Studies on the beneficial effects of aspirin in endotoxic shock. Relationship to inhibition of arachidonic acid metabolism.
Endotoxic shock is associated with increased metabolism of arachidonic acid into thromboxanes and prostaglandins. This study assessed the effects of varied doses of aspirin, an inhibitor of arachidonic acid metabolism, on Salmonella enteritidis endotoxin-induced mortality, plasma levels of arachidonate metabolites, and other pathophysiologic sequelae in Long-Evans rats. Aspirin in doses of 3.75, 15, and 30 mg/kg given 30 minutes prior to endotoxin challenge significantly (p less than 0.01) improved 24-hour survival rates from 11 percent to approximately 65 percent, but 100 mg/kg afforded no protection. Pretreatment with aspirin (15 or 100 mg/kg) 30 minutes prior to endotoxin also significantly (p less than 0.001) decreased the endotoxin-induced elevations in plasma levels of immunoreactive thromboxane B2, a stable metabolite of thromboxane A2, and immunoreactive 6-keto prostaglandin F1 alpha, a stable metabolite of prostacyclin. Aspirin doses of 15 or 100 mg/kg given 24 hours prior to challenge with endotoxin significantly improved 24-hour survival rates from 17 percent to 42 percent (p less than 0.01) and 44 percent (p less than 0.005), respectively. Pretreatment with an aspirin dose of 15 mg/kg 24 hours prior to challenge with endotoxin significantly (p less than 0.05) inhibited thrombin-induced immunoreactive thromboxane B2 synthesis in platelet-rich plasma (in vitro) and endotoxin-induced immunoreactive 6-keto-prostaglandin F1 alpha and immunoreactive thromboxane B2 synthesis by rat peritoneal macrophages. Although 24-hour pretreatment with aspirin (15 or 100 mg/kg) significantly (p less than 0.001) reduced endotoxin-induced elevations in immunoreactive thromboxane B2, only the 100 mg/kg dose significantly lowered plasma levels of immunoreactive 6-keto prostaglandin F1 alpha. These observations are consistent with the notion that the beneficial effects of aspirin seen in experimental endotoxic shock may be mediated, in part, via inhibition of arachidonic acid metabolism.
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001241:Aspirin / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011863:Radioimmunoassay; D051381:Rats; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism; D013929:Thromboxane B2 / Q000096:biosynthesis
D001095:Arachidonic Acids; D005338:Fibrin Fibrinogen Degradation Products; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D001241:Aspirin