Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of parathyroid hormone (PTH) were examined in three model systems to determine the mechanism of PTH action in vascular tissue. Bovine parathyroid extract and synthetic bPTH-(1-34) relaxed norepinephrine-contracted rabbit aortic strips in a dose-dependent fashion. The ED50 was 33.1 nM (21.8-50.1 nM). The hypotensive diterpene, forskolin and the phosphodiesterase inhibitors, methylisobutylxanthine and papaverine, all greatly potentiated the relaxant action of PTH. Primary cultures of vascular smooth muscle cells isolated from rabbit and rat aorta and bovine pulmonary artery all responded to bPTH-(1-34) with 5- to 10-fold increases in intracellular cyclic AMP concentrations within 1 min. Again, this action of PTH was also markedly augmented (3-fold or greater) by methylisobutylxanthine, papaverine or forskolin. In addition, 1 microM bPTH-(1-34) stimulated adenylate cyclase activity in membrane preparations from vascular smooth muscle cells in the presence or absence of 100 microM GMPPNHP. These results indicate that PTH exerts direct relaxant actions on vascular smooth muscle and that cyclic AMP may be involved in the mechanism of PTH action in vascular tissue.
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PMID:Increased cyclic AMP in cultured vascular smooth muscle cells and relaxation of aortic strips by parathyroid hormone. 241 15

The isolated, perfused rat mesenteric vascular bed was used as a sensitive model of resistance vessel dynamics to evaluate the vascular actions of parathyroid hormone (PTH). Periarterial sympathetic nerve stimulation (PNS) was carried out at 8 Hz, 2 msec in pulse duration (supramaximal voltage) for 30 sec. The pressor response to PNS was decreased in a dose-dependent fashion by synthetic bovine PTH(1-34). Reduction of the PNS response was greater than 30% at 30 nM PTH. The concentration of PTH required to produce a half-maximal (ED50) decrease in PNS-induced tone was 4 nM. The phosphodiesterase inhibitor, methylisobutylxanthine, at 300 nM did not alter the PNS response when given alone, but potentiated PTH action. Isoproterenol (1 microM) decreased the PNS response by only 20%. Propranolol (1 microM) inhibited the effect of isoproterenol on the PNS response, but not that of PTH. The inhibitory analog of PTH, bPTH(7-34), blocked PTH action completely only at 30- to 50-fold higher concentrations than that of PTH. PTH also decreased the pressor response to norepinephrine infusion, similar to the effects on PNS. Again, bPTH(7-34) blocked the actions of PTH on norepinephrine vasoconstriction. These findings indicate that PTH has greater efficacy and potency for reducing PNS pressor activity in the mesenteric vasculature than isoproterenol and demonstrate that PTH has significant vascular effects at nanomolar concentrations.
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PMID:Vasodilation of the rat mesenteric vasculature by parathyroid hormone. 241 96

The involvement of tissue cAMP in the vasodilating action of parathyroid hormone (PTH) was investigated. The bovine active fragment bPTH-(1-34) was used in all studies. In anesthetized dogs, theophylline, a phosphodiesterase inhibitor, potentiated the hypotensive action of bPTH-(1-34) at the dose of 1 microgram/kg. The potentiation was related to the dose of theophylline infused. In an in vitro rat tail artery helical strip assay, dibutyryl cAMP produced dose-related relaxation in arginine vasopressin (AVP) constricted blood vessels. bPTH-(1-34) also produced dose-related relaxation in the tail artery constricted by AVP. In the presence of isobutylmethylxanthine, another phosphodiesterase inhibitor, the bPTH-(1-34) dose--response curve was shifted to the left, indicating potentiation. Imidazole, which has phosphodiesterase stimulating activity, significantly decreased the in vitro vasorelaxing effect of bPTH-(1-34). In addition, bPTH-(1-34) increased significantly the rat tail artery cAMP content. b-PTH-(1-34) oxidized with hydrogen peroxide lost its vasorelaxing activity and was also ineffective in increasing the tail artery cAMP content. All these data strongly suggest that cAMP may be involved in eliciting the vasorelaxing action of bPTH-(1-34).
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PMID:Cyclic AMP and the vascular action of parathyroid hormone. 243 93

The effect of prostaglandin E2 (PGE2) on the kinetic of bone resorption in vitro was assessed by following the release of minerals and degradation of matrix in cultured mouse calvarial bones. PGE2 (1 and 3 mumol/liter) caused an initial inhibition of the release of 45Ca, stable calcium, and inorganic phosphate from unstimulated calvarial bones. The effect was transient and after 24 and 48 hours the release of 45Ca, stable calcium, and inorganic phosphate from PGE2-treated bones was enhanced. 0.3 mumol/liter of PGE2 stimulated the release of 45Ca after 24 hours, but at this concentration no initial inhibition was observed. The initial inhibitory effect of PGE2 (1 mumol/liter) could be further increased by three structurally different inhibitors of cyclic AMP breakdown. PGE2 (1 mumol/liter) caused not only an initial inhibition of mineral release but also an initial inhibition of matrix degradation, as assessed by the release of 3H from [3H]-proline labeled bones. In addition, PGE2 (3 mumol/liter), in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine, caused a rapid (6 hours) inhibition of the release of the lysosomal enzymes beta-glucuronidase and beta-N-acetyl-glucosaminidase, without affecting the release of the cytosolic enzyme lactate dehydrogenase. Similar specific initial inhibition of lysosomal enzyme release was also seen in the presence of calcitonin and dibutyryl cyclic AMP, but not in the presence of parathyroid hormone (PTH). Neither PGE2 nor the phosphodiesterase inhibitors rolipram and Ro 20.1724, could inhibit the initial stages of PTH-induced 45Ca release. Nor did PGE2 inhibit the stimulation of radioactive calcium mobilization induced by 1 alpha (OH)-vitamin D3.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostaglandin E2 causes a transient inhibition of mineral mobilization, matrix degradation, and lysosomal enzyme release from mouse calvarial bones in vitro. 244 May 32

The influence of the glucocorticoid dexamethasone on the cAMP response to parathyroid hormone (PTH) and various agonists was studied in epithelial monolayers of opossum kidney (OK) cells. The incubation with dexamethasone for 72 hours led to a dose-dependent higher cAMP response to PTH or forskolin in intact cells as well as in digitonin-permeabilized cells. This effect did not appear to result from changes in phosphodiesterase (PDE) activity nor from alterations in cAMP efflux from the cells. Moreover, dexamethasone increased the formation of domes by OK cell epithelium. Thus, dexamethasone seems to promote a more differentiated renal epithelial phenotype as suggested by enhanced hormonal response.
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PMID:Effect of dexamethasone on parathyroid hormone stimulation of cyclic AMP in an opossum kidney cell line. 244 15

When primary culture of C75BL6 mouse cortical kidney cells in serum-free medium were incubated with unlabeled 25(OH)D3, they produced a metabolite which co-migrated with authentic 1,25(OH)2D3 and which could be measured by competitive receptor assay. A metabolite co-migrating with authentic 10-oxo-19-nor-25-OH-D3 was also produced. However, when cultures were incubated with 25(OH)D3 for 1 hour or longer, 10-oxo-19-nor-25-OH-D accounted for less than 15% of the total 3H-1,25(OH)2D3 displacement activity. Production of 1,25(OH)2D3 increased with increasing content of the culture, with time of incubation, and with substrate concentration. The apparent Km was 1.4 +/- 0.6 microM and Vmax 2.6 +/- 0.4 pM/mg protein/hr. These cultures possessed a very high level of phosphodiesterase activity, as indicated by their high cyclic AMP (cAMP) response to IBMX. This high phosphodiesterase activity may have been responsible for the lack of stimulation of 1,25(OH)2D3 production by physiologic or near physiologic concentrations of parathyroid hormone (PTH) in the absence of IBMX. However, when IBMX 10(-6) M was present, bPTH 10(-9) M significantly increased production of both cAMP and 1,25(OH)2D3. There was a close correlation between 1,25(OH)2D3 production and cAMP content of the cultures (basal or stimulated). An incubation time of at least 4 hours was required for cAMP to increase 1,25(OH)2D3 production and was inhibited in the presence of cycloheximide and actinomycin D. This study further documents the regulation of renal 1,25(OH)2D3 synthesis by PTH in mammalian kidney and provides evidence for cAMP as a possibly important second messenger in this effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence that stimulation of 1,25(OH)2D3 production in primary cultures of mouse kidney cells by cyclic AMP requires new protein synthesis. 245 76

The diterpene forskolin which increases 3',5'-cyclic adenosine monophosphate concentrations (cAMP) in intact cells by directly activating the enzyme adenyl cyclase, was examined for its ability to alter bone resorption in fetal rat long bone cultures. After 48 h, forskolin inhibited resorption at 1.0 and 10 microM. However, after 120 h, it had a small stimulatory effect at 1.0 microM and no net effect on resorption at 10 microM. Isobutyl-methylxanthine (IBMX), which elevates cAMP levels in cells by inhibiting the enzyme 3',5'-cyclic adenosine monophosphate phosphodiesterase, produced a resorptive response which was slightly different from that of forskolin. After both 48 and 120 h, IBMX at 0.1 mM stimulated resorption while at 1.0 mM, it had only inhibitory effects. In bones which were stimulated to resorb with either parathyroid hormone or 1,25(OH)2 vitamin D, forskolin inhibited resorption. The inhibitory effects of forskolin on hormonally stimulated resorption were transient in cultures treated with 1.0 microM but were sustained with 10 microM. Inhibitory responses to forskolin did not appear to result from toxicity since they were completely reversed when forskolin was removed from the media. These results imply that agents which increases 3',5'-cyclic adenosine monophosphate concentrations in bone activate two resorptive pathways: one which is inhibitory and another which is stimulatory.
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PMID:Forskolin has both stimulatory and inhibitory effects on bone resorption in fetal rat long bone cultures. 245 10

Microelectrodes were used to investigate the possible involvement of cAMP and Ca2+ ions in the parathyroid hormone's, bPTH(1-34), effect on the membrane potential of rat osteoblasts in primary culture. Parathyroid hormone (10(-7) M) depolarized cell membrane by 25.0 +/- 6.1 mV (mean +/- standard deviation, SD; n = 17). Blocking Ca2+ influx with the Ca channel blocker cobalt revealed two phases in the hormone effect: a rapid and slight membrane hyperpolarization followed by sustained depolarization. In addition, cobalt significantly (p less than 0.01) decreased the magnitude of the PTH depolarizing action. The addition of dibutyryl-cAMP (10(-3) M) to the perfusion solution also resulted in a biphasic effect. At a lower concentration (10(-4) M), dibutyryl-cAMP produced only membrane hyperpolarization, suggesting a cAMP dose dependence of the opposite membrane potential changes. Forskolin (10(-5) M) and the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) (10(-4) M) mimicked the depolarizing effect of PTH. IBMX at a low concentration (5 x 10(-6) M) potentiated the depolarizing effect of PTH. Increases in [Ca2+]i using Ca2+ ionophore A23187 and intracellular injection of CaCl2 or inositol trisphosphate decreased the PTH depolarizing action, whereas intracellular injection of EGTA enhanced this effect. These results indicate that PTH evokes a biphasic change in rat osteoblast membrane potential that seems to be mediated by an increase in cAMP and modulated by intracellular calcium.
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PMID:Early effects of parathyroid hormone on membrane potential of rat osteoblasts in culture: role of cAMP and Ca2+. 246 41

The effect of synthetic human parathyroid hormone (hPTH) on the formation of matrix vesicles (MV), and on the rate of cell division, production of cellular alkaline phosphatase (AP) and protein by primary cultures of chicken epiphyseal growth plate hypertrophic chondrocytes was investigated. Addition to serum-containing or serum-free media of physiological levels of hPTH, in a range from 0.1 to 10 nM, caused a progressive decrease in the formation of AP-rich MV. However, studies on incorporation of [3H]choline into MV indicate that MV formation per se was not significantly decreased. hPTH was found to markedly decrease the expression of cellular AP, accompanied by an increase in cell division [( 3H]thymidine incorporation) and protein synthesis. Since these effects of hPTH were augmented by 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor, and mimicked by the cAMP analogue N6,O2'-dibutyryl-adenosine 3',5'-cyclic-monophosphate (DBcAMP), the findings clearly indicate that hPTH was acting through the classic cAMP-mediated mechanism. Inasmuch as elevation of AP in growth plate chondrocytes coincides with MV formation, maturation and hypertrophy of the cells, and induction of mineralization, the stimulation of cell division and suppression of cellular AP indicates that hPTH would cause the cells to revert to a less differentiated state. Thus, elevation in PTH, which results from lowered circulating levels of Ca2+, should inhibit mineral deposition in the growth plate. This may be a physiological protective mechanism to prevent a further drain on serum Ca2+.
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PMID:Effect of synthetic human parathyroid hormone on the levels of alkaline phosphatase activity and formation of alkaline phosphatase-rich matrix vesicles by primary cultures of chicken epiphyseal growth plate chondrocytes. 246 54

Intravenous injection of chicks with bovine parathyroid hormone (1-34) (3.3 micrograms/100 g body wt.) or 16,16-dimethyl PGE2 (5 micrograms/100 g body wt.) caused rapid (3 minute) net inhibition of 45Ca uptake into femur and calvarium. These agents also elevated bone adenosine 3',5'-cyclic monophosphate (cAMP) but not guanosine 3',5'-cyclic monophosphate (cGMP) levels at this time. Methylxanthine phosphodiesterase inhibitors (MXPI), caffeine, theophylline, and 3-isobutyl-1-methylxanthine (IBMX) (0.3-5 mg/100 g body wt.) similarly inhibited net 45Ca uptake into femur and to a lesser extent calvarium. Plasma 45Ca and total Ca levels were unaltered or showed a slight tendency to be increased over control values 3 minutes after injection. However, the effects of the non-MXPI, dibutyryl-cAMP (0.5-5 mg/100 g body wt.) on bone 45Ca uptake were negligible. Of the MXPI, only IBMX elevated total cAMP levels in chick bone at 3 minutes. These data implicate but do not confirm a mediatory role for cAMP in the rapid inhibitory actions of PTH and PGEs on bone net 45Ca uptake in chicks.
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PMID:Cyclic nucleotides and the rapid inhibitions of bone 45Ca uptake in response to bovine parathyroid hormone and 16,16-dimethyl prostaglandin E2 in chicks. 246 12


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