Protective effects of a novel nonglucocorticoid 21-aminosteroid (U74006F) during traumatic shock in rats.
The purpose of this study was to investigate the effect of the nonglucocorticoid steroid U74006F in the pathogenesis of a murine traumatic shock model. Pentobarbital-anesthetized (40 mg/kg) rats were subjected to Noble-Collip drum trauma and developed a lethal shock state characterized by a decreased mean arterial blood pressure (MABP) to 67 +/- 2 mm Hg and survival time (1.5 +/- 0.2 h). In contrast, sham trauma rats exhibited a MABP of 122 +/- 4 mm Hg at 5 h postanesthesia. Administration of U74006F at doses of 22.5 mg/kg at 15 to 20 min following trauma significantly maintained a higher MABP and prolonged survival compared to those trauma rats receiving only the vehicle for U74006F (0.002 N HCl). U74006F at 15 and 22.5 mg/kg prolonged survival time to 2.6 +/- 0.3 (p less than 0.05) and 3.1 +/- 0.6 h (p less than 0.02), respectively. U74006F also significantly attenuated the plasma accumulation of cathepsin D (p less than 0.02 to p less than 0.01) and free amino-nitrogen compounds (p less than 0.01) compared to the rats receiving only vehicle. Additionally, U74006F at 15 and 22.5 mg/kg blunted the production of the cardiotoxic peptide, myocardial depressant factor (MDF) (p less than 0.01 to p less than 0.001). Moreover, U74006F is a steroid without significant glucocorticoid or mineralocorticoid activity. These results suggest that U74006F may be useful as a therapeutic agent in traumatic shock.
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
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Aoki
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Lefer
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D006867:Hydrolases / Q000037:antagonists & inhibitors; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors*; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D011281:Pregnatrienes / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D012774:Shock, Traumatic / Q000503:physiopathology / Q000517:prevention & control*
D008054:Lipid Peroxides; D011281:Pregnatrienes; D006867:Hydrolases; D002402:Cathepsin D; C053355:tirilazad