bilateral or unilateral sympathetic nerve excision of BAT (Sx). Sham-operated rats were used as controls. In normal rats kept at 22 °C, GDP binding reached 94 ± 24 pmol/mg protein; untreated hypothyroid rats had normal binding values whereas the T₃-treated group showed an increased binding. Sx induced a sharp fall in the three groups (P<0·01). After 24-h exposure to 4 °C GDP binding increased in normal rats to about 410% (P<0·01) whereas binding failed to increase in response to cold in the untreated hypothyroid and the T₃-treated groups. Sx reduced GDP binding in the three groups significantly (P<0·01). The consumption of O₂ by BAT mitochondria showed similar variations in response to Sx and to cold exposure as did GDP binding. The data indicated that, at room temperature, BAT calorigenesis can function without the thyroid hormones, though not without the catecholamines. The findings in rats exposed to cold showed that the lack of NA was significantly more effective than the lack of thyroid hormones in preventing the BAT hyperactive response. This does not negate an active role for T₃ in BAT calorigenesis.

Journal of Endocrinology (1995) 145, 579–584