TY - JOUR
T1 - Enhanced phospholipase A2 activity in rat plasma, liver, and intestinal mucosa following endotoxin treatment
T2 - A possible explanation for the protective effect of indomethacin in endotoxic shock
AU - Shakir, K. M.Mohamed
AU - O'Brian, John T.
AU - Gartner, Susan L.
N1 - Funding Information:
From the Department of Medicine, Naval Hospital, Naval Medical Command, National Capital Region, the Uniformed Services University of the Health Sciences, and the Novol Medical Research institute. Bethesda, Md. Supported by the Naval Medical Research and Development Command, Research Work Unit No. MRO412OOI.0447. The opinions ond assertions contained herein are the private ones of the writers and are not to be construed as oficiol or as reflecting the views of the Navy Department or the Naval service ot large. Address reprint requests to CDR K.M.M. Shakir. Department of Medicine. Naval Hospital. NMC, NCR, Bethesdo. MD 20814. This is a US government work. There are no restrictions on its use.
PY - 1985/2
Y1 - 1985/2
N2 - Endotoxin administration in rats produced a significant increase in plasma, hepatic, and intestinal phospholipase A2 activity within three minutes after injection. The elevated phospholipase A2 activity seen in these tissues returned to normal levels six minutes after injection. The changes in phospholipase A2 activity were dose-dependent within the 0, 10, and 20 mg/kg range of treatment with Escherichia coli endotoxin. This increase in plasma, hepatic, and intestinal phospholipase A2 was abolished by prior treatment of the rats with 3 mg/kg indomethacin, a drug known to improve survival in endotoxic shock. The fact that the change in phospholipase A2 occurs soon after endotoxin administration and that the change in phospholipase is blocked by protective doses of indomethacin suggests that phospholipase A2 activation may be an important initial event in the lethal action of endotoxin, and that the protective effects of indomethacin may be directly related to inhibition of phospholipase A2 activity. Further, in vitro studies of the effects of indomethacin on hepatic phospholipase A2 activity showed that indomethacin significantly inhibited this enzyme. Indomethacin (25 μmol/L) produced 56% inhibition in phospholipase A2 activity and the apparent Ki for indomethacin was 9.2 μmol/L. Kinetic analysis using the Lineweaver-Burk method showed that the indomethacin inhibition was of the noncompetitive type.
AB - Endotoxin administration in rats produced a significant increase in plasma, hepatic, and intestinal phospholipase A2 activity within three minutes after injection. The elevated phospholipase A2 activity seen in these tissues returned to normal levels six minutes after injection. The changes in phospholipase A2 activity were dose-dependent within the 0, 10, and 20 mg/kg range of treatment with Escherichia coli endotoxin. This increase in plasma, hepatic, and intestinal phospholipase A2 was abolished by prior treatment of the rats with 3 mg/kg indomethacin, a drug known to improve survival in endotoxic shock. The fact that the change in phospholipase A2 occurs soon after endotoxin administration and that the change in phospholipase is blocked by protective doses of indomethacin suggests that phospholipase A2 activation may be an important initial event in the lethal action of endotoxin, and that the protective effects of indomethacin may be directly related to inhibition of phospholipase A2 activity. Further, in vitro studies of the effects of indomethacin on hepatic phospholipase A2 activity showed that indomethacin significantly inhibited this enzyme. Indomethacin (25 μmol/L) produced 56% inhibition in phospholipase A2 activity and the apparent Ki for indomethacin was 9.2 μmol/L. Kinetic analysis using the Lineweaver-Burk method showed that the indomethacin inhibition was of the noncompetitive type.
UR - http://www.scopus.com/inward/record.url?scp=0022016136&partnerID=8YFLogxK
U2 - 10.1016/0026-0495(85)90129-5
DO - 10.1016/0026-0495(85)90129-5
M3 - Article
C2 - 3881649
AN - SCOPUS:0022016136
SN - 0026-0495
VL - 34
SP - 176
EP - 182
JO - Metabolism
JF - Metabolism
IS - 2
ER -