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  • 1
    ISSN: 1432-1041
    Keywords: Key words Propranolol; stereoselectivity ; chirality ; enantiomers ; isomers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We recently reported a highly stereoselective increase in plasma concentrations of (S)-atenolol during exercise which is most likely due to a release of the drug from adrenergic cells. The objective of the present study was to investigate the influence of physical exercise on plasma concentrations of the (R)- and (S)-enantiomers of propranolol. Methods: Blood samples were taken immediately before and at the end of exercise in 12 patients receiving chronic treatment with racemic (R, S)-propranolol. Plasma concentrations of (R)- and (S)-propranolol were determined by HPLC. Results: In contrast to atenolol, mean plasma concentrations of (S)-propranolol were significantly higher (+20%) than those of (R)-propranolol at rest. During exercise there was an increase in plasma concentrations of both (R)-propranolol (+129%) and (S)-propranolol (+109%). Conclusion: Based on information from in vitro studies we conclude that the increase in plasma concentrations of (S)-propranolol during exercise is caused by a release of the drug from adrenergic nerves, whereas the reason for the increase in (R)-propranolol remains to be determined. This release of the β-adrenoceptor blocking (S)-enantiomer directly at the synaptic gaps might be one reason for the poor correlation between plasma concentration and effect of β-adrenoceptor antagonists repeatedly described in the literature.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0827
    Keywords: Key words: Skeletal alkaline phosphatase — Osteoblasts — Calcium — Growth factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Abstract. Skeletal alkaline phosphatase (ALP) is anchored to membrane inositol-phosphate on the outer surface of osteoblasts. Although skeletal ALP activity in serum is, essentially, all in an anchorless (soluble) form, in vitro studies indicate that ALP can be released in either an anchorless, soluble form (e.g., by a phospholipase) or an anchor-intact, insoluble form (e.g., by vesicle exocytosis). The current studies were intended to define the contributions of each of these putative processes of ALP release and to assess the significance of regulation by calcium (Ca) and skeletal effectors. ALP activity was measured in serum-free medium from replicate cultures of human osteosarcoma (SaOS-2) cells and normal human bone cells. Temperature-sensitive phase distribution (in Triton X-114) allowed separation of soluble from insoluble ALP activity. Our studies revealed that most of the ALP activity released from SaOS-2 cells was in an insoluble form (78% ± 8%), a percentage that was constant between 2 and 96 hours. A similar result was seen for normal human bone cells. Calcium had a negative, biphasic dose-dependent effect on net release of ALP activity: r=−0.85, P 〈 0.001 at 24 hours, with KIapparent values for biphasic inhibition of 20 and 300 μmol/l Ca. Of the skeletal effectors tested, insulin-like growth factor-II (IGF-II) had the greatest effect, decreasing the net release of ALP activity in a dose-dependent manner (r=−0.82, P 〈 0.005). Neither Ca nor IGF-II affected the distribution of soluble/insoluble ALP activity by more than 9%. IGF-II had no effect on extracellular ALP stability, but the addition of Ca to Ca-free cultures resulted in parallel losses of extracellular ALP activity and ALP immunoreactive protein (P 〈 0.001 for each). A similar effect was seen when Ca was added to Ca-free, cell-free, conditioned medium, but not when Ca was added to purified ALP, which is consistent with the general hypothesis that a Ca-dependent protease might be present in the cell-conditioned medium. Together, these data suggest that most of the ALP activity released from osteoblasts is insoluble (and, presumably, anchorless), net release of ALP activity is negatively regulated by Ca and skeletal growth factors, the effect of Ca may reflect Ca-dependent protease activity, and an exogenous (e.g., serum) phospholipase may be responsible for releasing ALP from its insoluble anchor.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Calcified tissue international 62 (1998), S. 309-315 
    ISSN: 1432-0827
    Keywords: Key words: Zinc — Alkaline phosphatase — Tartrate-resistant acid phosphatase — Female mice.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Abstract. The current studies were intended to assess dose- and time-dependent effects of dietary zinc (Zn) on alkaline phosphatase (ALP) activity and tartrate-resistant acid phosphatase (TRAP) activity in adult female mice. In the first study, mice were given 0, 1×, 2×, 3×, or 4× normal dietary Zn for 2 weeks, 4 weeks, or 6 weeks. In the second study, mice were given 0, 1×, 2×, 3×, 4×, and 5× normal dietary Zn for 4 weeks. Sera were collected for measurements of ALP and (in the second study) osteocalcin. Tibiae and calvaria were extracted for measurements of ALP, protein, and TRAP. The first study showed positive correlations between dietary Zn and serum ALP (4 and 6 weeks, P 〈 0.001), Zn and tibial ALP (2, 4, and 6 weeks, P 〈 0.03), and Zn and tibial protein (2, 4, and 6 weeks, P 〈 0.001), as well as a negative correlation between dietary Zn and tibial TRAP (2, 4, and 6 weeks, P 〈 0.001). Covariant analyses showed that serum ALP, tibial ALP, tibial protein, and tibial TRAP were affected by the dose of Zn (P 〈 0.005) and by the treatment time (P 〈 0.03). Supplemental studies showed that (1) the dose-dependent effect of dietary Zn on serum ALP (at 6 weeks) was proportional to the effects on tibial ALP and calvarial ALP, but not to the effects of Zn on renal, hepatic, or intestinal ALP; (2) 6 weeks of dietary Zn caused dose-dependent increases in ALP specific activity in the tibia, calvaria, and liver, but not kidneys or intestines; and (3) Zn increased ALP activity and cell layer protein and decreased TRAP activity in monolayer cultures of the murine osteoblastic cell line, MC3T3-E1. The second dietary study confirmed the results of the first: 4 weeks of treatment with Zn caused significant increases in serum ALP, calvarial ALP, and tibial ALP activities, and a significant decrease in tibial TRAP (P 〈 0.05–0.005 for each). This study also revealed an effect of Zn to increase serum osteocalcin (P 〈 0.03 at 2× normal Zn). Together, these data indicate that incremental increases in dietary Zn are associated with increases in ALP activity in serum and in bone. The effect of Zn to decrease TRAP activity in osteoblast-line cells precludes the interpretation of a Zn-dependent decrease in tibial TRAP activity as evidence of decreased bone resorption.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Calcified tissue international 64 (1999), S. 163-172 
    ISSN: 1432-0827
    Keywords: Key words: Inorganic phosphate — Alkaline phosphate — Zinc deficiency-SaOS-2 cells.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Abstract. Inorganic phosphate (Pi) can regulate the level of skeletal alkaline phosphatase (ALP) activity in human osteoblast-like cells by stabilizing the enzyme (without affecting transcription, ALP release from the cell surface, or the amount of ALP protein). These observations suggest that Pi determines the level of ALP activity by modulating a process of irreversible inactivation. The current studies were intended to examine the hypothesis that this inactivation of ALP activity is caused by the dissociation of an active center Zn and that Pi inhibits that dissociation. Initial studies showed that Zn, like Pi, could increase ALP specific activity in human osteosarcoma SaOS-2 cells in a time- and dose-dependent manner (e.g., a 50% increase at 0.2 μmol/liter Zn, P 〈 0.005). This effect was specific for Zn (i.e., no similar effect was seen with Ca, Fe, Co, Mg, Mn, or Cu), but not for SaOS-2 cells. Zn also increased ALP specific activity in (human osteosarcoma) MG-63 cells and in cells derived from normal human vertebrae (P 〈 0.001 for each). The effect of Zn to increase ALP activity was not associated with parallel increases in total protein synthesis, collagen production, or tartrate-resistant acid phosphatase activity (no change in any of these indices), net IGF-2 synthesis (a Zn-dependent decrease, P 〈 0.005), or PTH-dependent synthesis of cAMP (a biphasic increase, P 〈 0.02). Kinetic studies of Pi and Zn as co-effectors of ALP activity showed that Zn was a mixed-type effector with respect to Pi, whereas Pi was competitive with respect to Zn. Mechanistic studies showed that (1) Zn reversed the effect of Pi withdrawal to decrease ALP activity, but not by reactivating inactive ALP protein (the process required protein synthesis, without increases in ALP mRNA or the level of ALP immunoreactive protein); (2) Zn increased the half-life of ALP activity in intact cells and after a partial purification; and (3) Pi inhibited the process of ALP inactivation by EDTA (which chelates active center Zn). All these findings are consistent with the general hypothesis that Pi increases the half-life of skeletal ALP by preventing the dissociation of active center Zn and with a mechanistic model of skeletal ALP activity in which active center Zn participates in Pi-ester binding and/or hydrolysis.
    Type of Medium: Electronic Resource
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