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Medical therapy for primary hyperparathyroidism
Abstracts
413
from the Calcified Tissues Workshop
Specific LysisX
Fresh serum Inactivated serum Gamma globulin Guinea pig serum Inactivated serum + guinea pig serum Gamma globulin + guinea pig serum
64 3 4
1 52 56
CALCITONIN GENE-RELATED PEPTIDE (CGRP) IN MAN: ORIGIN, RECEPTORS AND CARDIOVASCULAR ACTION J.A. Fischer, W. Born, S. Brem, J.B. Petermann, M.A. Dambacher, C. Gennari
R. Muff,
Research Laboratory for Calcium Metabolism, University of Zurich, Zurich, Switzerland, and Institute of Medical Semeiotics, University of Siena, Siena, Italy Alternative splicing of primary calcitonin (CT) gene transcripts generates two distinct mRNA encoding CGRP and CT that exert different biological effects. CGRP and CT have been recognized in serum and thyroid extracts from normal subjects and medullary thyroid carcinoma patients. CGRP-like peptides have, moreover, been identified in the central nervous system (CNS), pituitary and the heart using a combination of gel filtration analysis, HPLC and specific RIA and RRA. CT is also present in the pituitary and brain, albeit in smaller amounts than in normal human thyroid glands. Binding sites for 125~I-CGRP have been recognized by receptor autoradiography and in membranes throughout the CNS and the heart, and 125-lsalmon CT receptors have been demonstrated in the hypothalamus, the brain stem and the kidney. In the rat heart, CGRP binding sites are predominantly localized around blood vessels concomitant with the presence of endogenous CGRP, and CGRP stimulates adenylate cyclase activity (ED-50 10-8M). CT receptors, on the other hand, have not been detected in the heart. In normal human subjects, CGRP had pronounced cardiovascular effects causing an increase in heart rate and contractility, hypotension and marked vasodilatation. Labetolol, blocking adrenergic receptors left the tachycardic, hypotensive and vasodilatatory effects of CGRP unchanged. In equimolar amounts, CT had only minor vasodilatatory properties, CT is a well known hypocalcemic peptide; the same effect was obtained with CGRP in the rat in vivo, but only in 200to lOOO-fold higher amounts than of human CT. In conclusion, CGRP is a potent neuropeptide present throughout the body whereas CT is predominantly secreted by the Ccells of the thyroid gland. The different regional distribution of CGRP and CT and of their binding sites indicates distinct, but overlapping biological properties. They can be explained by limited structural homologies of the two peptides which may have evolved by gene duplication.
THE OSTEOBLASTIC HORMONE ACTION
CYTOSKELETON
G.A. Rodan,* J.J Egan, G. Gronowicz,
AND
C.K. Yeh
*Merck Sharp & Dohme Res. Labs, West Point, PA, University of Connecticut, Farmington, CT, USA The object
of these studies was to examine
the effect of
bone resorbing hormones on the osteoblastic cytoskeleton and the effect of cytoskeletal changes on cell function. Actin and myosin depolymerization and myosin light chain phosphorylation were followed by PAGE in calvaria-derived osteoblasts exposed to parathyroid hormone [hPTH(l-34)]. PTH caused a rapid dose-dependent reduction in polymerized actin and myosin to about 50% of control levels, within 5 min. Cyclic AMP-stimulating agents produced similar effects. The PTH-dependent depolymerization was preceded by a rapid, transient reduction in myosin light chain phosphorylation. This effect was also seen in the presence of 0.3 ~J,Mcalcium ionophore, suggesting CAMP rather than Ca*+ mediation of the PTH effect. The PTH-induced cytoskeletal depolymerization was associated with increased secretion of several proteins. The effect of 1,25(OH),D, was studied in ROS 17/2.8 osteosarcoma/osteobIastic cells in serum-free medium. This hormone caused cytoplasmic retractions and a redistribution of actin. The effect was dose-dependent (I- 100 PM), was much slower than the PTH effect (12-72 hrs) and required protein synthesis. 1,25(OH),D, increased the amount of extracellular osteonectin. 1,25(OH),D, had no effect on microtubules. On the other hand, microtubule disruption enhanced prostaglandin E production in calvaria-derived osteoblasts. The effect was dose-dependent, was detectable at 4 hrs and peaked between 8 and 24 hrs. Two hour exposure to colchicine was required to produce a maximum effect. The effect was due to a rise in cyclooxygenase activity, which did not require protein synthesis. In summary, calcium regulating hormones cause cytoskeletal and shape changes in osteoblasts; PTH acts via CAMP and 1,25(OH),D, via protein synthesis: disruption of microtubules raises PGE synthesis via increased PGE-synthase.
MEDICAL THERAPY FOR PRIMARY HYPERPARATHYROIDISM J. Foldes, I. Halperin,
G. Kidroni, J. Menczel
Department of Internal Medicine, Hospital, Mt. Scopus, Jerusalem,
Hadassah Israel
University
The benefit of surgery to patients with primary hyperparathyroidism (PHPT) is a matter of controversy. Furthermore, surgery is contraindicated in some PHPT subjects due to coexisting medical problems. Recently, there were reports suggesting medical management of PHPT with agents which either block the resorptive effect of PTH on bone or directly inhibit PTH secretion. In an attempt to elucidate the effects of several of these agents on calcium and bone metabolism, they were given consequently to a PHPT patient who could not undergo immediate surgery because of acute myocardial infarction. The effects of propranolol, cimetidine, calcitonin and disodium etidronate were assessed by measuring serum PTH and vitamin D metabolites and urinary CAMP, as well as common biochemical indices of bone and calcium metabolism. While none of the treatments corrected the hyperparathyroid state, a combination of propranolol with either cimetidine or disodium etidronate was associated with some reduction of serum calcium levels. Several changes in vitamin D metabolites status were observed during the hyperparathyroid state and later, following delayed parathyroidectomy.
413
from the Calcified Tissues Workshop
Specific LysisX
Fresh serum Inactivated serum Gamma globulin Guinea pig serum Inactivated serum + guinea pig serum Gamma globulin + guinea pig serum
64 3 4
1 52 56
CALCITONIN GENE-RELATED PEPTIDE (CGRP) IN MAN: ORIGIN, RECEPTORS AND CARDIOVASCULAR ACTION J.A. Fischer, W. Born, S. Brem, J.B. Petermann, M.A. Dambacher, C. Gennari
R. Muff,
Research Laboratory for Calcium Metabolism, University of Zurich, Zurich, Switzerland, and Institute of Medical Semeiotics, University of Siena, Siena, Italy Alternative splicing of primary calcitonin (CT) gene transcripts generates two distinct mRNA encoding CGRP and CT that exert different biological effects. CGRP and CT have been recognized in serum and thyroid extracts from normal subjects and medullary thyroid carcinoma patients. CGRP-like peptides have, moreover, been identified in the central nervous system (CNS), pituitary and the heart using a combination of gel filtration analysis, HPLC and specific RIA and RRA. CT is also present in the pituitary and brain, albeit in smaller amounts than in normal human thyroid glands. Binding sites for 125~I-CGRP have been recognized by receptor autoradiography and in membranes throughout the CNS and the heart, and 125-lsalmon CT receptors have been demonstrated in the hypothalamus, the brain stem and the kidney. In the rat heart, CGRP binding sites are predominantly localized around blood vessels concomitant with the presence of endogenous CGRP, and CGRP stimulates adenylate cyclase activity (ED-50 10-8M). CT receptors, on the other hand, have not been detected in the heart. In normal human subjects, CGRP had pronounced cardiovascular effects causing an increase in heart rate and contractility, hypotension and marked vasodilatation. Labetolol, blocking adrenergic receptors left the tachycardic, hypotensive and vasodilatatory effects of CGRP unchanged. In equimolar amounts, CT had only minor vasodilatatory properties, CT is a well known hypocalcemic peptide; the same effect was obtained with CGRP in the rat in vivo, but only in 200to lOOO-fold higher amounts than of human CT. In conclusion, CGRP is a potent neuropeptide present throughout the body whereas CT is predominantly secreted by the Ccells of the thyroid gland. The different regional distribution of CGRP and CT and of their binding sites indicates distinct, but overlapping biological properties. They can be explained by limited structural homologies of the two peptides which may have evolved by gene duplication.
THE OSTEOBLASTIC HORMONE ACTION
CYTOSKELETON
G.A. Rodan,* J.J Egan, G. Gronowicz,
AND
C.K. Yeh
*Merck Sharp & Dohme Res. Labs, West Point, PA, University of Connecticut, Farmington, CT, USA The object
of these studies was to examine
the effect of
bone resorbing hormones on the osteoblastic cytoskeleton and the effect of cytoskeletal changes on cell function. Actin and myosin depolymerization and myosin light chain phosphorylation were followed by PAGE in calvaria-derived osteoblasts exposed to parathyroid hormone [hPTH(l-34)]. PTH caused a rapid dose-dependent reduction in polymerized actin and myosin to about 50% of control levels, within 5 min. Cyclic AMP-stimulating agents produced similar effects. The PTH-dependent depolymerization was preceded by a rapid, transient reduction in myosin light chain phosphorylation. This effect was also seen in the presence of 0.3 ~J,Mcalcium ionophore, suggesting CAMP rather than Ca*+ mediation of the PTH effect. The PTH-induced cytoskeletal depolymerization was associated with increased secretion of several proteins. The effect of 1,25(OH),D, was studied in ROS 17/2.8 osteosarcoma/osteobIastic cells in serum-free medium. This hormone caused cytoplasmic retractions and a redistribution of actin. The effect was dose-dependent (I- 100 PM), was much slower than the PTH effect (12-72 hrs) and required protein synthesis. 1,25(OH),D, increased the amount of extracellular osteonectin. 1,25(OH),D, had no effect on microtubules. On the other hand, microtubule disruption enhanced prostaglandin E production in calvaria-derived osteoblasts. The effect was dose-dependent, was detectable at 4 hrs and peaked between 8 and 24 hrs. Two hour exposure to colchicine was required to produce a maximum effect. The effect was due to a rise in cyclooxygenase activity, which did not require protein synthesis. In summary, calcium regulating hormones cause cytoskeletal and shape changes in osteoblasts; PTH acts via CAMP and 1,25(OH),D, via protein synthesis: disruption of microtubules raises PGE synthesis via increased PGE-synthase.
MEDICAL THERAPY FOR PRIMARY HYPERPARATHYROIDISM J. Foldes, I. Halperin,
G. Kidroni, J. Menczel
Department of Internal Medicine, Hospital, Mt. Scopus, Jerusalem,
Hadassah Israel
University
The benefit of surgery to patients with primary hyperparathyroidism (PHPT) is a matter of controversy. Furthermore, surgery is contraindicated in some PHPT subjects due to coexisting medical problems. Recently, there were reports suggesting medical management of PHPT with agents which either block the resorptive effect of PTH on bone or directly inhibit PTH secretion. In an attempt to elucidate the effects of several of these agents on calcium and bone metabolism, they were given consequently to a PHPT patient who could not undergo immediate surgery because of acute myocardial infarction. The effects of propranolol, cimetidine, calcitonin and disodium etidronate were assessed by measuring serum PTH and vitamin D metabolites and urinary CAMP, as well as common biochemical indices of bone and calcium metabolism. While none of the treatments corrected the hyperparathyroid state, a combination of propranolol with either cimetidine or disodium etidronate was associated with some reduction of serum calcium levels. Several changes in vitamin D metabolites status were observed during the hyperparathyroid state and later, following delayed parathyroidectomy.