Adenylate Cyclase of GH and ACTH Producing Tumors of Human: Activation by Non-specific Hormones and Other Bioactive Substances
Shigeru MatsukuraT. KakitaYukio HirataHiroki YoshimiMasaaki FukaseYoshiko IwasakiYUZURU KATOHiroo Imura
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The adenylate cyclase responses of the human GH or ACTH producing pituitary adenomas and ectopic ACTH producing tumors to TRH, LH-RH, biogenic amines, peptides hormones, PGE, and rat median eminence extract (MEE) have been examined. Out of 4 GH producing pituitary adenomas obtained from patients with active acromegaly at hypophysectomy two were stimulated by TRH, two by LH-RH, three by norepinephrine, one by dopamine, four by PGEj and none by serotonin. Glucagon stimulated the adenylate cyclase in one of three and MEE in both of two tested. The positive responses of paradoxical GH release after TRH and/or LH-RH before surgery in these patients coincidentally related to the response of adenylate cyclase of each pituitary adenoma. There seems, however, to be no consistent correlation between the adenylate cyclase responses to biogenic amines and the GH release after L-Dopa or 5-hydroxytryptophan tested. The adenylate cyclase of a pituitary adenoma from case of Cushing′s disease was stimulated by LH-RH, norepinephrine, glucagon and MEE but not by TRH. Plasma levels of ACTH, β-MSH and cortisol increased after LH-RH but not after TRH in this patient before hypophysectomy. The adenylate cyclase of two ectopic ACTH producing tumors (gastric carcinoid and malignant thymoma) was activated by TRH, LH-RH, norepinephrine, epinephrine, serotonin, PGE, and MEE. These results indicate the presence of multiple hormone receptors in GH or ACTH producing pituitary adenomas and ectopic ACTH producing tumors, and suggest that the paradoxical GH or ACTH release after TRH and/or LH-RH injection in acromegaly and Cushing′s syndrome might be caused by an alteration of the cellular membrane receptors of the pituitary adenomas.Keywords:
Hypophysectomy
The adenylate cyclase responses of the human GH or ACTH producing pituitary adenomas and ectopic ACTH producing tumors to TRH, LH-RH, biogenic amines, peptides hormones, PGE, and rat median eminence extract (MEE) have been examined. Out of 4 GH producing pituitary adenomas obtained from patients with active acromegaly at hypophysectomy two were stimulated by TRH, two by LH-RH, three by norepinephrine, one by dopamine, four by PGEj and none by serotonin. Glucagon stimulated the adenylate cyclase in one of three and MEE in both of two tested. The positive responses of paradoxical GH release after TRH and/or LH-RH before surgery in these patients coincidentally related to the response of adenylate cyclase of each pituitary adenoma. There seems, however, to be no consistent correlation between the adenylate cyclase responses to biogenic amines and the GH release after L-Dopa or 5-hydroxytryptophan tested. The adenylate cyclase of a pituitary adenoma from case of Cushing′s disease was stimulated by LH-RH, norepinephrine, glucagon and MEE but not by TRH. Plasma levels of ACTH, β-MSH and cortisol increased after LH-RH but not after TRH in this patient before hypophysectomy. The adenylate cyclase of two ectopic ACTH producing tumors (gastric carcinoid and malignant thymoma) was activated by TRH, LH-RH, norepinephrine, epinephrine, serotonin, PGE, and MEE. These results indicate the presence of multiple hormone receptors in GH or ACTH producing pituitary adenomas and ectopic ACTH producing tumors, and suggest that the paradoxical GH or ACTH release after TRH and/or LH-RH injection in acromegaly and Cushing′s syndrome might be caused by an alteration of the cellular membrane receptors of the pituitary adenomas.
Hypophysectomy
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Secretin
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Abstract. Zinc deficiency and altered myocardial adenylate cyclase activity commonly occur in diabetes. To determine whether the zinc intake of the animal can account for the altered β-adrenergic receptor activity in the diabetic heart, we determined the β-adrenergic receptor number and isoproterenol-, NaF- and forskolin-stimulated adenylate cyclase activity in diabetic and control rats maintained on low, normal and high zinc diets for 3 weeks. Scatchard analysis of [ 125 I]iodocyanopindolol binding to control heart membrane preparations revealed a binding capacity of 17.3 ± 1.3 fmol/mg protein with a K d of 35 ± 1.0 pmol/l. Neither the diabetic state nor the zinc status altered these binding parameters. The isoproterenol-stimulated adenylate cyclase acticity was significantly lower in diabetic rats on low zinc diets compared with controls. The NaF- (65.1 ± 5.4 vs 60.8 ± 6.4 pmol cAMP·mg protein −1 ·min −1 ) and forskolin-stimulated adenylate cyclase activities (161 ± 9.3 vs 154 ± 21.2 pmol cAMP·mg protein −1 · min −1 ) were not significantly altered in diabetic rats. Low dietary zinc intake compared with high zinc diet significantly increased NaF- and forskolin-stimulated adenylate cyclase activity both in diabetic rats and controls. The effect of dietary zinc content on isoproterenol-stimulated adenylate cyclase was significant in control rats only. Thus zinc intake appears to be an important determinant of cardiac adenylate cyclase activity level. Additional factors peculiar to the diabetic state are involved in the modulation of β-adrenergic responsiveness of the diabetic heart.
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The number of ACTH-(1–24) receptors and the adenylate cyclase (AC) responsiveness to several stimuli have been measured in crude adrenal membranes from fetal and newborn lambs. At 124 days of gestation, the number of ACTH-(1–24)-binding sites was 51 ± 9 (SE) pmol/μg DNA, and AC was stimulated by 2 × 10-2 M NaF (195 ± 5%) and 10< >-5 M guanosine (β,γ-imido) triphosphate [Gpp(NH)p]; (168 ± 8%) but not by 10-6 M ACTH-(1–24). However, when Gpp(NH)p was added to ACTH-(1–24), the response was significantly higher than with Gpp(NH)p alone. On the contrary, at 140 days, despite no increase in the number of ACTH-(1–24) receptors, AC was stimulated by ACTH-(1–24) (135 ± 6%), and Gpp(NH)p enhanced this response. In addition, the response to NaF and to Gpp(NH)p alone was higher at 140 than at 124 days. Between day 140 of gestation and birth, the stimulation of AC by ACTH-(1–24) and ACTH-(1–24) plus Gpp(NH)p increased, but the response to NaF and to Gpp(NH)p alone did not. During the same time, the number of ACTH-(1–24) receptors was increased by a factor of 3. No change in the Kd and Km of ACTH-(1–24) was observed during the period studied. Neither prostaglandin E2 (10-5 M) nor αMSH (10-6 M) stimulated AC at any stage. The relative insensitivity of AC before 140 days can thus be related to 1) a defect of availability of GTP, and 2) a low activity of the catalytic subunit of AC (subunit C) or, alternatively, a defect in the GTP-binding component (subunit N). The increased sensitivity to ACTH-(1–24) of the enzyme just before parturition correlates closely with an increase in the number of ACTH-(1–24) receptors.
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To determine the site of action of TRH and 2-brom-alpha-ergocriptine (CB154) on pituitary hormone release in acromegalic patients, the effect of these substances on GH and PRL secretion was examined in perfused pituitary adenoma tissues obtained at surgery from subjects with acromegaly. Relatively stable baseline secretion levels of GH and PRL were followed by an abrupt and marked discharge of the hormones after TRH infusion in all of the experiments. The pattern of GH response was essentially the same as that of PRL. Moreover, a dose-response relationship was obtained between the TRH concentrations infused and the magnitude of GH and PRL responses. The infusion of CB154, on the other hand, inhibited both GH and PRL secretion in three experiments performed on different adenoma tissues. This effect of CB154 was prompt and lasted for a long period even after the infusion was discontinued. When TRH was perfused concomitantly with CB154, the stimulatory effect of TRH on GH release was maintained, while TRH-induced PRL secretion was completely blocked. The results suggest that both TRH and CB154 possess a direct action on pituitary adenoma cells of acromegaly and that aberrant GH responses to TRH and dopaminergic agonists in acromegalic patients may be explained by the altered cellular membrane receptors of the adenoma of these subjects.
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Glucoregulatory Mechanisms Following Hypophysectomy in Diabetic Dogs with Residual Insulin Secretion
It is known that in pancreatectomized dogs completely deprived of insulin, hypophysectomy normalizes plasma glucagon and prevents ketoacidosis, but rarely normalizes glucose levels. The present study concerns diabetic dogs with only partial insulin deficiency in whom we studied the effects of hypophysectomy on glucoregulatory mechanisms. Eleven dogs were alloxanized and hypophysectomized 2–3 wk later. Withholding exogenous insulin from alloxan-diabetic dogs resulted in hypoinsulinemia (6 ± 1 μU/ml), hyperglucagonemia (341 ± 44 pg/ml), elevated plasma FFA levels (1442 ±125 μeq/ml), hyperglycemia (333 ± 27 mg/dl), increased hepatic glucose production (Ra, 4.2 ± 0.3 mg/kg/min) and decreased clearance of glucose (CR, 1.8 ± 0.1 ml/kg/min). After hypophysectomy, glucagon and FFA fell to normal in 7 of 11 hypophysectomized alloxan-diabetic dogs (106 ± 7), while 4 remained hyperglycemic (337 ± 28 mg/dl). Normoglycemia was the result of a reduced Ra to subnormal in the presence of unaltered glucose clearance. However, normoglycemia could not be equated with normal metabolism: glucose turnover was well below normal, and peripheral glucose uptake was impaired. The sensitivity of the liver to glucagon was investigated by infusing somatostatin alone (ST, 0.24 μg/kg/min) and with replacement (1 mg/kg/min) or with excess of glucagon (3.6 ng/kg/min). Even in hypophysectomized dogs, glucagon suppression resulted in a sustained decrease in Ra and plasma glucose. Glucagon replacement restored glucose kinetics and excess of glucagon led to hyperglycemia (300 ± 20 mg/dl). This was due to a prompt rise in Ra which, however, plateaued at levels lower than in diabetic dogs, suggesting that normalization of glucagon following hypophysectomy is an important but not the sole factor responsible for the marked reduction in Ra. The persistence of hyperglycemia in four diabetic dogs was attributed to a diminished effect of the hypophysectomy: in spite of hyperglycemia, Ra was not lower than in normoglycemic dogs, it was insensitive to glucagon suppression, and glucose clearance was more impaired than in normoglycemic dogs. It is hypothesized, therefore, that these dogs had a smaller residual insulin reserve than normoglycemic hypophysectomized dogs. Thus a critical amount of insulin may be indispensible for the maintenance of normoglycemia. In conclusion, in alloxan-diabetic dogs, hypophysectomy can fully normalize postabsorptive glycemia, due to suppression of glucose production. Normoglycemia is, however, associated with an abnormally low glucose turnover. Hyperglucagonemia is important but not the sole factor responsible for diabetic overproduction of glucose. Hypophysectomy does not abolish the hepatic sensitivity to glucagon in insulin-deficient dogs. Persistence of hyperglycemia in some dogs after hypophysectomy is associated with less effective suppression of glucose production and with a very low glucose clearance.
Hyperglucagonemia
Hypophysectomy
Alloxan
Diabetic ketoacidosis
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Short term (30 min) infusion of cyclic somatostatin (50 μg/rat), insulin (1 U/rat) or the two together significantly suppressed urinary cyclic AMP excretion in streptozotocin-diabetic rats. While somatostatin tended to increase cyclic GMP excretion, insulin had an opposite effect in diabetic but not in normal rats. It is suggested that somatostatin suppresses cyclic AMP excretion by inhibiting directly adenylate cyclase in liver and perhaps in other organs. The possibility that suppression of urinary cyclic AMP is due to inhibition of glucagon secretion is also considered.
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SUMMARY Plasma glucagon and insulin responses to l ‐arginine were compared in normal controls and patients with isolated growth hormone deficiency and acromegaly. Patients with isolated growth hormone deficiency were characterized by high plasma glucagon response and low plasma insulin response, whereas acromegalic patients showed exaggerated plasma glucagon response and almost normal insulin response. These results suggest that growth hormone is probably required for optimum function of the islets, and since hyperglucagonaemia was observed in both growth hormone deficiency and acromegaly, metabolic disturbances stemming from the respective primary diseases may affect glucagon secretion.
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The basal adenylate cyclase activity of the bovine adrenal medullais similar to that of the adrenal cortex. The medullary enzyme is less responsive in vitro to stimulation by optimal fluoride ion concentrations (8 HIM), and is not elevated by ACTH. Medullary adenylate cyclase activity is also unaffected by carbamylcholine, nerve-growth factor, prostaglandin E1, or dexamethasone. (Endocrinology94: 591, 1974)
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Basal (medicine)
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