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Daily low-dose administration of growth hormone secretagogue stimulates pulsatile growth hormone secretion and elevates plasma insulin-like growth factor-1 levels in pigs

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Abstract

Repeated administration of growth hormone secretagogues (GHSs) has proven to be a delicate matter owing to development of tolerance. The aim of the present study was to define conditions during which the responsiveness to the orally active NN703 was maintained over several days. Growing pigs were fitted with stomach and vascular catheters, permitting unstressed intragastric administrations and blood sampling. NN703 or vehicle was administered once daily. When NN703 was given at a dose of 18 mg/kg, there was a massive acute increase in plasma growth hormone (GH) levels, but this was only seen on the first day of administration. A dose of 1.8 mg/kg did not cause a significant acute increase in plasma GH concentrations, whereas stimulation of pulsatile GH release was sustained over a 4-d period. During the first 7 h following injection of vehicle, the area under the curve of plasma GH was 1211 ± 144 (µg/[L·7 h]), but increased to 1770 ± 269 and 1824 ± 198 (µg/[L·7 h]) on the first and fourth day of NN703 administration, respectively. Deconvolution analysis of the 7-h profiles revealed that the GH mass per burst as well as the GH burst amplitude were significantly (p < 0.001) increased during treatment with NN703, which led to an increase in pulsatile GH secretion rate (p < 0.001). Insulin-like growth factor-1 plasma concentrations increased steadily during NN703 administration (p < 0.01) and decreased after termination of treatment. The sustained increase in GH pulsatility observed with low-dose NN703 treatment suggests that development of tolerance to this GHS may be obviated by minimization of dose.

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References

  1. Smith, R. G., Van der Ploeg, L. H., Howard A. D., Feighner, S. D., Cheng, K., Hickey, G. J., Wyvratt, M. J. Jr., Fisher, M. H., Nargund, R. P., and Patchett, A. A. (1997). Endocr. Rev. 18, 621–645.

    Article  PubMed  CAS  Google Scholar 

  2. Hansen, T. K., Ankersen, M., Hansen, B. S., Raun, K., Nielsen, K. K., Lau, J., Peschke, B., Lundt, B. F., Thogersen, H., Johansen, N. L., Madsen, K., and Andersen, P. H. (1998). J. Med. Chem. 41, 3705–3714.

    Article  PubMed  CAS  Google Scholar 

  3. Smith, R. G., Palyha, O. C., Feighner, S. D., Tan, C. P., McKee, K. K., Hreniuk, D. L., Yang, L., Morriello, G., Nargund, R., Patchett, A. A., and Howard, A. D. (1999). Horm. Res. 51, 1–8.

    PubMed  CAS  Google Scholar 

  4. Hansen, B. S., Raun, K., Nielsen, K. K., Johansen, P. B., Hansen, T. K., Peschke, B., Lau, J., Andersen, P. H., and Ankersen, M. (1999). Eur. J. Endocrinol. 141, 180–189.

    Article  PubMed  CAS  Google Scholar 

  5. Ankersen, M., Nielsen K. K., Hansen, T. K., Raun, K., and Hansen, B. S. (2000). Eur. J. Med. Chem. 35, 487–497.

    Article  PubMed  CAS  Google Scholar 

  6. Momany, F. A., Bowers, C. Y., Reynolds, G. A., Chang, D., Hong, A., and Newlander, K. (1981). Endocrinology 108, 31–39.

    PubMed  CAS  Google Scholar 

  7. Dickson, S. L., Leng, G., Dyball, R. E., and Smith, R. G. (1995). Neuroendocrinology 61, 36–43.

    PubMed  CAS  Google Scholar 

  8. Cheng, K., Chan, W. W., Barreto, A., Convey, E. M., and Smith, R. G. (1989). Endocrinology 124, 2791–2798.

    Article  PubMed  CAS  Google Scholar 

  9. Howard, A. D., Feighner, S. D., Cully, D. F., et al. (1996). Science 273, 974–977.

    Article  PubMed  CAS  Google Scholar 

  10. Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H., and Kangawa, K. (1999). Nature 402, 656–660.

    Article  PubMed  CAS  Google Scholar 

  11. Date, Y., Murakami, N., Kojima, M., Kuroiwa, T., Matsukura, S., Kangawa, K., and Nakazato, M. (2000). Biochem. Biophys. Res. Commun. 275, 477–480.

    Article  PubMed  CAS  Google Scholar 

  12. Seoane, L. M., Tovar, S., Baldelli, R., Arvat, E., Ghigo, E., Casanueva, F. F., and Dieguez, C. (2000). Eur. J. Endocrinol. 143, R007-R009.

    Article  Google Scholar 

  13. Nakazato M., Murakami, N., Date, Y., Kojima, M., Matsuo, H., Kangawa, K., and Matsukura, S. (2001). Nature 409, 194–198.

    Article  PubMed  CAS  Google Scholar 

  14. Chen, C. (2000). Clin. Exp. Pharmacol. Physiol. 27, 323–329.

    Article  PubMed  CAS  Google Scholar 

  15. Fletcher, T. P., Thomas, G. B., and Clarke, I. J. (1996). Domest. Anim. Endocrinol. 13, 251–258.

    Article  PubMed  CAS  Google Scholar 

  16. Bowers, C. Y., Reynolds, G. A., Durham, D., Barrera, C. M., Pezzoli, S. S., and Thorner, M. O. (1990). J. Clin. Endocrinol. Metab. 70, 975–982.

    PubMed  CAS  Google Scholar 

  17. Blake, A. D. and Smith, R. G. (1991). J. Endocrinol. 129, 11–19.

    PubMed  CAS  Google Scholar 

  18. Klinger, B., Silbergeld, A., Deghenghi, R., Frenkel, J., and Laron, Z. (1996). Eur. J. Endocrinol. 134, 716–719.

    Article  PubMed  CAS  Google Scholar 

  19. Hickey, G. J., Jacks, T. M., Schleim, K. D., Frazier, E., Chen, H. Y., Krupa, D., Feeney, W., Nargund, R. P., Patchett, A. A., and Smith, R. G. (1997). J. Endocrinol. 152, 183–192.

    Article  PubMed  CAS  Google Scholar 

  20. Zdravkovic, M., Sogaard, B., Ynddal, L., Christiansen, T., Agerso, H., Thomsen, M. S., Falch, J. E., and Ilondo, M. M. (2000). Growth Horm. IGF Res. 10, 193–198.

    Article  PubMed  CAS  Google Scholar 

  21. McDowell, R. S., Elias, K. A., Stanley, M. S., Burdick, D. J., Burnier, J. P., Chan, K. S., Fairbrother, W. J., Hammonds, R. G., Ingle, G. S., and Jacobsen, N. E. (1995). Proc. Natl. Acad. Sci. USA 92, 11,165–11,169.

    Article  CAS  Google Scholar 

  22. Guan, X. M., Yu, H., Palyha, O. C., McKee, K. K., Feighner, S. D., Sirinathsinghji, D. J., Smith, R. G., Van der Ploeg, L. H., and Howard, A. D. (1997). Mol. Brain Res. 48, 23–29.

    Article  PubMed  CAS  Google Scholar 

  23. Bailey, A. R., Giles, M., Brown, C. H., Bull, P. M., Macdonald, L. P., Smith, L. C., Smith, R. G., Leng, G., and Dickson, S. L. (1999). Neuroendocrinology 70, 83–92.

    Article  PubMed  CAS  Google Scholar 

  24. Bennett, P. A., Thomas, G. B., Howard, A. D., Feighner, S. D., Van der Ploeg, L. H., Smith, R. G., and Robinson, I. C. (1997). Endocrinology 138, 4552–4557.

    Article  PubMed  CAS  Google Scholar 

  25. Nass, R., Gilrain, J., Anderson, S., Gaylinn, B., Dalkin, A., Day, R., Peruggia, M., and Thorner, M. O. (2000). Endocrinology 141, 2084–2089.

    Article  PubMed  CAS  Google Scholar 

  26. Sato, M., Chihara, K., Kita, T., Kashio, Y., Okimura, Y., Kitajima, N., and Fujita, T. (1989). Neuroendocrinology 50, 139–151.

    PubMed  CAS  Google Scholar 

  27. Chapman, I. M., Pescovitz, O. H., Murphy, G., Treep, T., Cerchio, K. A., Krupa, D., Gertz, B., Polvino, W. J., Skiles, E. H., Pezzoli, S. S., and Thorner, M. O. (1997). J. Clin. Endocrinol. Metab. 82, 3455–3463.

    Article  PubMed  CAS  Google Scholar 

  28. Chapman, I. M., Hartman, M. L., Pezzoli, S. S., and Thorner, M. O. (1996). J. Clin. Endocrinol. Metab. 81, 2874–2880.

    Article  PubMed  CAS  Google Scholar 

  29. Shah, N., Evans, W. S., Bowers, C. Y., and Veldhuis, J. D. (1999). J. Clin. Endocrinol. Metab. 84, 2140–2150.

    Article  PubMed  CAS  Google Scholar 

  30. Svensson, J., Wiklund, O., and Ottosson, M., Johannsson, G., Taskinen, M. R., Wiklund, O., and Bengtsson, B. A. (1999). J. Clin. Endocrinol. Metab. 84, 2028–2033.

    Article  PubMed  CAS  Google Scholar 

  31. Malmlof, K., Cortova, Z., Saxerholt, H., Karlsson, E., Arrhenius-Nyberg, V., and Skottner, A. (1995). Clin. Sci. (Colch.) 88, 285–292.

    CAS  Google Scholar 

  32. Raun, K., Hansen, B. S., Johansen, N. L., Thogersen, H., Madsen, K., Ankersen, M., and Andersen, P. H. (1998). Eur. J. Endocrinol. 139, 552–561.

    Article  PubMed  CAS  Google Scholar 

  33. Malmlof, K., Johansen, P. B., Haahr, P. M., Wilken, M., and Oxlund, H. (1999). Growth Horm. IGF Res. 9, 445–450.

    Article  PubMed  CAS  Google Scholar 

  34. Veldhuis, J. D. and Johnson, M. L. (1992). Methods Enzymol. 210, 539–575.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Pharmacological Research 3, Novo Nordisk A/S, Måløv, Denmark

    Kjell Malmlöf, Michael K. Bauer & Peter B. Johansen

  2. MedChem Research 1, Novo Nordisk A/S, Måløv, Denmark

    Michael Ankersen

  3. Division of Endocrinology & Metabolism, Department of Internal Medicine, University of Virginia, Charlottesville, VA

    Johannes D. Veldhuis

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  1. Kjell Malmlöf
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  2. Michael K. Bauer
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  4. Michael Ankersen
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Correspondence to Kjell Malmlöf.

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Malmlöf, K., Bauer, M.K., Johansen, P.B. et al. Daily low-dose administration of growth hormone secretagogue stimulates pulsatile growth hormone secretion and elevates plasma insulin-like growth factor-1 levels in pigs. Endocr 16, 195–199 (2001). https://doi.org/10.1385/ENDO:16:3:195

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  • DOI: https://doi.org/10.1385/ENDO:16:3:195

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