We have used a recombinant human basic fibroblast growth factor (basic FGF) to study its effects on cell proliferation, gene expression and accumulation of cyclic AMP (cAMP) and inositol phosphates in two well-characterized endocrine cell lines, FRTL-5 rat thyroid and GH3 rat pituitary cells. Basic FGF induced a dose-dependent increase in mitogenesis (assessed by measuring incorporation of [3H]thymidine) in FRTL-5 cells (40 ng basic FGF/ml increased mitogenesis above the control value by 2148 +/- 108% (mean +/- S.E.M.), but inhibited mitogenesis in GH3 cells at all doses (85 +/- 4% of control with 40 ng basic FGF/ml]. Thyroglobulin mRNA concentration was increased in FRTL-5 cells (126 +/- 6% of control with 40 ng basic FGF/ml) as was prolactin mRNA in GH3 cells (246 +/- 11% of control with 40 ng basic FGF/ml), but GH mRNA in GH3 cells was not significantly affected by any dose of basic FGF. Intracellular cAMP was reduced by basic FGF in both FRTL-5 and GH3 cells (40 ng bFGF/ml giving 80 +/- 5% of the control value in FRTL-5, and 67 +/- 15% of the control value in GH3 cells) despite increased levels when FRTL-5 cells were stimulated with 150 microU TSH/ml (5645 +/- 484% of control) or GH3 cells were stimulated by 10 mumol forskolin/l (3347 +/- 396% of control). In both FRTL-5 and GH3 cells, accumulation of [3H]inositol phosphates were increased by 40 ng basic FGF/ml (201 +/- 6 and 330 +/- 51% of control values respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
We have reported previously the effect of thyroid status in vivo on pituitary cytoplasmic concentrations of messenger RNA (mRNA) encoding the thyrotrophin (TSH) beta-subunit (Franklyn, Lynam, Docherty et al, 1985). Studies in vitro of the regulation of TSH beta gene transcription have been confined to thyrotrophic tumour cells. We now report the demonstration of TSH beta-subunit mRNA in non-tumorous rat pituitary cells in primary culture. Treatment of cells with thyrotrophin-releasing hormone (TRH) and with forskolin resulted in a marked increase in cellular concentration of TSH beta-mRNA. These results suggest that TRH exerts a direct effect on the pretranslational events involved in TSH synthesis and further that the adenylate cyclase system may be involved in the regulation of synthesis. We have thus described a novel system for the study of TSH beta-subunit gene expression in normal rat pituitary cells in vitro.
IGF-I mRNA has been demonstrated in testicular tissue and, more recently, localized specifically to Leydig cells. This study investigated the expression of IGF-I and side-chain cleavage enzyme (SCC) mRNA in two preparations of rat interstitial testicular cells which were separated by buoyant density into Leydig cell-enriched and -depleted fractions. RNA was prepared from interstitial cells obtained from the testes of untreated adult and immature rats and adult rats treated with human chorionic gonadotrophin (hCG) or ethane dimethanesulphonate (EDS; to destroy Leydig cells). IGF-I mRNA was detected in all samples, with five major transcripts ranging from 7.5 to 0.6 kb. Leydig cells (3 beta-hydroxysteroid dehydrogenase-positive and sensitive to EDS) expressed abundant IGF-I and SCC mRNAs, and levels of both were increased following hCG treatment. However, in addition, IGF-I mRNA which was derived from non-Leydig interstitial cells was detected, in the complete absence of SCC message, either in the more buoyant interstitial cells or in both interstitial cell fractions following the destruction of Leydig cells by EDS treatment. IGF-I expression in the Leydig cell-depleted cell fraction was also increased by hCG treatment, and it is therefore suggested that at least part of this non-Leydig interstitial cell IGF-I mRNA originates in Leydig cell precursors. In conclusion, Leydig cells are not the sole origin of IGF-I mRNA in the testis, and the non-Leydig cell expression may be an important component of testicular IGF-I production.
Circulating free thyroid hormone concentrations are reduced in subjects taking long-term phenytoin, a finding at variance with their euthyroid clinical state and normal serum TSH concentration. It is suggested, therefore, that phenytoin may modify the cellular effects of thyroid hormones. In order to examine the influence of phenytoin on thyroid hormone action in the pituitary gland we studied its effect on the binding of tri-iodothyronine (T3) to isolated nuclei prepared from rat anterior pituitary tissue. Phenytoin inhibited the nuclear binding of T3 in a dose-dependent fashion. Phenytoin also partially inhibited thyrotrophin-releasing hormone-stimulated TSH release from cultured rat anterior pituitary cells. These studies provide evidence for a direct effect of phenytoin on the thyrotroph mediated via nuclear T3 receptor binding.
SUMMARY Plasma free captopril concentrations and haemodynamic response to captopril were studied in 20 patients with severe chronic heart failure. A 25 mg oral dose of captopril produced a 36% reduction in systemic vascular resistance, with individual responses varying from 13% to 64%. Mean systemic pressure fell by 200% and cardiac output rose 28%. The absorption of captopril was rapid. Peak plasma free captopril concentration occurred at 45 minutes after the dose and was followed by a smaller second peak. Peak plasma free captopril concentrations varied more than 20-fold but did not correlate with the maximal reduction in systemic vascular resistance. Elimination half life was seven hours. Fourteen patients were restudied after 1-2 months of captopril treatment and 12 showed symptomatic benefit. There was a sustained improvement in haemodynamic state and in non-invasive indices of myocardial function. During long term treatment the predose plasma free captopril concentration correlated well with dosage, but steady state captopril concentrations did not show a significant relation with haemodynamic response. On a dosage regimen of 25-50 mg three times daily the morning predose plasma free captopril concentration and plasma renin activity were relatively low and suggested that maximal inhibition of the renin-angiotensin system was not maintained throughout the dosage interval.Captopril, a vasodilator which acts by inhibiting conversion of angiotensin I to angiotensin II, has been shown to benefit patients with chronic severe heart failure.
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