guanylyl-imidodiphosphate and Adenoma

The effects of chronic MtTW15 pituitary adenoma implantation on beta-adrenergic responsiveness, cardiac beta-adrenoreceptors, and muscarinic receptors were studied in the rat. Five weeks after s.c. administration of tissue fragments of the MtTW15 adenoma, there was a 51 and 20% increase in the heart weight and body weight, respectively, and a 49-fold increase in the serum prolactin level as compared to the controls. At this time there was also an attenuation in the adenoma-bearing group of the ability of isoproterenol to produce a dipsogenic response and to increase the heart rate. In contrast, isoproterenol stimulated cardiac ornithine decarboxylase (ODC) activity 4.2-fold in both the control and adenoma-bearing groups. There was no change between the two groups in the cardiac ventricular beta-adrenoreceptor or muscarinic receptor concentration as measured by specific (-)-[125I]iodocyanopindolol (CYP) and (-)-[3H]quinuclidinyl benzilate (QNB) respectively. In addition, the concentrations of isoproterenol and carbachol required to inhibit by 50% (IC50) [125I]CYP and [3H]QNB binding, respectively, in the absence of 5'-guanylylimidodiphosphate (Gpp(NH)p) were not different between the two groups. In the presence of Gpp(NH)p, the isoproterenol IC50 value was not different between the two groups, whereas the carbachol IC50 value was increased slightly in the adenoma-bearing group. The data indicate that chronic MtTW15 adenoma implantation attenuated beta-mediated dipsogenic and heart rate responses but had little or no effect on cardiac ODC activity or cardiac autonomic receptor concentrations and agonist binding properties.

Topics: Adenoma; Animals; Cardiomegaly; Drinking; Guanylyl Imidodiphosphate; Heart Rate; Hypothyroidism; Isoproterenol; Male; Myocardium; Neoplasm Transplantation; Ornithine Decarboxylase; Pituitary Neoplasms; Rats; Rats, Inbred Strains; Receptors, Adrenergic, beta; Receptors, Muscarinic

Thyrotropin (TSH), stimulators of guanyl nucleotide regulatory protein, (sodium fluoride and guanyl-5'-yl-imido-diphosphate [Gpp(NH)p]) and a stimulator of the catalytic unit of adenylate cyclase (AC) (forskolin) were used to probe the TSH receptor-guanyl nucleotide regulatory protein-cyclase unit in normal and neoplastic thyroid tissue from 17 patients. Eleven of these patients had benign follicular adenomas and six patients had differentiated thyroid carcinomas. An 8000 X g particulate fraction that is rich in thyroid plasma membranes was prepared, and the activity of AC was determined by the conversion of alpha-32P-ATP to P32-cAMP. Thyroid neoplasms had a greater AC response to TSH than did normal thyroid tissue removed from the same patients (p less than 0.001). The AC response to NaF and Gpp(NH)p was greater in the neoplastic thyroid tissue, although in these experiments the increase was not significant. In contrast, the AC response to forskolin was comparable in normal (573 +/- 129) and neoplastic (526 +/- 132) thyroid tissue (mean +/- SEM). The effects of NaF, Gpp(NH)p, and forskolin on AC activity were additive with TSH when used at concentrations for optimal AC activity. Low concentrations of NaF and Gpp(NH)p stimulated AC activity whereas high concentrations of NaF and Gpp(NH)p assayed either together or separately inhibited AC activity. When forskolin and NaF were assayed together there was a greater than additive effect or potentiated effect on activity. Basal AC activity was increased in the presence of manganese (Mn+2) (2 mM) over magnesium (Mg+2) (2 mM) (p less than 0.001), whereas TSH-stimulated (p less than 0.01) and Gpp(NH)p-stimulated AC activity (p less than 0.05) were lower in the presence of Mn+2 than Mg+2. There was an excellent correlation between basal AC activity and AC activity in response to forskolin in both normal and neoplastic thyroid tissue, whereas there was no correlation between basal AC activity and TSH-stimulated AC activity in the thyroid neoplasms. These data suggest that the abnormality responsible for the greater AC response to TSH in neoplastic thyroid tissue is proximal to the catalytic unit of AC and most probably is due to an alteration in the guanyl nucleotide regulatory protein or in the coupling of the guanyl nucleotide regulatory protein to either the receptor or the catalytic unit of AC.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adenoma; Adenylyl Cyclases; Adult; Aged; Carcinoma; Colforsin; Cyclic AMP; Diterpenes; Female; Guanylyl Imidodiphosphate; Humans; Male; Middle Aged; Receptors, Cell Surface; Receptors, Thyrotropin; Sodium Fluoride; Thyroid Gland; Thyroid Neoplasms; Thyrotropin

Topics: Adenoma; Adenylyl Cyclases; Adult; Aged; Colforsin; Diterpenes; Enzyme Activation; Female; Guanylyl Imidodiphosphate; Humans; Male; Middle Aged; Receptors, Cell Surface; Receptors, Thyrotropin; Sodium Fluoride; Thyroid Neoplasms; Thyrotropin

To determine whether the beta-blocking drug propranolol had any physiologic effect on normal (n = 14) and adenomatous (n = 15) human thyroid tissues, experiments were performed to study the binding of the beta-blockers 125I-iodocyanopindolol (125I-ICYP) and 125I-iodohydroxybenzylpindolol (125I-IHYP) and the stimulation of adenyl cyclase (AC) by isoproterenol. 125I-ICYP and 125I-IHYP failed to show high-affinity binding in 27 of 29 specimens, whereas two (one normal and one adenomatous) thyroid tissues demonstrated high-affinity binding (Kd 5.5 +/- 1 X 10(-9) M) for 125I-ICYP. Thyroid-stimulating hormone (0.3 IU/ml), guanosine triphosphate (10(-4) M), and Gpp (NH)p(10(-4) M) stimulated AC in all thyroid tissues, although in two tissues (normal) Gpp (NH)p failed to cause a significant increase. Isoproterenol (10(-4) M), in contrast, had no effect on basal AC activity or on guanosine triphosphate, and Gpp (NH) p stimulated AC activity in 26 of the 29 thyroid tissues. In one of the two tissues that increased AC in response to isoproterenol, the beta-blocking drugs propranolol hydrochloride, bunitrolol hydrochloride, and tolilprolol hydrochloride decreased AC stimulation to isoproterenol at concentrations of 10(-6) M (p less than 0.05). Higher concentrations of propranolol (10(-4) - 10(-2) M) decreased AC stimulation to thyroid-stimulating hormone (p less than 0.01), not only in this responsive tissue but also in tissues that failed to demonstrate high-affinity binding for 125I-ICYP and AC stimulation to isoproterenol (p less than 0.01). Thus most normal and adenomatous human thyroid tissues lack beta-receptors and a functioning beta-receptor AC system. High concentrations of propranolol in vitro decreased AC response by thyroid-stimulating hormone, but this is probably a nonreceptor-mediated effect.

Topics: Adenoma; Adenylyl Cyclases; Guanosine Triphosphate; Guanylyl Imidodiphosphate; Humans; In Vitro Techniques; Iodocyanopindolol; Isoproterenol; Pindolol; Propanolamines; Propranolol; Receptors, Adrenergic, beta; Thyroid Gland; Thyroid Neoplasms; Thyrotropin

To examine whether alterations in parathyroid adenylate cyclase might be associated with glandular hyperfunction, we compared enzyme activity in membranes from 7 normal glands with activity from 18 abnormal and 5 noninvolved glands from patients with primary hyperparathyroidism. Compared with the normal glands, the specific enzyme activity after full stimulation with guanyl-5'yl imidodiphosphate was significantly decreased in both hyperplastic and noninvolved glands from the hyperparathyroid subjects. While the enzyme activity of all tissues could be suppressed by calcium, a twofold higher calcium concentration was required for comparable suppression of the enzyme from adenomas as compared with normal or noninvolved glands. Alterations in the adenylate cyclase complex of hyperplastic parathyroid glands may explain, in part, the elevated "set point" for calcium homeostasis in primary hyperparathyroidism.

Topics: Adenoma; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Adult; Aged; Calcimycin; Calcium; Child; Dose-Response Relationship, Drug; Female; Guanylyl Imidodiphosphate; Humans; Hyperparathyroidism; In Vitro Techniques; Male; Middle Aged; Parathyroid Glands; Parathyroid Neoplasms

Recent evidence suggests that the histamine receptor blocking agent cimetidine can decrease parathyroid hormone release from human parathyroids. To determine the mechanism for inhibition we examined the ability of histamine 1 X 10(-5) moles/liter to stimulate adenylate cyclase in a particulate membrane preparation from 13 human parathyroid glands. Histamine significantly increased adenylate cyclase activity as compared to control; however, the degree of stimulation was variable among the individual tissue samples. Enzyme stimulation was dose dependent over the concentration range of 1 X 10(-7) to 1 X 10(-4) moles/liter. Cimetidine at 1 X 10(-4) moles/liter completely abolished the histamine mediated increase in activity, but did not block the epinephrine-induced stimulation. The identification of an adenylate cyclase system in certain human parathyroid adenomas that is stimulated by histamine and blocked by cimetidine may offer a basis for the pharmacologic alteration of parathyroid hormone secretion.

Topics: Adenoma; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Cimetidine; Dose-Response Relationship, Drug; Enzyme Activation; Epinephrine; Guanidines; Guanylyl Imidodiphosphate; Histamine; Humans; Parathyroid Neoplasms; Sodium Fluoride