Abstract
The original view of glucocorticoid effects as being divided into physiological and pharmacological ones is no longer acceptable, i.e. all glucocorticoid effects are apparently mediated by receptor occupation which triggers RNA/protein synthesis. The concentrations needed for receptor-mediated effects are low, e.g. theK D value for dexamethasone is in the nanomolar range. The high-dose pulse glucocorticoid therapy results in blood concentrations much higher than those necessary for receptor saturation. This makes sense only when nonspecific effects may be expected to occur which necessitate concentrations higher than 10−6 mol·1−1. In this paper the question of nonspecific glucocorticoid effects in adjuvant arthritis and carrageenin paw edema of rats was investigated using the glucocorticoid receptor antagonist RU 38486 and by injecting the RNA/protein synthesis inhibitors actinomycin D or cycloheximide. We did not find convincing evidence for nonspecific gluocorticoid mechanisms.
References
J. V. Fahey, P. M. Guyre and A. Munck,Mechanisms of antiinflammatory action of glucocorticosteroids. Adv. Inflamm. Res.2, 21–51 (1981).
A. Munck, P. M. Guyre and N. J. Holbrook,Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocrine Rev.5, 25–44 (1984).
J. Vane and Regina Botting,Inflammation and the mechanism of action of anti-inflammatory drugs. FASEB J.1, 89–96 (1987).
Z. Werb, R. Foley and A. Munck,Interaction of glucocorticoids with macrophages. Identification of glucocorticoid receptors in monocytes and macrophates. J. Exp. Med.147, 1684–1694 (1978).
D. R. Varma and S. Mulay,Anti-inflammatory and ulcerogenic effects and pharmacokinetics of dexamethasone in protein-deficient rats. J. Pharmacol. Exp. Therap.214, 197–202 (1980).
E. B. Thompson,Glucocorticoids and lysosomes in glucocorticoid hormone action (Eds. J. D. Baxter and G. G. Rousseau) pp. 575–581, Springer, Berlin, Heidelberg, New York 1979.
S. Tsurufuji, K. Sugio and F. Takemasa,The role of glucocorticoid receptor and gene expression in the anti-inflammatory action of dexamethasone. Nature200, 408–410 (1979).
R. Hirschelmann and H. Bekemeier,Problems and results in testing the possible mode of anti-inflammatory glucocorticoid action in carrageenin rat paw edema: Advantages of local substance injection. Int. J. Tiss. React.VI, 471–475 (1984).
R. Hirschelmann and R. Schade,Regulation of acute phase reaction in rat adjuvant arthritis. Agents and Actions19, 335–336 (1986).
S. H. Peers, D. Moon and R. J. Flower,Reversal of the anti-inflammatory effects of dexamethasone by the glucocorticoid antagonist RU 38486. Biochem. Pharmacol.37, 556–557 (1988).
W. Buerger, R. Schade and R. Hirschelmann,The rat C-reactive protein—isolation and responses to experimental inflammation and tissue damage. Agents and Actions21, 93–97 (1987).
D. R. Varma and T. L. Yue,Influence of protein-calorie malnutrition on the pharmacokinetics, placental transfer and tissue localization of dexamethasone in rats. Br. J. Pharmac.83, 131–137 (1984).
R. Rohdewald, J. Rehder, H. Möllmann, J. Barth and H. Derendorf,Zur Pharmakokinetik und Pharmakodynamik von Prednisolon nach extrem hoher Dosierung als Prednisolonhemisuccinat. Arzneim.-Forsch./Drug Res.37, 194–198 (1987).
M. Angelo-Khattar, O. Thulesius and T. Cherian,The effect of glucocorticosteroids on in vitro motility of the ureter of the sheep. Br. J. Pharmacol.96, 527–530 (1989).
P. J. Pentikäinen,Pharmacological aspects of corticosteroid pulse therapy. Scand. J. Rheumatol. Suppl.54, 6–9 (1984).
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Hirschelmann, R., Schade, R., Bürger, W. et al. Nonspecific action of glucocorticosteroids after high-dose pulse therapy?. Agents and Actions 31, 148–151 (1990). https://doi.org/10.1007/BF02003235
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DOI: https://doi.org/10.1007/BF02003235