Essential fatty acid deficient rats: a new model for evaluating arachidonate metabolism in shock.
Essential fatty acid deficient (EFAD) rats are significantly more resistant to the lethal effects of S. enteritidis endotoxin (20 mg/kg, IV) than normal control rats. Compared to endotoxin-treated normal rats, EFAD rats also manifested less severe alterations of hepatic and lysosomal integrity and became less hypoglycemic. Administration of the ethyl ester of the essential fatty acid, arachidonic acid (100 mp, IP) two days prior to challenge with S. enteritidis endotoxin (20 mg/kg) in EFAD rats restored their sensitivity to endotoxin, as denoted by a 100% mortality compared to a 24% mortality (P less than 0.01) in EFAD rats. Treatment of EFAD rats with the fatty acid docosahexaenoic acid, a non-prostaglandin and thromboxane precursor, (100 mg, IP) produced significantly less (less than 0.01) mortality than ethyl-arachidonate-treated groups (ie, 40% vs 100%). The arachidonate metabolite, thromboxane B2 (TxB2), increased from nondetectable plasma levels (less than 200 pg/ml) to 2285 +/- 449 pg/ml (N = 10) at 30 min and remained elevated for 180 minutes after endotoxin administration in nondeficient rats. However, plasma TxB2 was not detectable in endotoxin-treated EFAD rats and was only slightly elevated in groups supplemented with docosahexaenoic acid (273 +/- 104 pg/ml, N = 6) after 30 minutes. In ethyl arachidonate (100 mg, IP) supplemented EFAD rats, plasma TxB2 rose to 873 +/- 204 pg/ml (N = 8), 30 min after endotoxin. Pretreatment of the ethyl-arachidonate-supplemented EFAD group with a specific thromboxane synthetase inhibitor, 7-(1-imidazolyl)-heptanoic acid (30 mg/kg, IV), significantly reduced mortality 100% to 50% (P less than 0.05) from endotoxic shock. These observations suggest a deleterious role for arachidonic acid and its conversion to TxA2 in the pathogenesis of endotoxic shock.
D000135:Acid Phosphatase / Q000097:blood; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D004195:Disease Models, Animal; D005228:Fatty Acids, Essential / Q000172:deficiency*; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D008297:Male; D009115:Muridae; D011247:Pregnancy; D012772:Shock, Septic / Q000201:enzymology* / Q000401:mortality; D013929:Thromboxane B2 / Q000097:blood
D001095:Arachidonic Acids; D001786:Blood Glucose; D005228:Fatty Acids, Essential; D005338:Fibrin Fibrinogen Degradation Products; D016718:Arachidonic Acid; D013929:Thromboxane B2; D000135:Acid Phosphatase