[Treatment of chronic arsenic poisoning with etretinate].
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Arsenic↗
Biomedical subjects
M Szabo
Publications and source records attributed to M Szabo.
TRH and GRF stimulate release of growth hormone through different mechanisms.
Thyrotropin-releasing hormone (TRH) is an effective stimulator of growth hormone (GH) release from cultured adenohypophysial cells of chronically hypothyroid rats in vitro. The present study explored the question of cAMP and calcium mediation of the GH-stimulatory effect of TRH in this system. A maximally stimulatory concentration of TRH was added together with various concentrations of human GH-releasing factor 40 (hGRF-40) whose action is cAMP mediated, or of dibutyryl cAMP (DBcAMP), to primary monolayer cultures of adenohypophysial cells from thyroidectomized rats. The GH responses to the combined addition of TRH with all doses of GRF or DBcAMP were fully additive, causing parallel elevations of the dose-response curves. Whereas the GH response to maximally effective concentrations of hGRF-40 and DBcAMP, added together, was not greater than that to either secretagogue alone, the inclusion of TRH increased the response to a new Emax. The calcium inhibitors, verapamil, EGTA, and CoCl2, markedly suppressed basal GH release and virtually completely blocked the GH response to TRH, suggesting calcium mediation. In chronically hypothyroid, urethan-anesthetized rats, the in vivo effect of the combined administration of maximally effective doses of TRH and GRF on plasma GH levels was also additive. These findings indicate that TRH stimulates GH release in adenohypophysial cells of hypothyroid rats by a cAMP-independent, calcium-dependent mechanism.
Animals↗
Differential responsiveness of the somatotroph to growth hormone-releasing factor during early neonatal development in the rat.
The effects of human pancreatic GH-releasing factor-40 (hpGRF-40; 0.01-100 nM) and (Bu)2cAMP (0.015-1.5 mM) on GH release from primary monolayer cultures of pituitary cells were evaluated in rats of three age groups: postnatal days 2 and 12, and young adult males (3-4 months). Both hpGRF-40 and (Bu)2cAMP elicited a dose-related increase in GH release in cell cultures from each age group. However, the magnitude of the fractional increase over basal release was markedly age dependent. hpGRF-40-stimulated GH release (expressed as a percentage of control values) was greater in cultured cells of 2-day-old than of 12-day-old rats, which was, in turn, significantly greater than in cells of adult rats (P less than 0.001). Maximum hpGRF-40-stimulated GH release was 1058 +/- 50% of control values (+/- SE) in 2-day-old, 617 +/- 21% of control values in 12-day-old, and 405 +/- 6% of control values in adult pituitary cell cultures. The slopes of the dose-response curves differed significantly among the three age groups (P less than 0.001) and varied inversely with increasing age. GH release induced by (Bu)2cAMP was similarly age dependent; maximal stimulated release was 1073 +/- 20%, 414 +/- 4%, and 259 +/- 7% of control values in cultured cells of 2-day-old, 12-day-old, and adult rats, respectively (P less than 0.001 for age effect at each dose). As with hpGRF-40, the slopes of the dose-response curves for (Bu)2cAMP decreased with advancing age (P less than 0.001). Intracellular GH storage during culture, basal release of GH, and serum GH were also age dependent. Pooled serum GH was consistently elevated in 2-day-old rats (139 +/- 2 ng ml-1), became lower and more variable in 12-day-old rats (62 +/- 14 ng ml-1), and was even more variable in adult male rats (79 +/- 23 ng ml-1), owing to random sampling during spontaneous secretory pulses. These results indicate that the stimulatory effects of GRF and (Bu)2cAMP on GH secretion from cultured rat pituitaries vary with age; pituitary cells of newborn rats are relatively more sensitive to these secretagogues than those of adult rats. This increased responsiveness of the neonatal somatotroph to GRF may contribute to the elevation of the plasma GH concentration which is characteristic of the perinatal period in the rat.
Aging↗
The effect of age on somatostatin suppression of basal, growth hormone (GH)-releasing factor-stimulated, and dibutyryl adenosine 3',5'-monophosphate-stimulated GH release from rat pituitary cells in monolayer culture.
To test the hypothesis that relative resistance of the somatotroph to somatostatin (SRIF) contributes to elevated circulating levels of GH in the newborn rat, we examined the effects of SRIF (0.1, 0.33, and 1 nM) on basal, human pancreatic GH-releasing factor-40 (hpGRF-40; 1 nM)-stimulated, and (Bu)2cAMP (0.5 mM)-stimulated GH release from pituitary cells of 2-day-old, 15-day-old, and adult Sprague-Dawley rats in monolayer culture. The effect of SRIF on basal GH release varied markedly with age. SRIF, in the doses studied, did not inhibit basal GH release (nanograms of GH per 10(5) cells/3 h) from pituitary cultures of 2-day-old rats. In those of 15-day-old rats, only the two higher doses of SRIF (0.33 and 1 nM) suppressed GH release. By contrast, in pituitary cell cultures of adult male and female rats, all doses of SRIF significantly inhibited basal GH release (P less than 0.001). Similarly, the degree of SRIF suppression of both hpGRF-40- and (Bu)2cAMP-stimulated GH release differed among the age groups. In pituitary cultures of 2-day-old rats, SRIF did not significantly inhibit stimulated GH release. In 15-day-old rat pituitary cells, SRIF inhibited GH release, but did not eradicate the stimulatory effect of hpGRF-40 or (Bu)2cAMP. By contrast, in pituitary cell cultures of adult male and female rats, SRIF completely abolished the stimulatory effect of both hpGRF-40 and (Bu)2cAMP. When expressed as a percentage of the control (or stimulated) value, GH release at each SRIF dose varied markedly with age (P less than 0.001). Furthermore, a similar age-associated trend was evident when, in a separate series of experiments (n = 37), we examined the suppressive effect of a single concentration of SRIF (0.33 nM) on (Bu)2cAMP (0.5 mM)-stimulated GH release in cultured pituitary cells of rats ranging in age from -1 (day 20 of gestation) to 78 days. The degree of suppression increased progressively with advancing age; GH release decreased from 82 +/- 2% (+/- SE) of stimulated values in cultured cells of perinatal rats to 20 +/- 1% of stimulated values in cultured cells of 78-day-old rats. There was a significant negative correlation between age and SRIF-inhibited GH release (r = -0.89; P less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)
Age Factors↗
Ontogeny of the in vitro growth hormone stimulatory effect of thyrotropin-releasing hormone in the rat.
The ontogenic changes in the somatotroph's responsiveness to TRH were examined in enzymatically dissociated rat pituitary cells in primary monolayer culture. Exposure to TRH (10(-8) M) caused a significant increase in GH release in cultured pituitary cells from rats ranging in age from -1 day (20 days of gestational age) to 90 days. The magnitude of the response, expressed as a percent increment above control rat GH (rGH) release, rose progressively until it reached a maximum of 209 +/- 5% (mean +/- SE) on postnatal day 12. Thereafter, the response declined to values ranging from 10-30% above control rGH release. In cultured adenohypophyseal cells of rats on postnatal day 12, the effect of TRH was dose related; the effective concentration range was 10(-10)-10(-7) M, with an EC50 of 2.5 +/- 0.6 X 10(-9) M. TRH (10(-8) M) potentiated the GH stimulatory effect of a submaximally effective concentration of human GH-releasing factor-40 (hGRF-40; 10(-9) M) in cultured pituitary cells of developing rats, aged -1 to 30 days, and that of (Bu)2cAMP (5 X 10(-4) M) in cultured pituitary cells of rats aged -1 to 45 days. The rGH response to the combined addition of TRH with either hGRF-40 or (Bu)2cAMP was up to 2 times greater (P less than 0.05) than the sum of the individual responses. When the interaction of TRH (10(-8) M) with multiple concentrations of hGRF-40 (10(-10), 10(-9), and 10(-8) M) was tested in cultured pituitary cells of 4- to 36-day-old rats at 4-day intervals, synergism was least at the lowest and greatest at the highest concentration of hGRF-40; synergistic interaction decreased progressively after 20 days of age to undetectable levels by 36 days. In cultured anterior pituitary cells of 12-day-old rats, maximally stimulatory TRH (10(-7) M) potentiated the GH stimulatory effects of both hGRF-40 and (Bu)2cAMP at concentrations at the EC50 value or greater, with synergism being most pronounced at maximally effective concentrations. Whereas the GH response to the combined addition of maximal hGRF-40 (10(-7) M) and (Bu)2cAMP (1.5 X 10(-3) M) was not greater than that to maximal hGRF alone, TRH potentiated the responses to both secretagogues whether added separately or combined.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Growth hormone response to thyrotropin-releasing hormone in the urethane-anesthetized rat: effect of thyroid status.
To evaluate the role of thyroid hormones in regulation of the GH-stimulatory effects of TRH and human pancreatic GH-releasing factor (hpGRF-40), we studied the plasma GH responses to these secretagogues under conditions of thyroid hormone deprivation and replacement in the urethane-anesthetized rat. In euthyroid control rats, TRH (1 microgram/kg) elicited a small transient rise in plasma GH, which peaked at 2-5 min and returned to basal by 20 min. In chronically hypothyroid rats (10 weeks after thyroidectomy), intrapituitary GH was markedly depleted to less than 0.1% of normal, and TRH was completely ineffective in eliciting a plasma GH response to TRH. In chronically hypothyroid rats given T4 (20 micrograms/kg daily) for 4 days, intrapituitary GH was partially repleted, and the GH response to TRH was markedly enhanced compared to that in euthyroid rats. The extent to which the GH response to TRH was enhanced by chronic hypothyroidism, followed by short term T4 treatment, depended on the duration of T4 administration. The plasma GH response was greatest after 1-3 days of T4 treatment; treatment for 7 days, on the other hand, suppressed the GH response to below that of euthyroid rats. The minimal duration of hypothyroidism which, in combination with short term (2 days) T4 treatment, enhanced the plasma GH response to TRH, was 6 weeks, with 8 weeks or longer being optimal. The effect of TRH on plasma GH was dose dependent in thyroidectomized rats given T4 for 2 days; the lowest maximally stimulatory dose was 10 times less than that in the euthyroid rat (1 vs. 10 micrograms/kg). The GH-stimulatory effect of TRH in thyroidectomized rats given T4 for 2 days was abolished by the simultaneous administration of SRIF (40 micrograms/kg). That the failure of TRH to stimulate GH release in the chronically hypothyroid rat may have been the consequence of a depletion of intrapituitary GH available for release was suggested by the finding that in parallel studies, hpGRF-40, a more potent stimulator of GH release in the euthyroid rat, was also without effect. In contrast to the GH response to TRH, the GH response to hpGRF-40 was only partially restored by T4 treatment of chronically hypothyroid rats for 2 days. We conclude that chronic thyroid hormone deficiency selectively sensitizes the somatotroph to TRH. Short term thyroid hormone replacement is needed to replete intrapituitary GH and allow the expression of this enhanced GH secretory response to TRH. More prolonged treatment with T4, on the other hand, appears to desensitize the somatotroph to TRH.
Animals↗
Thyrotropin-releasing hormone stimulates growth hormone release from the anterior pituitary of hypothyroid rats in vitro.
We have examined the interaction of thyroid hormone and TRH on GH release from rat pituitary monolayer cultures and perifused rat pituitary fragments. TRH (10(-9) and 10(-8)M) consistently stimulated the release of TSH and PRL, but not GH, in pituitary cell cultures of euthyroid male rats. Basal and TRH-stimulated TSH secretion were significantly increased in cells from thyroidectomized rats cultured in medium supplemented with hypothyroid serum, and a dose-related stimulation of GH release by 10(-9)-10(-8) M TRH was observed. The minimum duration of hypothyroidism required to demonstrate the onset of this GH stimulatory effect of TRH was 4 weeks, a period significantly longer than that required to cause intracellular GH depletion, decreased basal secretion of GH, elevated serum TSH, or increased basal secretion of TSH by cultured cells. In vivo T4 replacement of hypothyroid rats (20 micrograms/kg, ip, daily for 4 days) restored serum TSH, intracellular GH, and basal secretion of GH and TSH to normal levels, but suppressed only slightly the stimulatory effect of TRH on GH release. The GH response to TRH was maintained for up to 10 days of T4 replacement. In vitro addition of T3 (10(-6) M) during the 4-day primary culture period significantly stimulated basal GH release, but did not affect the GH response to TRH. A GH stimulatory effect of TRH was also demonstrated in cultured adenohypophyseal cells from rats rendered hypothyroid by oral administration of methimazole for 6 weeks. TRH stimulated GH secretion in perifused [3H]leucine-prelabeled anterior pituitary fragments from euthyroid rats. A 15-min pulse of 10(-8) M TRH stimulated the release of both immunoprecipitable [3H]rat GH and [3H]rat PRL. The GH release response was markedly enhanced in pituitary fragments from hypothyroid rats, and this enhanced response was significantly suppressed by T4 replacement for 4 days. The PRL response to TRH was enhanced to a lesser extent by thyroidectomy and was not affected by T4 replacement. These data suggest the existence of TRH receptors on somatotrophs which are suppressed by normal amounts of thyroid hormones and may provide an explanation for the TRH-stimulated GH secretion observed clinically in primary hypothyroidism.
Animals↗
Inhibitory feedback effects of prolactin on its secretion involve central nervous system dopaminergic mediation.
Feedback regulation of basal and stimulated release of prolactin (Prl) was studied in primary cultures of rat pituitary cells and in adult male rats bearing right atrial catheters. Exposure of cell cultures to ovine (o) Prl, which does not crossreact in the radioimmunoassay for rat (r) Prl, did not affect rPrl release during in vitro incubations. oPrl, 4 mg/kg, injected subcutaneously into male rats 4 h previously, significantly suppressed basal rPrl levels and blunted the rPrl response to ether (2 min), cimetidine (25 mg/kg i.v.), thyrotropin-releasing hormone (40 or 400 ng i.v.), or a low dose of metoclopramide (25 micrograms/kg i.v.). At a higher dose of metoclopramide (500 micrograms/kg i.v.), no effect of oPrl could be observed. These data support the hypothesis that Prl feedback control occurs within the central nervous system rather than at the pituitary and involves predominantly, if not exclusively, a dopaminergic mechanism.
Animals↗
Ectopic growth hormone-releasing factor stimulates growth hormone secretion in the urethane-anesthetized rat in vivo.
The in vivo bioactivity of ectopic growth hormone-releasing factor (GHRF) was examined in estrogen-primed, urethane-anesthetized male rats bearing intracarotid catheters. Ectopic GHRF was isolated from a carcinoid tumor metastatic to the liver from a patient with gigantism and elevated plasma growth hormone (GH) levels and was partially purified by reverse phase high performance liquid chromatography for intracarotid injection. Ectopic GHRF elicited a promt rise in plasma GH which peaked at 5 min. The time course of the response resembled that to prostaglandin E1, a known potent direct stimulator of GH secretion in vivo. The effect of ectopic GHRF was dose related in the range of 10-100 U/rat which represents approximately 30x the effective in vitro dose range/10(5) cells in rat adenohypophyseal cell cultures. The in vivo response to ectopic GHRF was completely blocked by the simultaneous intracarotid administration of the GH release inhibitory peptide, somatostatin. These findings lend further support for a role of GHRF from human tumors as a potent physiological stimulator of GH release.
Animals↗
Ectopic growth hormone-releasing factor and dibutyryl cyclic adenosine monophosphate-stimulated growth hormone release in vitro: effects of corticosterone and estradiol.
Glucocorticoids and estrogens each affect GH secretion in vivo. The effects of corticosterone and estradiol (E2) were studied singly and in combination on GH secretion and cell content of primary cultures of rat adenohypophyseal cells grown in media containing intact or hormone-deficient serum. Secretion was measured under basal conditions and in response to maximally stimulatory doses of ectopic GH-releasing factor (E-GHRF) derived from a carcinoid tumor and dibutyryl cAMP [(DBcAMP) 10(-3) M]. Basal GH release measured over a 4-h period was suppressed by 40% (P less than 0.001) when hormone-deficient serum was substituted for normal serum in the growth media, and the stimulatory responses to DBcAMP and E-GHRF were markedly attenuated (P less than 0.001). The GH content of unstimulated cells was also decreased [29 +/- (SE) 7%, P less than 0.001]. The addition of corticosterone, 3 X 10(-8) M to 3 X 10(-6) M, to the 4-day growth media resulted in dose-related increases in basal and DBcAMP-stimulated GH release during the 4-h test period which was proportional to the increases in total cellular GH content. In contrast, corticosterone exposure caused a dose-related enhancement of E-GHRF-stimulated release above that accounted for by the increase in total GH content alone. Concomitant exposure to the releasing stimuli and corticosterone during a 4-h incubation, however, reduced the effects of the releasing stimuli. The addition of E2, 10(-10) M to 10(-8) M, during the 4-day growth period and/or the 4-h stimulation period did not affect the secretion of GH either basally or in response to the stimuli. E2 did increase the cell content of GH, but the effects were not additive to those of corticosterone. These studies indicate that long term (4-day) exposure to corticosterone increases net GH synthesis and E-GHRF-stimulated release, but that acute (4 h) exposure inhibits stimulated release. Although E2 also increases cellular content of GH, it exhibits no demonstrable direct effects on GH secretion or content in the presence of corticosterone.
Animals↗
Somatostatin-like immunoactivity and biological activity is present in a human pheochromocytoma.
Somatostatin (SRIF)-like immunoreactivity (SRIF-LI) has previously been demonstrated immunohistochemically in sympathetic nerves and ganglia and in adrenal medullary cells. Studies were therefore performed to determine whether SRIF-LI was present in an adrenal pheochromocytoma. Acetic cid extracts of pheochromocytoma tissue contained high SRIF-LI concentrations (5.52 micrograms/g wet wt). On Sephadex G-75 gel filtration, the major peak of pheochromocytoma SRIF-LI coeluted with synthetic SRIF. SRIF-LI of a larger molecular size was also present in the tumor. Pheochromocytoma SRIF-LI coeluted with synthetic SRIF on reverse phase high pressure liquid chromatography. Pheochromocytoma SRIF-LI purified by high pressure liquid chromatography was equipotent to synthetic SRIF in inhibiting (Bu)2cAMP-stimulated GH release by rat pituitary cells in monolayer culture. Serum SRIF-LI was elevated in the patient before surgery and was restored toward normal after removal of the tumor. Serum levels of GH, TSH, and insulin were not obviously different before and after tumor removal. The results indicate that SRIF-LI is produced in excessive quantities by a pheochromocytoma. The immunological, chromatographic, and biological properties of the pheochromocytoma SRIF-LI suggest that it is indistinguishable from synthetic SRIF. This finding extends the list of peptides produced by pheochromocytoma and may provide an additional serum marker for the tumor in man.U
Adrenal Gland Neoplasms↗
The in-vitro caffeine contracture test: influence of the muscle histochemical profile on test results.
In vitro caffeine contracture tests were carried out on whole rat muscle composed primarily of either histochemical type I or type II fibers. Muscles composed primarily of type I fibers developed contractures at lower concentrations of caffeine and had lower caffeine specific concentrations than muscles composed primarily of type II fibers. These findings indicate that the histochemical profile of a muscle can influence the results of the in-vitro caffeine contracture test.
Animals↗
Effects of neurotensin on hypothalamic and pituitary hormone secretion.
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Animals↗
Somatostatin-like immunoactivity and biological activity is present in Tetrahymena pyriformis, a ciliated protozoan.
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Animals↗
Biological effects of an ectopic growth hormone-releasing peptide in cultured adenohypophyseal cells: comparison with growth hormone-releasing activity of porcine hypothalamus.
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Adenoma↗
Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitary.
Somatomedin-C stimulates somatostatin release to a maximum of 390 percent of basal release during short-term (20-minute) incubation of rat hypothalamus. It has no effect on basal or stimulated growth hormone release from primary cultures of rat adenohypophyseal cells during a 4-hour incubation, but inhibits stimulated release by more that 90 percent after 24 hours. These findings suggest that somatomedin-C participates in the growth hormone negative feedback loop with an immediate effect on hypothalamic somatostatin and a delayed effect on the anterior pituitary.
Animals↗
Ectopic production of growth hormone-releasing factor by carcinoid and pancreatic islet tumors associated with acromegaly.
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Acromegaly↗
Partial purification and characterization of a peptide with growth hormone-releasing activity from extrapituitary tumors in patients with acromegaly.
Growth hormone (GH)-releasing activity has been detected in extracts of carcinoid and pancreatic islet tumors from three patients with GH-secreting pituitary tumors and acromegaly. Bioactivity was demonstrated in 2 N acetic acid extracts of the tumors using dispersed rat adenohypophyseal cells in primary monolayer culture and a rat anterior pituitary perifusion system. The GH-releasing effect was dose responsive and the greatest activity was present in the pancreatic islet tumor. Small amounts of activity were also found in two other tumors (carcinoid and small cell carcinoma of lung) unassociated with GH hypersecretion. Each of the tumors contained somatostatin-like immunoreactivity but the levels did not correlate with the net biologic expression of the tumor. Sephadex G-75 gel filtration indicated the GH-releasing activity to have an apparent molecular size of slightly greater than 6,000 daltons. The GH-releasing activity was adsorbed onto DEAE-cellulose at neutral pH and low ionic strength, from which it could be eluted by increasing ionic strength. The GH-releasing activity was further purified by high pressure liquid chromatography using an acetonitrile gradient on a cyanopropyl column to yield a preparation that was active at 40 ng protein/ml. Partially purified GH-releasing activity, from which most of the bioactive somatostatin had been removed, increased GH release by pituitary monolayer cultures to five times base line. Enzymatic hydrolysis studies revealed that the GH-releasing activity was resistant to carboxypeptidase, leucine-aminopeptidase, and pyroglutamate-amino-peptidase but was destroyed by trypsin and chymotrypsin, indicating that internal lysine and/or arginine and aromatic amino acid residues are required for biologic activity and that the NH2-terminus and CO9H-terminus are either blocked or not essential. The results provide an explanation for the presence of GH-secreting tumors in some patients with the multiple endocrine neoplasia syndrome, type I, and warrant the addition of GH-releasing activity to the growing list of hormones secreted by tumors of amine precursor uptake and decarboxylation cell types.
Acromegaly↗