Anti-inflammatory drugs in experimental atherosclerosis Part 3. Evaluation of the atherogenicity of homocystine in rabbits

Abstract

This report concerns development of simple animal models which reproduce the association between homocystinemia and atherosclerotis observed in humans. Attempts were made to confirm reports that dietary homocystine administration induces atherosclerotic plaque formation in rabbits. Forty New Zealand white male rabbits were fed a diet supplemented with 200 mg daily of dl-homocysteine thiolactone hydrochloride for 12 weeks. Twenty of the rabbits received in addition 200 mg of cholesterol daily in order to investigate possible synergism between cholesterol and homocystine. Plasma levels of homocystine were measured at intervals by ion-exchange chromatography using an amino acid analyzer. Only marginal elevations of 1–2 mg/100 ml were observed. At 12 weeks, the animals were sacrificed and the thoracic aortas examined. No atherosclerotic lesions were observed in the animals of either group. Additional studies in which dl-homocystine, dl-homocysteine thiolactone, or dl-homocysteic acid were administered in doses of 600 mg orally, 500 mg subcutaneously or 100 mg intravenously, produced only transient elevations of plasma homocystine. Intravenous administration gave the highest plasma level (20 mg/100 ml), which was approximately 85% cleared in 15 min. Platelet aggregation studies were carried out at various intervals after homocystine administration. Aggregation was not affected during induced periods of transient homocystinemia, nor was it significantly altered during subsequent periods of homocystine clearance. These experiments show that the rabbit has very efficient plasma clearance mechanisms for homocystine and its derivatives. Consequently, no significant changes either in platelet aggregation or atherosclerotic plaque formation can be induced by any practicable regimen of homocystine administration in this species.