Investigations of the antiatherosclerotic effect of the thromboxane A2 receptor antagonist Daltroban.
In the pathogenesis of atherosclerosis an accumulation of lipids, predominantly in the form of cholesteryl esters within the blood vessel wall is observed. Interaction of the plaques, e.g. with platelets, is suggested to contribute considerably to their growth. Compounds affecting both processes should prevent atherosclerotic progression and therefore are of great interest for potential therapeutic use. We investigated the effect of Daltroban, which has been characterized as a selective thromboxane receptor antagonist with platelet inhibiting activity, in two models: 1) cholesterol metabolism in liver cells and 2) progression of atherosclerosis in aorta of hypercholesterolemic rabbits. Daltroban reduced 14C-acetate incorporation into cholesteryl esters stronger than into cholesterol in rat hepatocyte monolayer cultures. In male white New Zealand rabbits fed 0.5% cholesterol enriched diet for 96 days, coadministration of Daltroban beginning at the 42th day on diet reduced aortic cholesterol content, plaque covered surface of aortic wall, and lumen stenosis by plaques more than 30 percent. The significant inhibition of the progression of atherosclerosis in the hypercholesterolemic rabbits by Daltroban is suggested to be effected by both inhibition of cholesterol metabolism as well as of platelets.
Pill
J
J
Department of Anatomy and Cell Biology, University of Heidelberg, FRG.
Wolf
O
O
Schmelz
A
A
Stegmeier
K
K
Metz
J
J
D000818:Animals; D001161:Arteriosclerosis / Q000097:blood*; D002784:Cholesterol / Q000097:blood*; D006937:Hypercholesterolemia / Q000097:blood*; D008099:Liver / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010648:Phenylacetates / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011917:Rats, Inbred Lew; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013449:Sulfonamides / Q000494:pharmacology*; D013931:Thromboxanes / Q000037:antagonists & inhibitors*
D010648:Phenylacetates; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013931:Thromboxanes; D002784:Cholesterol; C051762:daltroban