Anti-inflammatory drugs in experimental atherosclerosis. Part 4. Inhibition of atherosclerosis in vivo and thromboxane synthesis and platelet aggregation in vitro.
Groups of New Zealand white male rabbits were fed atherogenic diets containing 1% cholesterol. The diets of experimental groups were supplemented additionally with either aspirin, phenylbutazone, mefenamic acid, flufenamic acid, oxyphenylbutazone or aminopyrine. Blood cholesterol and phospholipids were measured at 3--4 week intervals. After 12 weeks the animals were sacrificed and the severity of atherosclerosis in the thoracic aorta was measured. In separate experiments, rabbit platelets were incubated with each of the drugs individually and conversion of [14C]arachidonic acid to thromboxanes and related compounds was assayed. Inhibition of collagen and arachidonic acid-induced platelet aggregation by each drug was also measured. All drugs inhibited thromboxane synthesis and platelet aggregation in varying degrees with flufenamate and aspirin being most and aminopyrine least effective. The pattern of metabolite formation from [14C]arachidonate was consistent with a block in the cyclooxygenase reaction. Phenylbutazone, flufenamic acid and oxyphenylbutazone produced significant reductions in atherosclerotic plaque formation without major changes in blood cholesterol levels or blood cholesterol--phospholipid ratios. Aspirin and aminopyrine were ineffective. The results indicate that the effectiveness of anti-inflammatory drugs as inhibitors of thromboxane synthesis and platelet aggregation in vitro does not afford a sufficient predictive index of their anti-atherogenicity in vivo. The significance of these findings is discussed in terms of the possible involvement of cyclooxygenase derivatives in atherogenesis.
D000632:Aminopyrine / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001161:Arteriosclerosis / Q000517:prevention & control*; D001241:Aspirin / Q000627:therapeutic use; D004341:Drug Evaluation; D005439:Flufenamic Acid / Q000627:therapeutic use; D066298:In Vitro Techniques; D008297:Male; D008528:Mefenamic Acid / Q000627:therapeutic use; D010653:Phenylbutazone / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects*; D011817:Rabbits; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D000632:Aminopyrine; D008528:Mefenamic Acid; D013929:Thromboxane B2; D005439:Flufenamic Acid; D010653:Phenylbutazone; D001241:Aspirin