B Hinz1, R Hirschelmann. 1. Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nürnberg, Germany. hinz@pharmakologie.uni-erlangen.de
Abstract
PURPOSE: Membrane-stabilizing effects may be part of glucocorticoid action during high-dose glucocorticoid therapy. The present study investigates the mode of action of dexamethasone megadoses on rat liver lysosomal membranes. METHODS: Following intravenous administration of dexamethasone in rats, the release of beta-glucuronidase from liver lysosomes was assessed ex vivo as a marker for lysosomal membrane integrity. RESULTS: Dexamethasone megadoses significantly inhibited beta-glucuronidase release 10 min post-administration by 38% (3 mg/kg dexamethasone) and 33% (10 mg/kg dexamethasone) at corresponding dexamethasone liver concentrations of 3.9 x 10(-5) mol/kg and 15.1 x 10(-5) mol/kg, respectively. Comparable inhibition of beta-glucuronidase release (34% for 3 mg/kg and 38% for 10 mg/kg) was observed 24 h after administration of dexamethasone, although dexamethasone liver concentrations had already declined to 0.09 x 10(-5) mol/kg and 0.19 x 10(-5) mol/kg, respectively. A 2-h oral pretreatment of rats with the glucocorticoid receptor antagonist RU 486 (10 mg/kg) did not alter immediate (10 min) stabilization by dexamethasone (3 mg/kg). but almost completely prevented lysosomal membrane protection 24 h after dexamethasone injection. CONCLUSIONS: Dexamethasone megadoses may preserve lysosomal membrane integrity by a dual action involving both rapid nongenomic effects occurring instantaneously after administration and long-term receptor-dependent genomic events.
PURPOSE: Membrane-stabilizing effects may be part of glucocorticoid action during high-dose glucocorticoid therapy. The present study investigates the mode of action of dexamethasone megadoses on rat liver lysosomal membranes. METHODS: Following intravenous administration of dexamethasone in rats, the release of beta-glucuronidase from liver lysosomes was assessed ex vivo as a marker for lysosomal membrane integrity. RESULTS:Dexamethasone megadoses significantly inhibited beta-glucuronidase release 10 min post-administration by 38% (3 mg/kg dexamethasone) and 33% (10 mg/kg dexamethasone) at corresponding dexamethasone liver concentrations of 3.9 x 10(-5) mol/kg and 15.1 x 10(-5) mol/kg, respectively. Comparable inhibition of beta-glucuronidase release (34% for 3 mg/kg and 38% for 10 mg/kg) was observed 24 h after administration of dexamethasone, although dexamethasone liver concentrations had already declined to 0.09 x 10(-5) mol/kg and 0.19 x 10(-5) mol/kg, respectively. A 2-h oral pretreatment of rats with the glucocorticoid receptor antagonist RU 486 (10 mg/kg) did not alter immediate (10 min) stabilization by dexamethasone (3 mg/kg). but almost completely prevented lysosomal membrane protection 24 h after dexamethasone injection. CONCLUSIONS:Dexamethasone megadoses may preserve lysosomal membrane integrity by a dual action involving both rapid nongenomic effects occurring instantaneously after administration and long-term receptor-dependent genomic events.
Authors: P P Youssef; D R Haynes; S Triantafillou; A Parker; J R Gamble; P J Roberts-Thomson; M J Ahern; M D Smith Journal: Arthritis Rheum Date: 1997-08
Authors: M B Bracken; M J Shepard; W F Collins; T R Holford; D S Baskin; H M Eisenberg; E Flamm; L Leo-Summers; J C Maroon; L F Marshall Journal: J Neurosurg Date: 1992-01 Impact factor: 5.115