The effect of verapamil on the action of parathyroid hormone on embryonic bone in vitro

Herrmann‐Erlee, M. P. M.; Gaillard, Pieter J.; Hekkelman, J. W.; Nijweide, Peter J.

doi:10.1016/0014-2999(77)90143-1

Cited by 49 publications

(15 citation statements)

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“…In earlier studies utilizing mouse calvarial bones, verapamil was shown to inhibit bone resorption induced either by parathyroid hormone (Herrmann-Erlee et al 1977& 1988 or by 1,25-dihydroxyvitamin D3 (Lerner & Gustafson 1981). In the latter case, the effect of verapamil was reversible but only up to 5X10-5 M. It should be noted that at this concentration the drug has been shown to cause inhibition of osteoclast activity through a paradoxical increase in intracellular calcium (Zaidi et al 1990).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the other dihydropyridine, amlodipine, as well as the phenylalkylamines verapamil and gallopamil were either ineffective or, at the inhibitory concentration of lop4 M, apparently induced an irreversible change in bone cell functions. It is therefore doubtful that L-type channel blockade in osteoblasts necessarily causes inhibition of osteoclastic bone resorption.In earlier studies utilizing mouse calvarial bones, verapamil was shown to inhibit bone resorption induced either by parathyroid hormone (Herrmann-Erlee et al 1977& 1988 or by 1,25-dihydroxyvitamin D3 (Lerner & Gustafson 1981). In the latter case, the effect of verapamil was reversible but only up to 5X10-5 M. It should be noted that at this concentration the drug has been shown to cause inhibition of osteoclast activity through a paradoxical increase in intracellular calcium (Zaidi et al 1990).…”

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confidence: 99%

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Comparative Study on the Effect of Calcium Channel Blockers on Basal and Parathyroid Hormone‐Induced Bone Resorption in vitro

Redlich

Pietschmann

Štulc

et al. 1997

Pharmacology & Toxicology

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A number of clinical and experimental studies suggest that the effects of calcium channel blockers are not limited to the cardiovascular system but might also involve skeletal calcium metabolism due to the presence of L-type calcium channels in osteoblastic cells. We therefore investigated the influence of calcium channel blockers of the dihydropyridine type (nifedipine, amlodipine) as well as of the phenylalkylamine type (verapamil, gallopamil) on basal and parathyroid hormone-induced bone resorption utilizing organ-cultured neonatal mouse calvaria. Only at M, amlodipine, verapamil and gallopamil reduced basal and parathyroid hormone-induced resorption In contrast, nifedipine, between M, exhibited a dose-dependent inhibitory effect on parathyroid hormone-related bone resorption by up to 50%. When calvariae were cultured for 48 hr in the presence of inhibitory concentrations of the calcium channel blockers and then stimulated with parathyroid hormone, only parietal bones pretreated with nifedipine remained completely responsive to the bone resorbing action of the hormone.For more than two decades calcium channel blockers have been extensively and successfully used for treatment of cardiovascular disorders such as hypertension, angina, or cardiac arrhythmias (Snyder & Reynolds 1985). Typically, calcium channel blockers are prescribed to patients in their middle age or later, i.e., at a life time with increasing incidence of osteoporosis. The question was raised therefore whether calcium channel blockers, as many other drugs, could have adverse effects on bone metabolism and thereby possibly contribute to deterioration of bone mass in advanced age. Although experimental studies suggest that calcium channel blockers through modulation of osteoblast function could interfere with bone remodeling (Guggino et al. 1989), in vivo investigations in experimental animals and humans on that issue have yielded only conflicting results. In growing rabbits nifedipine lowers cancellous bone volume, mineral apposition rate and growth plate thickness (Duriez ef al. 1993). In line with these findings chronic treatment with verapamil in female rats induces osteopenia, whereas in male rats bone growth was inhibited (Samnegard & Sjadtn 1992). Boesgard et al. (1991) reported that prolonged treatment with clinical doses of verapamil did not affect indices of calcium and bone metabolism in humans. Also, chronic nifedipine use seems not to be associated with either beneficial or adverse effects on bone metabolism in males (Albers et al. 1991). In contrast, SjiSden et al. (1990) in patients with postsurgical hypoparathyroidism, verapamil increased serum calcium and phosphate levels without changing intestinal absorption or urinary excretion of calcium. This suggests that verapamil affects bone mineral metabolism .Calcium channel blockers exert multiple effects on osteoblasts. Verapamil for instance inhibits DNA synthesis in mouse calvarial MC3T3-El cells (Kim et al. 1991), and suppresses basal and 1,2S-dihydroxyvitamin D3-sti...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Comparative Study on the Effect of Calcium Channel Blockers on Basal and Parathyroid Hormone‐Induced Bone Resorption in vitro

Redlich

Pietschmann

Štulc

et al. 1997

Pharmacology & Toxicology

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“…The divalent cation ionophore A23187, like PTH, increases cyclic AMP in bone cells and promotes the resorption of organ-cultured bones'J10-13]. By contrast, verapamil and its methoxy derivative, D600, which block cellular Ca 2+ accumulation, inhibit bone resorption mediated by PTH and PGE2 [14,15]. Incubation of cultured bone cells at raised extracellular Ca 2+ concentrations replicates certain of the metabolic effects of PTH [16].…”

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confidence: 87%

Calcium-mediated enhancement of the cyclic AMP response in cultured bone cells

1981

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We have examined the influence of extracellular Ca2+ on cyclic AMP metabolism in an osteoblast-enriched population of bone cells isolated from the calvaria of rat fetuses. The cyclic AMP response to stimulators of cyclic AMP formation (PTH and PGE2), but not basal cyclic AMP levels, increased progressively as the extracellular Ca2+ concentration was raised from 0.2 to 4.0 mM. The response to changes in extracellular Ca2+ were rapid (within 3.5 min), and the level of responsivity that characterized each Ca2+ concentration persisted for at least 6 h when the Ca2+ concentration was kept constant. The effect of Ca2+ spanned the entire time course of PTH action, was not accompanied by altered excretion of cyclic AMP from the cells, and was evident at low as well as at high hormone concentrations. Ca2+ augmented the action of PTH in the presence as well as in the absence of cyclic AMP phosphodiesterase inhibitors, and failed to decrease cyclic AMP phosphodiesterase activity in the short term. Mn2+ and, to a smaller degree, Ba2+ substituted for Ca2+ in promoting the cyclic AMP response to PTH. Verapamil, an inhibitor of Ca2+ penetration, blunted the Ca2+-mediated increments in the cyclic AMP response, and the divalent cation ionophore A23187 enhanced these increments. These results indicate that Ca2+ and other cations are positive effectors of the stimulated cyclic AMP response in isolated bone cells. Accumulation into an as yet unknown cellular compartment may be required for the cation effect. The data are most consistent with enhancement of adenylate cyclase reactivity as the mode of cation action.

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“…In vitro exposure of whole bones to PTH resulted in the production of lactate and citrate (13,(45)(46)(47), and local pH is important in controlling bone mineral content (23)(24)(25). Activated osteoclasts concentrate acid in the resorptive compartment, resulting in the solubilization of Ca 2ϩ and P i from hydroxyapatite crystals, allowing for subsequent degradation of matrix proteins by proteases (13,21,22).…”

Section: Role Of Na ϩ /H ϩ Exchange In the Pth-induced Increase In Ecar-mentioning

confidence: 99%

A New Action of Parathyroid Hormone

Barrett

Belinsky

Tashjian

1997

Journal of Biological Chemistry

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The major physiological function of parathyroid hormone (PTH) is the maintenance of Ca 2؉ /P i homeostasis via the parathyroid hormone/parathyroid hormone-related protein receptor (PTHR) in kidney and bone. An important consequence of PTHR activation in bone is enhanced local acidification of the extracellular space. Agonist activation of some seven transmembrane-domain receptors increases the extracellular acidification rate (ECAR). We utilized microphysiometry to investigate PTH-stimulated, receptor-mediated increases in ECAR in human osteoblast-like SaOS-2 cells. PTH-(1-34) elicited a large, acute, dose-dependent increase in ECAR with an EC 50 of about 2 nM. The PTH-induced increase in ECAR was specific to cells expressing the PTHR and was inhibited by PTHR antagonists. Rapid, partial, homologous desensitization of the PTH-induced increase in ECAR was observed. Incubation of SaOS-2 cells with 8-bromo-cyclic AMP neither mimicked nor abrogated the PTH effect, and PTH stimulated an acute increase in ECAR in cAMP-resistant SaOS-2 Ca#4A cells. Stimulation of ECAR by PTH was independent of transient increases in cytosolic free calcium. Both inhibition and down-regulation of PKC reduced the PTH-induced increase in ECAR. Inhibition of Na ؉ /H ؉ exchange did not affect the PTH-induced ECAR response. We conclude that PTH caused a receptor-mediated, concentration-dependent, increase in ECAR, which was not dependent on the cAMP/PKA signaling pathway or the Na ؉ /H ؉ exchanger but involved the action of PKC. Thus, acid production in bone, a physiologically important action of PTH, is not confined to osteoclasts as previously considered but is also mediated by osteoblasts.The parathyroid hormone/parathyroid hormone-related protein receptor (PTHR) 1 is a member of the G protein-coupled, seven-transmembrane domain superfamily of receptors (1). The principal physiological action of PTH is on the regulation of Ca 2ϩ /P i homeostasis, which is mediated by the PTHR in kidney and bone. The biochemical and molecular mechanisms of the receptor-mediated actions of PTH are not completely understood. PTH stimulates osteoclast-mediated bone resorption indirectly via the activation of the PTHR on osteoblasts (2); however, the mechanism coupling these events is not known. Additionally, PTH has an anabolic effect on bone when administered intermittently (3). It has been proposed that the diverse actions of PTH may be a consequence of activation of both the cAMP/PKA and inositol lipid/Ca 2ϩ /PKC signaling pathways by the PTHR in osteoblasts (4). Receptor regulation is also important in the action of PTH on osteoblasts (4 -9). Homologous desensitization of PTH-stimulated increases in intracellular cAMP accumulation ([cAMP] i ) and in cytosolic free calcium concentration ([Ca 2ϩ ] i ) and down-regulation of the PTHR have been described in several target cell systems (4 -9).Previous investigations of the physiological actions of PTH have largely used animal and whole bone experimental systems (10 -14), while studies of PTHR signaling have co...

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The effect of verapamil on the action of parathyroid hormone on embryonic bone in vitro

Cited by 49 publications

References 10 publications

Comparative Study on the Effect of Calcium Channel Blockers on Basal and Parathyroid Hormone‐Induced Bone Resorption in vitro

Comparative Study on the Effect of Calcium Channel Blockers on Basal and Parathyroid Hormone‐Induced Bone Resorption in vitro

Calcium-mediated enhancement of the cyclic AMP response in cultured bone cells

A New Action of Parathyroid Hormone

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