Abnormalities in the hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats (SHR) during development of hypertension were investigated using in vivo and in vitro methods. Plasma ACTH responses to hemorrhage and ether stress were significantly smaller in 7-week-old SHR than in age-matched Wistar-Kyoto rats (WKY), while plasma corticosterone baseline levels and its response to stress were greater in SHR than in WKY. There was no significant difference in the plasma ACTH response to ether stress between bilaterally adrenalectomized SHR and WKY replaced with a 25% corticosterone pellet for 6 days. Adrenalectomy prevented the development of hypertension in SHR; however, corticosterone replacement restored hypertension. Plasma ACTH showed a smaller response to iv CRH injection in SHR than in WKY, while the ACTH response to arginine vasopressin was not different between SHR and WKY. CRH concentrations in the median eminence, posterior pituitary, and cerebral cortex were lower in SHR than in WKY, while the CRH concentration in the median eminence was not different in SHR and WKY when they were adrenalectomized with or without corticosterone replacement. Basal in vitro CRH release from hypothalamic tissue was reduced in SHR, while CRH release in response to 56 mM KCl was not different in SHR and WKY. These results suggest that adrenocortical function is enhanced in young SHR, that reduced ACTH response to stress and exogenous CRH in SHR may be ascribed to higher plasma corticosterone levels, and that corticosterone is essential for the development of hypertension in SHR.

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The involvement of prostaglandin E2 (PGE2), adenosine 3',5'-cyclic monophosphate (cAMP), and vasopressin in lithium-induced polyuria was investigated in rats. Administration of LiCl (4 mmol/kg body wt) for 7 days induced a marked polyuria with a significant excretion of urinary PGE2. Administration of indomethacin (IND, 5 mg/kg body wt) for 4 days to lithium-induced diabetes insipidus (LiDI) rats diminished urine volume by 80% and urinary PGE2 by 85%. The in vitro data of the intact rat kidney showed that lithium stimulated arginine vasopressin (AVP)-induced PGE2 production and suggested that PGE2 suppressed cAMP synthesis in rat renal medulla. The AVP-induced PGE2 synthesis was greater and the AVP-stimulated cAMP production lower in the LiDI rat kidney in vitro. Interference of the vasopressin-associated cAMP system and the increased PGE2 synthesis in the kidney may be involved in the development of LiDI. The reduced cAMP production in the LiDI rat kidney might be partly due to the increased PGE2 synthesis. In LiDI rats plasma vasopressin increased, whereas AVP concentration in the hypothalamus and the neurohypophysis significantly decreased. It is postulated that lithium stimulates vasopressin release from the central nervous system and that elevated plasma vasopressin potentiates PGE2 production in the kidney synergistically with lithium.

AbstractsThe effect of lithium on the hypothalamo-pituitary-adrenal axis was studied in vivo and in vitro.The levels of plasma vasopressin, ACTH and corticosterone increased after the administration of lithium (LiCl 4mmol/kg BW, 11 days) in rats, while the tissue vasopressin concentration in the median eminence, the rest of the hypothalamus and the posterior pituitary was decreased. The CRF concentration in the posterior pituitary increased markedly, but it did not change significantly in the median eminence or the rest of the hypothalamus.The elevated plasma ACTH level might be at least partly due to the increased vasopression secretion.Lithium stimulated ACT H secretion per se and also enhanced vasopressininduced ACTH secretion in cultured pituitary cells and in half pituitary incubations, while it did not affect CRF-induced ACTH secretion. Lithium inhibited CRF-induced cAMP accumulation in half pituitary incubations, while lithium and vasopressin did not affect cAMP accumulation per se or even when administered together.The results suggest that lithium-induced ACTH release is via a cAMP-independent mechanism. Thus, it is possible that lithium stimulates ACTH release by acting directly on the corticotroph, stimulating vasopressin release and potentiating vasopressin-induced ACTH release.

Previous work showed that treatment of rats with tumour necrosis factor-\g=a\ produced a model of nonthyroid illness in which there was reduction of circulating thyroid hormones and TSH, reduced thyroid response to TSH, and reduced thyroid iodide uptake. In vitro studies showed that tumour necrosis factor-\g=a\ binds to a specific receptor on FRTL-5 rat thyroid cells, that TSH increases the number of tumour necrosis factor-\g=a\ receptors, and that tumour necrosis factor-\g=a\ inhibits iodide uptake by these cells. In the present study, we obtained additional data on the effects of tumour necrosis factor-\g=a\ on FRTL-5 cells and studied the mechanism of action of tumour necrosis factor-\g=a\ in these cells. Tumour necrosis factor-\g=a\ inhibited both basal and TSH-stimulated [125I]iodide uptake; tumour necrosis factor-\g=a\ slowed the recovery of [125I]iodide trapping after the cells were exposed to TSH and augmented the loss of the [125I]iodide trapping function after the cells were deprived of TSH; tumour necrosis factor-\g=a\ inhibited[125I]iodide trapping in a noncompetitive manner; tumour necrosis factor-\g=a\ did not affect cell growth of FRTL-5 cells. Interleukin-1 (IL-1) also inhibited basal and TSH-stimulated [125I]iodide uptake, but it stimulated cell growth. Tumour necrosis factor-\g=a\ and IL-1 did not affect the generation of cAMP in the presence or absence of TSH; these cytokines blocked the cAMP-induced stimulation of [125I]iodide uptake. Tumour necrosis factor-\g=a\ did not affect [3H]arachidonic acid uptake or release by FRTL-5 cells. The inhibitors of the phospholipase A2\ x=r eq-\ arachidonic acid pathway did not affect the action of tumour necrosis factor-\g=a\. The H2O2 scavenger, catalase, did not block the action of tumour necrosis factor-\g=a\. The results show that both tumour necrosis factor-\g=a\ and IL-1 inhibit FRTL-5 function and that the site of action of these cytokines is distal to the production of cAMP. The actions of tumour necrosis factor-\g=a\ on FRTL-5 cells do not appear to be mediated by the phospholipase A2-arachidonic acid pathway or by H2O2.Tumour necrosis factor-a (TNF) and interleukin 1 (IL-1) are very important mediators in inflamma¬ tory processes. The biological actions of these cy¬ tokines in vivo and in vitro have received much attention recently (1-3). These cytokines may be responsible for changes of thyroid function in nonthyroid illness, such as infections. Studies in an¬ imals have shown that TNF and IL-1 treatment causes reduction of circulating thyroid hormones, thyrotropin, reduced thyroid [l2T]iodide uptake, and reduced thyroid response to TSH (4-7). FRTL-5 rat thyroid cells have TNF receptors (8). The number of TNF receptors is upregulated by TSH, but TNF does not affect TSH binding to the TSH receptor. TNF treatment causes inhibition of TSH stimulated [12T]iodide uptake by the FRTL-5 cells (7,8). Recent reports showed that the mRNAs of TNF and IL-1 are synthesized at considerable levels even in normal tissues (9). This suggests that TNF and II-1 may h...